Datasets:

clinicalnlplab

/

PubmedSumm_train

like 1

Follow

Clinical NLP Lab 22

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: to screen it employees by a questionnaire that include details of health illnesses , family history of illness , diet , lifestyle , exercise and yoga activities and health checkup reports.to assess the severity of stress using holmes and rahe stress scale scoring which would measure stress with the number of life change units and the final score would give a rough estimate of how stress affects health of it employees . to screen it employees by a questionnaire that include details of health illnesses , family history of illness , diet , lifestyle , exercise and yoga activities and health checkup reports . to assess the severity of stress using holmes and rahe stress scale scoring which would measure stress with the number of life change units andthe final score would give a rough estimate of how stress affects health of it employees . as there are no such studies available , i have done a pilot study with 30 it employees and collected data from 1,000 it employees . the study was started after getting ethical committee approval and getting consent from the employees in it industry . the employees enrolled voluntarily to the study should be working for at least 2 years in the industry . a detailed questionnaire , including the health history , diet pattern , lifestyle and stress score was given to them - holmes , and rahe stress score scale .22 % had newly diagnosed hypertension , 10 % had diabetes , 36 % had dyslipidemia , 54 % had depression , anxiety and insomnia , 40 % had obesity [ figure 1 ] . musculoskeletal symptoms included cervical and lumbar strain with or without disc disease , polyarthralgia , and muscle spasm and heel pain . percentage of health problems in it and bpo employees the stress score was higher in employees who developed diabetes , hypertension , dyslipidemia and obesity . of the metabolic disorders employees with higher stress score had dyslipidemia , followed by hypertension and diabetes [ figure 2 ] . health problems and stress scores in it , bpo employees to measure stress according to the holmes and rahe stress scale , the number of life change units that apply to events in the past year of an individual 's life are added and the final score will give a rough estimate of how stress affects health . score of 300 : at risk of illness.score of 150 - 299 : risk of illness is moderate ( reduced by 30 % from the above risk ) . score 150 : only have slight risks of illness . score of 150 - 299 : risk of illness is moderate ( reduced by 30 % from the above risk ) . employees with health problems 67 % were men and 33 % were women [ figure 3 ] . stress at work has been linked with coronary heart disease and metabolic syndrome in retrospective and prospective studies . the pathophysiological mechanisms involve direct neuroendocrine effects and indirect effects mediated by adverse health behaviors . the metabolic syndrome is a cluster of risk factors that increases the risk of heart disease and type 2 diabetes . characteristics of the metabolic syndrome are abdominal obesity , atherogenic dyslipidemia ( raised triglycerides , small low - density lipoprotein particles , and low concentrations of high - density lipoprotein cholesterol ) , high blood pressure ( bp ) , insulin resistance ( with or without glucose intolerance ) , and prothrombotic and proinflammatory states . studies have found a social gradient in work stress and the metabolic syndrome , suggesting a greater exposure to working stress among less advantaged social groups . cross - sectional studies have linked work stress with components of the syndrome , but this association is not consistent . technostress is the word used to explain the phenomenon of stress arising due to the usage of computers . it is a modern disease of adaptation caused by the inability to cope with new computer technologies in a healthy manner . transduction is the translation of emotional distress to physiological change and then to a physical symptom . complex autoimmune , humoral and neuromuscular mechanisms mediate this reaction , and may itself affect the environment by a social response that may yield a positive or a negative response . effects of stress on mind and body are due to increased sympathetic nervous system activity and increased secretion of adrenaline , cortisol and other stress hormones . occupational ( job , work or workplace ) stress has become one of the most serious health issues in the modern world ( lu et al . , 2003 , 479 ) , as it occurs in any job and is even more present than decades ago . namely , the world of work differs considerably from the working environment of 30 years ago : longer hours at work are not unusual , frequent changes in culture and structure are often cited , as well as the loss of lifetime career paths ( cooper and locke , 2000 in fotinatos - ventouratos and cooper 2005 ) , which all leads to greater presence and levels of stress . the stress of exhilarating , creative , successful work is beneficial , while that of failure , humiliation or infection is detrimental . selye believed that the biochemical effects of stress would be experienced irrespective of whether the situation was positive or negative . job stress occurs in response to both workplace and employee factors , but the characteristics of the workplace likely play the primary role . job stress can be defined as the harmful physical and emotional responses that occur when the requirements of the job do not match the capabilities , resources or needs of the worker . ( stress at work , united states national institute of occupational safety and health , cincinnati , 1999 ) . a canadian graduate school study suggested companies should invest in it specific employee assistance programs . survey conducted by techweb network research on behalf of op tier quantified how stressed managers are . this survey showed the greatest cause of job stress were complexity of company it infrastructures and poorly defined goals . working in it calls for a high degree of accuracy over the long period of time , and a small lapse would be disastrous . studies have shown that employees with chronic work stress ( three or more exposures ) were nearly twice as likely to develop the metabolic syndrome than those with no exposure to work stress . women with chronic work stress were over five times more likely to have the metabolic syndrome . greater exposure to job stress over 14 years was linked to greater risk of the metabolic syndrome , in a dose - response manner . it is unclear whether the development of risk seen here is due in part to the direct effects of chronic stress on insulin resistance , resting bp , and lipoprotein metabolism , although this interpretation is supported by whitehall ii and other studies . stress is , of course , essential for every human being as it is considered as a boost that takes an employee to the highest ladder in the organization . the various types of stress is mentioned below : eustress is a type of short - term stress that provides immediate strength . distress , on the other hand , is a negative stress brought about by constant readjustments and alternatives in a routine . hyper stress occurs when an individual is pushed beyond what he or she can handle . people who experience hypo stress are often restless . according to pestonjee ( 1992 ) work stress progresses through a series of five stages . the honeymoon stage : euphoric feeling if excitement , enthusiasm , challenges and pride on getting a new job . dysfunctional processes include the depletion of energy reserves in coping and adapting to the new environment.the full throttle stage : going full swing leads to a depletion of resources . other symptoms include dissatisfaction , sleep disturbances , overeating , drinking or smoking.the chronic symptom stage : development of chronic symptoms like physical illness , anger and depression.the crisis stage : persistence of symptoms leads to disease , chronic backache , headache , high bp , insomnia , etc . , would develop.hitting the wall stage : no person can continue under strain for too long and one may reach the end of one 's professional career . burnout stress syndrome takes over.the opposite : rust our stress syndrome occurs under extreme hypo stress . this is likely to occur when the gap between one capabilities and environmental demands becomes too wide . the honeymoon stage : euphoric feeling if excitement , enthusiasm , challenges and pride on getting a new job . dysfunctional processes include the depletion of energy reserves in coping and adapting to the new environment . the full throttle stage : going full swing leads to a depletion of resources . the chronic symptom stage : development of chronic symptoms like physical illness , anger and depression . the crisis stage : persistence of symptoms leads to disease , chronic backache , headache , high bp , insomnia , etc . , would develop . hitting the wall stage : no person can continue under strain for too long and one may reach the end of one 's professional career . this is likely to occur when the gap between one capabilities and environmental demands becomes too wide . prolonged exposure to work stress may affect the autonomic nervous system and neuroendocrine activity directly , contributing to the development of the metabolic syndrome . a case control study showed that participants in the whitehall ii study with the metabolic syndrome had raised cortisol and normetanephrine output , and also had reduced variability in heart rate . decrements in cardiac autonomic function have been linked to the metabolic syndrome in other populations and to low job control and social isolation among men in the whitehall ii study . psychobiological studies have also shown that heightened stress reactivity and impaired recovery after stress , assessed by bp and inflammatory markers , predict the 5 years progression of the metabolic syndrome . cortisol is an insulin antagonist , and cortisol output is increased in the metabolic syndrome . low concentrations of high density lipoprotein cholesterol and glucose intolerance have been linked with high basal secretion of cortisol . stress at work is associated with coronary heart disease , but the biological mechanisms underlying this association are unclear information technology industry causes stress among employees in many ways : software packages used as the operating system for companies releases 3 - 4 updates in a year . otherwise they would lag behind others causing pressure on the employee and increased job risk if he fails to perform well.training program sanctioned by the company is not employee oriented as each employanother form of stress is called technologist . this can cause alienated feelings among colleagues.employees working in it industry need to work with a high degree of accuracy over a long period . software packages used as the operating system for companies releases 3 - 4 updates in a year . otherwise they would lag behind others causing pressure on the employee and increased job risk if he fails to perform well . training program sanctioned by the company is not employee oriented as each employ another form of stress is called technologist . employees working in it industry need to work with a high degree of accuracy over a long period . stress is , of course , essential for every human being as it is considered as a boost that takes an employee to the highest ladder in the organization . the various types of stress is mentioned below : eustress is a type of short - term stress that provides immediate strength . distress , on the other hand , is a negative stress brought about by constant readjustments and alternatives in a routine . hyper stress occurs when an individual is pushed beyond what he or she can handle . according to pestonjee ( 1992 ) work stress progresses through a series of five stages . the honeymoon stage : euphoric feeling if excitement , enthusiasm , challenges and pride on getting a new job . dysfunctional processes include the depletion of energy reserves in coping and adapting to the new environment.the full throttle stage : going full swing leads to a depletion of resources . other symptoms include dissatisfaction , sleep disturbances , overeating , drinking or smoking.the chronic symptom stage : development of chronic symptoms like physical illness , anger and depression.the crisis stage : persistence of symptoms leads to disease , chronic backache , headache , high bp , insomnia , etc . , would develop.hitting the wall stage : no person can continue under strain for too long and one may reach the end of one 's professional career . burnout stress syndrome takes over.the opposite : rust our stress syndrome occurs under extreme hypo stress . this is likely to occur when the gap between one capabilities and environmental demands becomes too wide . the honeymoon stage : euphoric feeling if excitement , enthusiasm , challenges and pride on getting a new job . dysfunctional processes include the depletion of energy reserves in coping and adapting to the new environment . the full throttle stage : going full swing leads to a depletion of resources . other symptoms include dissatisfaction , sleep disturbances , overeating , drinking or smoking . the chronic symptom stage : development of chronic symptoms like physical illness , anger and depression . the crisis stage : persistence of symptoms leads to disease , chronic backache , headache , high bp , insomnia , etc . , would develop . hitting the wall stage : no person can continue under strain for too long and one may reach the end of one 's professional career . burnout stress syndrome takes over . the opposite : rust our stress syndrome occurs under extreme hypo stress . this is likely to occur when the gap between one capabilities and environmental demands becomes too wide . prolonged exposure to work stress may affect the autonomic nervous system and neuroendocrine activity directly , contributing to the development of the metabolic syndrome . a case control study showed that participants in the whitehall ii study with the metabolic syndrome had raised cortisol and normetanephrine output , and also had reduced variability in heart rate . decrements in cardiac autonomic function have been linked to the metabolic syndrome in other populations and to low job control and social isolation among men in the whitehall ii study . psychobiological studies have also shown that heightened stress reactivity and impaired recovery after stress , assessed by bp and inflammatory markers , predict the 5 years progression of the metabolic syndrome . cortisol is an insulin antagonist , and cortisol output is increased in the metabolic syndrome . low concentrations of high density lipoprotein cholesterol and glucose intolerance have been linked with high basal secretion of cortisol . stress at work is associated with coronary heart disease , but the biological mechanisms underlying this association are unclear information technology industry causes stress among employees in many ways : software packages used as the operating system for companies releases 3 - 4 updates in a year . otherwise they would lag behind others causing pressure on the employee and increased job risk if he fails to perform well.training program sanctioned by the company is not employee oriented as each employanother form of stress is called technologist . this can cause alienated feelings among colleagues.employees working in it industry need to work with a high degree of accuracy over a long period . software packages used as the operating system for companies releases 3 - 4 updates in a year . otherwise they would lag behind others causing pressure on the employee and increased job risk if he fails to perform well . training program sanctioned by the company is not employee oriented as each employ another form of stress is called technologist . employees working in it industry need to work with a high degree of accuracy over a long period . the daily impact of it on our lives continues unabated . as innovations and computer capacitiesincrease this influence will continue to grow in the coming years at an increasing rate . as technology advances , there is also increased stress that is associated with it called as technology stress . it is here to stay . this brings extra pressure on people to adapt to new advancements and update their knowledge in their field . annual stress scoring has to be done and a score above 300 needs stress management program like yoga , meditation and other destressing activities like aerobics , dance etc . , would prevent or reduce risk of disease due to stress in it people which in turn will produce a healthy community . to manage stressthese people need to play sport , have a hobby or just have a good holiday . stress score helps us to screen who would be prone to stress related physical illness and people with a score more than 300 are at risk of illness and care should be taken at the earliest to relive their stress . annual stress scoring has to be done , and employees are having a score more than 300 should be involved in active antistress management .\noutput:\n" }, { "from": "agent", "value": "stress is high in software profession because of their nature of work , target , achievements , night shift , over work load . 1 . to study the demographic profile of the employees . 2 . to access the level of job stress and quality of life of the respondents . 3 . to study in detail the health problems of the employees . all employees working in it and bpo industry for more than two years were included into the study . a detailed questionnaire of around 1000 it and bpo employees including their personal details , stress score by holmes and rahe to assess the level of stress and master health checkup profile were taken and the results were analysed . around 56 % had musculoskeletal symptoms . 22 % had newly diagnosed hypertension ,10 % had diabetes , 36 % had dyslipidemia , 54 % had depression , anxiety and insomnia , 40 % had obesity . the stress score was higher in employees who developed diabetes , hypertension and depression . early diagnosis of stress induced health problems can be made out by stress scores , intense lifestyle modification , diet advice along with psychological counselling would reduce the incidence of health problems in it sector and improve the quality of work force ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 35 - year - old , 157 cm , 52 kg , woman was hospitalized for surgical treatment of peroneal tendonitis in her right foot . she had no significant medical history , allergy , or previous neurological disease . spinal anesthesia was performed and the operation was uneventful . after transferring to the general ward , the patient experienced no further problem . on a preoperative visit to our hospital , she expressed no fear regarding spinal anesthesia and agreed to undergo spinal anesthesia again . premedication consisted of 2.5 mg of midazolam , administered intramuscularly 30 min before surgery . in the operating room , standard monitoring ( non - invasive blood pressure , peripheral oxygen saturation , and electrocardiogram ) was used . the patient was placed in the right lateral decubitus position , and lumbar puncture was performed without difficulty at l3 - 4 . after free - flowing cerebrospinal fluid was obtained , 9 mg of heavy bupivacaine 0.5 % ( marcaine spinal 0.5 % heavy , astrazeneca , sweden ) and 0.2 mg of epinephrine were administered via a 25 g spinal needle . sensory input to t10 was blocked , and the surgery was completed uneventfully in approximately 50 min . approximately 100 min after administration of anesthesia , she began to experience bilateral , involuntary myoclonic movement of both legs and arms . sensory function in her arms was intact , and the rhythm of the movement varied widely in rate . approximately 10 min later , she was treated with 0.5 mg of oral clonazepam and 2 mg of iv midazolam . postoperative laboratory findings , including serum electrolytes and glucose , were within normal limits . when she was examined again the following day , one month later , she visited the hospital again ; no recurrence of spinal myoclonus had occurred . the present report describes an interesting case of spinal myoclonus that recurred after two episodes of spinal anesthesia with hyperbaric bupivacaine at a 1 - year interval in a 35 - year - old woman . the bupivacaine used in this patient was also used for spinal anesthesia at the other hospital . the development of spinal myoclonus in our patient did not appear be related to a spinal anesthesia technical problem . the second occurrence of spinal myoclonus had a more rapid onset and a longer duration , and a larger part of the body was involved , compared with the first attackonset and duration of myoclonus vary and are not correlated with baricity , dose , or needle gauge in uncomplicated spinal anesthesia . in one case , 12 mg of normobaric bupivacaine 0.5 % via a 25 - g spinal needle was used . myoclonus developed on day 1 postoperatively , and contractions disappeared completely on day 4 . in another case , 14 mg of tetracaine with 10 % dextrose in combination with 0.2 mg of epinephrine was injected . spinal myoclonus developed approximately 7 h after administration of anesthesia and lasted a few hours . lin et al . reported a patient who underwent spinal anesthesia with 2.5 ml of 0.5 % hypobaric bupivacaine , administered via a 26 - g spinal needle . approximately 1 h after anesthesia , the patient began to have bilateral , symmetrical , rhythmic myoclonic movement in the lower legs . myoclonus may be induced by drugs , such as local anesthetics , analgesics , or contrast material , administered via intrathecal or epidural routes . reported a case of spinal myoclonus that occurred immediately after intrathecal injection of bupivacaine and fentanyl in a 45 day - old healthy infant . onset was more rapid than in our case , and the duration was only 4 min . intrathecal bupivacaine appears to be the most likely cause , because there was no history of a seizure disorder , a normal neurological examination , and unremarkable follow - up imaging . the local anesthetic may have induced spinal cord irritation , resulting in spontaneous and repetitive discharges of the anterior horn cell groups . some have suggested that the effect of bupivacaine on inhibitory neurons may have led to a loss of inhibitory function in the spinal cord and heightened irritability of the alpha motor neuron , leading to myoclonus . because our patient had no specific disease history and had unremarkable neurologic and laboratory findings , the cause of spinal myoclonus was likely spinal anesthesia with bupivacaine . spinal myoclonus is an unusual and self - limiting adverse event during the practice of spinal anesthesia , and usually resolves after the disappearance of the drug 's effect . however , in some cases , specific treatment , including benzodiazepines and anticonvulsants , is needed . alfa and bamgbade suggested that midazolam is the benzodiazepine of choice for treating perioperative spinal myoclonus . for diagnosis , blood tests , including electrolytes , glucose , renal function tests , hepatic function tests , paraneoplastic antibody detection , and electromyography ( emg ) , are useful . mri of the spine or brain is also useful to rule out spinal cord or brain abnormalities . in our patent , blood tests , anesthesiologists must be aware of the potential for this very rare phenomenon to occur as a result of spinal anesthesia . also , anesthesiologists should carefully take past anesthetic histories and consider the recurrence when planning anesthetic technique for the patients who had an episode of spinal myoclonus .\noutput:\n" }, { "from": "agent", "value": "spinal myoclonus is an unusual , self - limiting , adverse event that may occur during spinal anesthesia . the exact cause and underlying biochemical mechanism of spinal myoclonus remain unclear . a few cases of spinal myoclonus have been reported after administration of intrathecal bupivacaine . we report a case in which spinal myoclonus recurred after two episodes of spinal anesthesia with bupivacaine at a 1 - year interval in a 35 - year - old woman . the myoclonus was acute and transient . the patient recovered completely , with no neurologic sequelae ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: pemetrexed is a potent inhibitor of thymidylate synthase , dihydrofolate reductase , and glycinamide ribonucleotide formyltransferase . the us food and drug administration approved pemetrexed as a single agent or in association with cisplatin as a treatment for patients with locally advanced or metastatic non - small cell lung cancer ( nsclc ) . pemetrexed has been approved for maintenance treatment in patients with locally advanced or metastatic nonsquamous nsclc whose disease has not shown progression after four cycles of platinum - based doublet induction chemotherapy . pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis . seven months before admission , he was diagnosed with stage iv lung adenocarcinoma ( ct3n2m1 for metastases of bone ) . he was an ex - smoker ( 45 packs / yr ) , and his performance status was eastern cooperative oncology group ( ecog ) 1 . he was treated with first - line chemotherapy , including gemcitabine ( 1,000 mg / m , days 1 and 8 ) and carboplatin ( area under the curve , 5.5 ) , every three weeks for six cycles . after four weeks from the last gemcitabine and carboplatin administration , the patient started second - line treatment with pemetrexed ( 500 mg / m , day 1 , every three weeks ) with vitamin supplementation and steroid pre - medication . on admission , his vital signs were as follows : blood pressure , 110/70 mm hg ; pulse rate , 74 / min ; respiration rate , 24 / min ; and body temperature , 36.8 . no abnormal heart sounds were detected on chest auscultation ; however , fine crackles were detected in the bilateral lower lung fields . results of arterial blood gas analysis showed severe hypoxia ( ph , 7.470 ; pco2 , 28.2 mm hg ; po2 , 39.5 mm hg ; hco , 20.7 mm ; and o2 saturation , 84.6 % ) ; thus , the patient received 4 l / min oxygen through a nasal cannula . peripheral blood tests showed the following : white blood cells , 7,600 / l ; hemoglobin , 11.0 g / dl ; and platelets , 170,000 / l . the patient 's c - reactive protein concentration increased to 3.991 mg / dl , and routine chemistry showed the following : na , 135 mm ; k , 4.1 mm ; cl , 103 mm ; aspartate transaminase , 26 iu / l ; alanine aminotransferase , 17 iu / l ; alkaline phosphatase , 113 iu / l ; gamma glutamyl transferase , 29 iu / l ; total bilirubin , 0.8 mg / dl ; blood urea nitrogen , 8.8 mg / dl ; and creatinine , 0.6 mg / dl . due to the patient 's immunocompromised status , treatment with broad - spectrum antibiotics ( levofloxacin ) and trimethoprim - sulfamethoxazole against pneumocystis jiroveci was started . a microbiological culture obtained from bronchoalveolar lavage fluid showed no evidence of bacterial , viral , or fungal pathogens . sputum cultures , acid - fast staining for bacilli , blood cultures , and p. jiroveci pneumonia polymerase chain reaction all showed negative results . an extensive microbiological investigation , including bronchoscopy , excluded the possibility of infection , including opportunistic infections . treatment with pemetrexed , which was suspected as the cause of the drug - induced pneumonitis , was stopped , and high - dose prednisolone was administered . we performed a tissue biopsy via video - assisted thoracoscopic surgery in order to confirm interstitial pneumonitis . a diagnosis of drug - induced interstitial pneumonitis caused by pemetrexed was ultimately made ; in response , antibiotic therapy was discontinued , and high - dose prednisolone therapy was continued for two weeks . treatment with oral prednisolone resulted in improvement of the patient 's clinical presentation and interstitial infiltration in both lung fields ( fig . here , we report on a case of pemetrexed - induced pneumonitis in a patient with nsclc . pemetrexed has a modest toxicity profile and is frequently used in patients with locally advanced or metastatic nsclc . the most frequently reported pemetrexed - related toxicity was fatigue ; other adverse events were less frequent . clinical studies of pemetrexed have reported a lack of patients with grade 3 - 4 pulmonary toxicity [ 1 - 4 ] . one phase ii study ( n = 244 ) reported eight cases , including one death from pneumonitis without definite clinical data , and three cases occurred in the arm that received 1,000 mg / m pemetrexed , which is greater than the usual 500 mg / m dosage . symptoms of drug - associated ild , as with all forms of the condition , include rapidly developing breathlessness and a dry and unproductive cough , together with fever . such symptoms are nonspecific and can occur with a large number of common illnesses often associated with nsclc . the onset of drug - associated ild during therapy for treatment of advanced nsclc usually occurs within a few weeks after the start of treatment . our patient presented with acute dyspnea and pulmonary infiltration on chest x - ray after three weeks of first - cycle pemetrexed treatment without evidence of an infectious cause . the time interval between the last gemcitabine cycle and the first pemetrexed cycle was four weeks , and no lesion indicative of penumonitis was observed on ct scans taken before the start of pemetrexed chemotherapy , therefore , the possibility of gemcitabine - related pneumonitis was low . no specific parenchymal change in the radiological pattern is observed with drug - associated ild ; however , common findings include the presence of ground - glass shadows and / or linear opacities on high - resolution ct ( hrct ) . it seemed reasonable to approach the radiological manifestations of drug - associated lung disease using the underlying histological pattern . the patient 's tissue showed the nonspecific interstitial pneumonia pattern of idiopathic interstitial pneumonia , according to the clinical - radiological - pathological diagnosis classification . nonspecific interstitial pneumonia is one of the most common forms of drug - associated pneumonitis . nonspecific interstitial pneumonia is characterized histologically by homogeneous alveolar wall thickening with fibrous tissue and the presence of mononuclear inflammatory cells . corresponding radiographical and hrct findings usually consist of patchy or diffuse ground - glass opacities . as the disease progresses , there may be evidence of fibrosis with development of a reticular pattern and traction bronchiectasis . drug - induced injury to the lungs is thought to result from either a direct toxic effect or an indirect effect by way of a hypersensitivity reaction . anticancer agents such as bleomycin , methotrexate , procarbazine hydrochloride , and paclitaxel can cause pulmonary opacities as part of a hyper - sensitivity reaction ; however , the pathophysiology of pemetrexed - related pneumonitis is unknown . in many instances , chemotherapy - associated lung disease may respond to withdrawal of the offending agent and the judicious application of corticosteroid therapy . in summary , we report on a rare case of pemetrexed - induced pneumonitis in a patient with nsclc , including radiological and pathological documentation . diagnosis of chemotherapy - associated lung disease remains an exclusionary process , particularly with respect to infections and recurrence of the underlying neoplastic process in immuno - compromised patients . given the increasing use of pemetrexed for treatment of lung cancer , physicians must be aware of this potential toxicity .\noutput:\n" }, { "from": "agent", "value": "pemetrexed is approved as a first - line treatment for advanced non - squamous non - small cell lung cancer ( nsclc ) with cisplatin and as a single agent for second - line treatment or for patients who show no disease progression after four cycles of platinum - based doublet induction chemotherapy as maintenance therapy . pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis . here , we report on a rare case of pemetrexed - induced pneumonitis in a patient with nsclc ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: serious complications including damage to the neural elements , stroke and death have been reported with epidural corticosteroid injections ( esis ) but are mostly anecdotal . their true incidence is unknown , but such outcomes seem to be rare.vascular penetration is possible , relatively more frequent in the cervical segments and potentially hazardous . intravascular injection can be reduced by use of injected contrast media.the use of a blunt needle , live fluoroscopy , digital subtraction angiography and the administration of a small test dose initially could help reduce the adverse effects.many complications can be avoided by a thorough understanding of the anatomy , accurate placement of the needle and familiarisation of the contrast patterns on fluoroscopy.more research must be performed regarding the benefits versus risk , techniques and outcome of esis . epidural corticosteroid injections ( esis ) have been used for decades as a therapeutic modality in the management of spinal pain syndromes attributed to disc pathology and spinal stenosis . although the exact pathophysiology of these conditions remains obscure , it has been suggested they occur through an ectopic firing action potentials mechanism in nerve roots derived from the mechanical compression . this mechanical compression could stimulate a local inflammatory process , which forms the rationale behind the administration of the corticosteroids . this theory is further strengthened by findings suggesting that the lavage of inflammatory mediators may reduce pain and inflammation . the interlaminar route is considered to be non - specific and the injectate is free to spread within the posterior epidural space with possible flow anteriorly , cephalad and caudally . this could be influenced by tissue fibrosis , scarring or hypertrophy , which may occur in spinal pathology . esi administered through this route could in theory deposit a larger mass of corticosteroid close to the pain generators at the ventral epidural space allowing a greater degree of drug diffusion , so transforaminal esi may be more efficacious in alleviating patients pain . however , several prospective randomised studies have failed to demonstrate a statistically significant difference in terms of pain reduction and functional score improvement between the transforaminal and interlaminar approaches . in a recent systematic literature review of comparative studies involving patients with lumbosacral radicular pain , chang - chien et al . , suggested that both approaches are equally effective and demonstrated only minor non - significant differences between them . in contrast to the interlaminar and transforaminal routes , caudal epidural injections require relatively higher volumes of corticosteroids but are considered to be easier and safer and are preferred in patients after spinal surgery . the modality of imaging may influence the efficacy of esi . currently , fluoroscopy , ultrasound and computed tomography ( ct ) imaging have been used and their utilisation continues to increase . the choice amongst them partly lies in personal preference but also on the availability and prior training on the device . limited evidence currently exists in terms of the effectiveness and safety differences between these techniques . for instance , a recent literature review by bui and bogduk concluded that ct - guided lumbar transforaminal injection of corticosteroids is neither more effective nor safer than the fluoroscopy - guided injections but that ct is associated with significantly higher radiation doses than conventional fluoroscopy . ultrasound has gained popularity and maybe a safe alternative to the other radiological imaging modalities . several authors have questioned the overall efficacy of esis for the management of radicular pain . in a systematic review of the available literature in 2009 by chou et al . , esis were moderately effective for short - term symptom relief in patients with low back pain but conferred no long - term benefit . in a similar manuscript , pinto et al . concluded that epidural corticosteroid injections offer only short - term relief of leg pain and disability for patients with sciatica . the authors questioned the clinical justification of this procedure when comparing the benefits with the risks . furthermore , in a systematic review including data from the cochrane central register of controlled trials , staal et al . concluded that there is insufficient evidence to support the use of injection therapy in subacute and chronic low back pain . these conclusions have been challenged by several other trials and systematic reviews . in patients with lumbar radicular pain caused by contained disc herniations , macvicar et al . suggested that lumbar transforaminal injection of corticosteroids is effective in reducing pain , restoring function , reducing the need for other healthcare modalities and avoiding surgery . in line with these deductions , quraishi concluded that in patients with lumbar radiculopathy , esis result in an improvement in pain but not disability . friedly et al . suggested that epidural injection of glucocorticoids plus lidocaine offered minimal or no short - term benefit as compared with epidural injection of lidocaine in the treatment of lumbar spinal stenosis alone . esis were found to have significant effect in relieving chronic intractable pain of cervical origin , providing long - term relief . some meta - analyses suggested that there is good evidence for the effectiveness of cervical interlaminar epidural injections in managing radiculitis secondary to disc herniation and fair evidence in managing axial or discogenic pain , pain of central spinal stenosis and pain of post - surgery syndrome . the same authors concluded that the evidence is poor for cervical transforaminal epidural injections . it should be mentioned , however , that several of these studies have been criticised for flaws and deficiencies , adding further overall confusion . in addition to the controversy surrounding the efficacy of esis , some authors have raised concerns regarding potential adverse events . on 23 april 2014 the us food and drug administration ( fda ) issued a warning to the medical community covering the potential risks of these injections . the warning states that injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events , including loss of vision , stroke , paralysis , and death . this systematic review aims to scrutinise the available literature , present the available data and documentation from several authors , and analyse the risks involved with the esis in the cervical and lumbar spine . data were documented according to a standardised protocol , where objectives and inclusion criteria were specified in detail . publications from the last 20 years ( september 1994 to september 2014 ) were considered for further analysis . studies selected were original articles , in the english language , publishing results on complications related to the technique used for the esis . only cervical and lumbar esis were included and the studies had to specify the approach used for injection . studies were identified by searching the following resources / databases to retrieve all available relevant articles : pubmed medline , ovid medline , embase , scopus , google scholar and the cochrane library . transforaminal , interlaminar , adverse events , complication and side effect . the identified articles and their bibliographies including any relevant reviews were manually searched for additional potential eligible studies . two of the authors ( ippokratis pountos and gavin walters ) of this systematic review performed 208 the assessment , in an independent , unblinded and standardised manner . most citations were excluded on the basis of information provided by their respective title or abstract . in any other case , of 3255 papers initially identified , 162 met the inclusion criteria ( fig . 1 ) . this included 58 studies , of which 38 recorded complications while the remaining 20 state that 217 no complications were encountered . 1011flowchart of study selection flowchart of study selection the review of the available literature identified 11 manuscripts presenting complications following interlaminar cervical esis ( table 1 ) . one manuscript that reports no complications has also been identified but only includes 14 interlaminar cervical esis . table2003 retrospective cohort study157 pts , 345 injections , c67 or c7t1triamcinolone acetonide 80 mgfloverall 16.8 % : 23 increased neck pain ( 6.7 % ) 16 non - positional headaches ( 4.6 % ) 6 insomnia ( 1.7 % ) 6 vasovagal reactions ( 1.7 % ) 5 facial flushing ( 1.5 % ) 1 pyrexia ( 0.3 % ) 1 dural puncture ( 0.3 % ) derby et al . , 2003 retrospective survey4389 injectionsnana3 dural punctures ( 0.07 % ) 17 vagal symptoms ( 0.4 % ) 3 paraesthesia and numbness ( 0.07 % ) goel and pollan , 2006 prospective cohort29 pts , 65 injectionsnafl16 .9 % headaches21 .5 % insomnia , flushing of the face , temperature6 .2 % of increased painkwon et al . , 2007 retrospective cohort study76 pts , 76 injectionstriamcinolone acetonide 40 mgfl2 dural punctures ( 2.6 % ) kranz et al . ,2011 retrospective cohort study50 pts , 53 injectionsbetamethasonect1 intra - thecal injectionmanchikanti et al . ,2012 prospective cohort study2376 injectionsnafl100 intravascular placement of needle ( 4.2 % ) 24 dural puncture ( 1 % ) 6 transient nerve root irritation ( 0.25 % ) 5 transient spinal cord irritation ( 0.21 % ) 16 profuse bleeding ( 0.7 % ) 1 vasovagal ( 0.04 % ) 2 facial flushing ( 0.08 % ) lee et al . , 2012 prospective cohort study ~ 127 injectionsdexamethasone sodium phosphate 10 mgfl1 vasovagal and syncope ( 0.8 % ) 1 dural puncture ( 0.8 % ) beyaz and eman , 2013 retrospective cohort study65 ptsnafl1 vasovagal ( 1.54 % ) 1 transient increase of pain ( 1.54 % ) manchikanti et al . , 2013 rct120 pts , 654 injectionsbetamethasone 6 mg ( n = 60 ) fl2 subarachnoid punctures ( 0.3 % ) 4 intravascular penetrations ( 0.6 % ) 5 nerve root irritations ( 0.76 % ) 1 pain lasting 1 week ( 0.15 % ) lee et al . ,2014 retrospective cohort study143 ptstriamcinolone acetonide 40 mg1 itching sensations1 facial flushing1 dry mouth1 erectile dysfunctionmanchikanti et al . , 2014 rct120 pts , 688 injectionsbetamethasone 6 mg ( n = 60 ) fl6 subarachnoid punctures ( 0.3 % ) 10 intravascular penetrations ( 0.6 % ) 3 nerve root irritations ( 0.76 % ) 1 pain lasting 1 week ( 0.15 % ) ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial complications reported with interlaminar cervical epidural corticosteroid injections ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial based on the available studies , the incidence of dural puncture ranged between 0.07 and 2.6 % . vasovagal reactions ranged between 0.04 and 1.7 % . in a prospective study including 2376 injections , manchikanti et al . reported 100 cases where intravascular placement of the needle occurred . however , complications that could potentially be correlated with inadvertent intravascular injection of corticosteroids were low and included 11 cases of transient nerve root or spinal cord irritation , one vasovagal event and two cases of facial flushing . in a retrospective analysis of the results of 345 c67 or c7t1 injections , botwin et ala large proportion of these adverse events were related to an increase of neck pain , headache , insomnia and vasovagal reactions . furman et al . presented 504 cervical ( c3c8 ) transforaminal esis performed on 337 patients . they reported identification of 98 intravascular injections that did not result in any adverse effects . similarly , other authors have reported no complications . in a retrospective review of 1579 injections , derby et al . reported two cases of aggravated radicular pain , two cases of prolonged paraesthesias and the development of skin rash in one patient . in another studyincluding 43 esis with prednisolone , 19 % of patients experienced minor neurovegetative manifestations . conducted an anonymous survey asking the us physician members of the american pain society about their experience with regards to serious complications following cervical transforaminal epidural corticosteroid injections ( tesis ) . from the 287 replies ,78 complications were reported , among which there were 30 brain or spinal cord infarcts and 24 neurologic complications including death of unsuspected aetiology ( n = 5 ) , high spinal anaesthesia ( n = 3 ) , transient ischaemic attacks ( n = 3 ) , and spinal cord or brainstem oedema ( n = 3 ) . the literature search found 11 studies that present adverse effects following interlaminar lumbar esis ( table 2 ) . in addition , four studies that involve more than 250 patients have reported no adverse events following interlaminar lumbar epidural esis . in a prospective cohort study including 1450 injections , manchikanti et al . reported an incidence of 0.8 % for dural puncture and profuse bleeding following the injection . a prospective , randomised blinded study including 106 patients has reported a rather high number of minor adverse effects . in particular , 26 % of the patients experienced discomfort and pain at the injection site , 18 % had non - positional headache and 10 % suffered from nausea after the injection . in an analysis of 6631 interlaminar lumbar esis , huang et al . the physician recognised the lumbar facet joint injection . a similar study design reported by candido et al . reported the incidence of intradiscal injection to be one in 4723 . table 2complications reported with interlaminar lumbar epidural corticosteroid injectionsstudy , yeardesignptsmedicationsimagingcomplicationscarette et al . , 1997 prospective randomised blinded study78 pts , 162 injectionsmethylprednisolone 80 mgbl1 dural puncture ( 0.6 % ) 27 transient headachekraemer et al . , 1997 rct87 pts , 87 injectionstriamcinolone 10 mgct1 .93.6 % headachevalat et al . , 2003 rct39 pts , 117 injectionsprednisolone acetate 50 mgbl2 headachearden et al . , 2005 rct115 pts , 3 injections eachtriamcinolone acetonide 80 mgbl4 non - specific headache2 postdural puncture headache , nausea5 otherkim et al . , 2010 retrospective cohort study150 pts , 150 injectionsdexamethasone 16 mgfl42 facial flushing ( 28 % ) kim et al . ,2011 prospective randomised study60 pts , 120 injectionsdexamethasone phosphate 15 mg or methylprednisolone acetate 80 mgfl1 intrathecal injectionmanchikanti et al . , 2012 prospective randomised blinded study120 pts , 213 injectionsbetamethasone 1 ml ( n = 60 ) fl3 subarachnoid punctures ( 1.4 % ) manchikanti et al . , 2012 prospective cohort study1450 injectionsnafl7 intravascular placement of needle ( 0.5 % ) 4 transient nerve root irritation ( 0.28 % ) 11 dural punctures ( 0.8 % ) 11 profuse bleeding ( 0.8 % ) 4 local haematoma ( 0.28 % ) 1 headache ( 0.07 % ) 2 facial flushing ( 0.13 % ) bartynski et al . ,2013 retrospective cohort study276 pts , 392 injectionmethylprednisolone acetate 80 mgfl1 dural puncture1 transient paraparesiscandido el al .2013 prospective randomised blinded study106 pts , l3s1methylprednisolone acetate 120 mgfl26 % discomfort and pain at the injection site18 % non - positional headache10 % nauseaevansa et al . , 2015 prospective randomised study120 pts , 120 injectionsmethylprednisolone acetate 80 mgfl ( n = 56 ) , us ( n = 56 ) 15 dizziness or pain at injection site or facial flushing1 intrathecal injection bl blind , ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial , us ultrasound complications reported with interlaminar lumbar epidural corticosteroid injections bl blind , ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial , us ultrasound fourteen studies were identified that presented adverse effects following transforaminal esis ( table 3 ) . in contrast , no adverse events were presented by a number of other authors . the most common complication reported was increased pain , which was encountered in half of the patients . two prospective studies analysing a large number of transforaminal lumbar esis reported an incidence of intravascular penetration of between 7.4 and 7.9 % . the main difference was an 8.7 % rate of vasovagal episodes reported by karaman et al . . a similar rate was reported by ploumis et al . , although only 20 patients were included in that study . identified six intradiscal injections among 249 transforaminal esis , which represents an incidence of 2.4 % . a lower incidence of one in 402 injections was reported by candido et al . , although this was tenfold higher than after interlaminar esi . table , 2000 retrospective cohort study207 pts , 322 injectionseither betamethasone 912 mg or methylprednisolone 80 mgfl10 non - positional headaches ( 3.1 % ) 8 increased back pain ( 2.4 % ) 2 increased leg pain ( 0.6 % ) 4 facial flushing ( 1.2 % ) 1 vasovagal reaction ( 0.3 % ) 1 increased blood sugar ( 258 mg / dl ) in an insulin - dependent patient with diabetes mellitus ( 0.3 % ) 1 intraoperative hypertension ( 0.3 % ) ahadian et al . , 2011 prospective randomised study98 pts , 98 injectionsdexamethasone 4 , 8 or 12 mgfl1 pain at injection site5 vascular uptake6 paraesthesia during procedurekaraman et al . , 2011 prospective cohortstudy562 pts , 1305 injectionstriamcinolone acetonidefl97 vascular penetration ( 7.4 % ) 8.7 % vasovagal episodes5 transient erectile dysfunction ( 0.9 % ) 5 facial flushing ( 0.9 % ) mcgrath et al . ,2011 retrospective cohort study1667 pts , 3964 injectionsnafl42 increased pain6 numbness9 pain at injection sitemanchikanti et al . , 2012 prospective cohort study1310 injectionsnafl104 intravascular placement of needle ( 7.9 % ) 16 transient nerve root irritation ( 4.6 % ) 8 profuse bleeding ( 1 % ) 1 vasovagal ( 0.08 % ) 2 facial flushing ( 0.15 % ) cansever et al . ,2012 cohort study37 pts , 65 injectionstriamcinolone 40 mgct3 transient weakness14 increased low back pain2 low blood pressure post - injectionkoh et al . , 2013 rct53 ptstriamcinolone 20 mgfl1 burning at injection site ( 1.9 % ) manson et al . ,2013 retrospective cohort study91 pts , 106 injectionstriamcinalone 40 mgfl2 vasovagal episodeshong et al . ,2014 prospective cohort study239 pts , 249 injectionsdexamethasone 5 mg and mepivacaine 3 mlfl6 intradiscal injectionmanchikanti et al . , 2014 rct120 pts , 601 injectionsbetamethasone 3 mgfl28 intravascular infiltrations ( 4.6 % ) 9 nerve root irritations ( 1.5 % ) kraiwattanapong et al . , 2014 prospective cohort study38 pts , 72 injectionsmethylprednisolone 80 mgfl3 worsening of leg painploumis et al . , 2014 prospective cohort study20 pts , l4s1betamethasone 9 mgfl2 vasovagal episodes ( 10 % ) tauheed et al . , 2014 rct60 ptsmethylprednisolone 60 mgfl3 transient paraesthesia of nerve distribution ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial complications reported with transforaminal lumbar epidural corticosteroid injections ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial a large number of case reports presenting rare adverse events following esis exist ( fig . the available literature has described deaths following esis . reviewing the available case reports , the most common and devastating complication was infarction of the spinal cord , cerebellum , brain and brainstem . infarctions could occur due to damage to the blood vessels , or either to vasospasm or an emboli from particulate matter associated with the corticosteroid injection . damage to the blood vessels could result in haematomas , and subdural and epidural haematomas have been reported . direct damage to the spinal cord by trauma or direct injection of esi medications into the cervical spinal cord has been also documented . such a complication can occur with an absence of pain being reported by the patient when the spinal cord structures were punctured . subdural and intrathecal spread or diffusion of the injected mixture of corticosteroids , anaesthetic and contrast dye could result in cauda equina and conus medularis syndromes , arachnoiditis , meningitis and temporary respiratory depression . furthermore , cases of pneumocephalus , pneumorrhachis and cerebrospinal fluid ( csf ) leak can occur . fig . 2reported major complications and approach used reported major complications and approach used infections and abscesses have been also reported following esi . with the exception of a fungal infection outbreak in the usa in 2012 , infection rates vary following an epidural injection , but , on average , are reported to be one in 60,000100,000 epidural injections . the documented outbreak in 2012 was possibly caused by a contaminated glucocorticoid product used for epidural and paraspinal injection . in single case reports , cases of meningitis , vertebral osteomyelitis , and spinal and paraspinal abscesses have been reported that are caused by microorganisms including aspergillus spp . , staphylococcus aureus and methicillin - resistant s. aureus . blindness after esi has been reported multiple times . it has been hypothesised that this complication is caused by an abrupt rise in the csf pressure caused by the volume of the injected pharmaceutical agents . in the cervical spine , this complication can be the result of the administration of radio contrast agents administered in the intracranial vasculature . the patient s vision returned to normal within 1 year of follow - up in some studies , but permanent visual impairment in patients vision was reported by some authors . vaginal bleeding has been reported as a potential complication of esi . have retrospectively reviewed 8166 esi procedures and reported an incidence of 2.5 % ( n = 201 ; 197 patients ) for abnormal vaginal bleeding . of these women , 70 % were premenopausal and 30 % were postmenopausal . ovarian axis causing anovulatory cycles has been hypothesised to be the mechanism for this adverse effect . case reports have also presented other complications including iatrogenic cushing s syndrome , persistent hiccups , convulsions , reversible posterior leukoencephalopathy syndrome , epidural granuloma formation , subdural block , brown squard syndrome , herpes zoster outbreak , steroid myopathy and corticosteroid - induced psychosis following esi . spinal epidural lipomatosis is a rare condition of adipose tissue hypertrophy in the epidural space and has been reported to occur after esi . in addition , cardiopulmonary arrest following esi and anaphylaxis and other adverse events due to the epidural corticosteroid compounds can occur . complex regional pain syndrome and development of neuropathic pain following esi have also occurred . the review of the available literature identified 11 manuscripts presenting complications following interlaminar cervical esis ( table 1 ) . one manuscript that reports no complications has also been identified but only includes 14 interlaminar cervical esis . table2003 retrospective cohort study157 pts , 345 injections , c67 or c7t1triamcinolone acetonide 80 mgfloverall 16.8 % : 23 increased neck pain ( 6.7 % ) 16 non - positional headaches ( 4.6 % ) 6 insomnia ( 1.7 % ) 6 vasovagal reactions ( 1.7 % ) 5 facial flushing ( 1.5 % ) 1 pyrexia ( 0.3 % ) 1 dural puncture ( 0.3 % ) derby et al . , 2003 retrospective survey4389 injectionsnana3 dural punctures ( 0.07 % ) 17 vagal symptoms ( 0.4 % ) 3 paraesthesia and numbness ( 0.07 % ) goel and pollan , 2006 prospective cohort29 pts , 65 injectionsnafl16 .9 % headaches21 .5 % insomnia , flushing of the face , temperature6 .2 % of increased painkwon et al . ,2007 retrospective cohort study76 pts , 76 injectionstriamcinolone acetonide 40 mgfl2 dural punctures ( 2.6 % ) kranz et al . , , 2012 prospective cohort study2376 injectionsnafl100 intravascular placement of needle ( 4.2 % ) 24 dural puncture ( 1 % ) 6 transient nerve root irritation ( 0.25 % ) 5 transient spinal cord irritation ( 0.21 % ) 16 profuse bleeding ( 0.7 % ) 1 vasovagal ( 0.04 % ) 2 facial flushing ( 0.08 % ) lee et al . , 2012 prospective cohort study ~ 127 injectionsdexamethasone sodium phosphate 10 mgfl1 vasovagal and syncope ( 0.8 % ) 1 dural puncture ( 0.8 % ) beyaz and eman , 2013 retrospective cohort study65 ptsnafl1 vasovagal ( 1.54 % ) 1 transient increase of pain ( 1.54 % ) manchikanti et al . , 2013 rct120 pts , 654 injectionsbetamethasone 6 mg ( n = 60 ) fl2 subarachnoid punctures ( 0.3 % ) 4 intravascular penetrations ( 0.6 % ) 5 nerve root irritations ( 0.76 % ) 1 pain lasting 1 week ( 0.15 % ) lee et al . , 2014 retrospective cohort study143 ptstriamcinolone acetonide 40 mg1 itching sensations1 facial flushing1 dry mouth1 erectile dysfunctionmanchikanti et al . , 2014 rct120 pts , 688 injectionsbetamethasone 6 mg ( n = 60 ) fl6 subarachnoid punctures ( 0.3 % ) 10 intravascular penetrations ( 0.6 % ) 3 nerve root irritations ( 0.76 % ) 1 pain lasting 1 week ( 0.15 % ) ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial complications reported with interlaminar cervical epidural corticosteroid injections ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial based on the available studies , the incidence of dural puncture ranged between 0.07 and 2.6 % . vasovagal reactions ranged between 0.04 and 1.7 % . in a prospective study including 2376 injections , manchikanti et al . reported 100 cases where intravascular placement of the needle occurred . however , complications that could potentially be correlated with inadvertent intravascular injection of corticosteroids were low and included 11 cases of transient nerve root or spinal cord irritation , one vasovagal event and two cases of facial flushing . in a retrospective analysis of the results of 345 c67 or c7t1 injections , botwin et al . reported an overall incidence of complications of 16.8 % . a large proportion of these adverse events were related to an increase of neck pain , headache , insomnia and vasovagal reactions . furman et al . presented 504 cervical ( c3c8 ) transforaminal esis performed on 337 patients . they reported identification of 98 intravascular injections that did not result in any adverse effects . similarly , other authors have reported no complications . in a retrospective review of 1579 injections , derby et al . reported two cases of aggravated radicular pain , two cases of prolonged paraesthesias and the development of skin rash in one patient . in another studyincluding 43 esis with prednisolone , 19 % of patients experienced minor neurovegetative manifestations . conducted an anonymous survey asking the us physician members of the american pain society about their experience with regards to serious complications following cervical transforaminal epidural corticosteroid injections ( tesis ) . from the 287 replies ,78 complications were reported , among which there were 30 brain or spinal cord infarcts and 24 neurologic complications including death of unsuspected aetiology ( n = 5 ) , high spinal anaesthesia ( n = 3 ) , transient ischaemic attacks ( n = 3 ) , and spinal cord or brainstem oedema ( n = 3 ) . the literature search found 11 studies that present adverse effects following interlaminar lumbar esis ( table 2 ) . in addition , four studies that involve more than 250 patients have reported no adverse events following interlaminar lumbar epidural esis . in a prospective cohort study including 1450 injections , manchikanti et al . reported an incidence of 0.8 % for dural puncture and profuse bleeding following the injection . a prospective , randomised blinded study including 106 patients has reported a rather high number of minor adverse effects . in particular , 26 % of the patients experienced discomfort and pain at the injection site , 18 % had non - positional headache and 10 % suffered from nausea after the injection . in an analysis of 6631 interlaminar lumbar esis , huang et al . the physician recognised the lumbar facet joint injection . a similar study design reported by candido et al . reported the incidence of intradiscal injection to be one in 4723 . table 2complications reported with interlaminar lumbar epidural corticosteroid injectionsstudy , yeardesignptsmedicationsimagingcomplicationscarette et al . , 1997 prospective randomised blinded study78 pts , 162 injectionsmethylprednisolone 80 mgbl1 dural puncture ( 0.6 % ) 27 transient headachekraemer et al . , 1997 rct87 pts , 87 injectionstriamcinolone 10 mgct1 .93.6 % headachevalat et al . , 2003 rct39 pts , 117 injectionsprednisolone acetate 50 mgbl2 headachearden et al . , 2005 rct115 pts , 3 injections eachtriamcinolone acetonide 80 mgbl4 non - specific headache2 postdural puncture headache , nausea5 otherkim et al . , 2010 retrospective cohort study150 pts , 150 injectionsdexamethasone 16 mgfl42 facial flushing ( 28 % ) kim et al . , 2011 prospective randomised study60 pts , 120 injectionsdexamethasone phosphate 15 mg or methylprednisolone acetate 80 mgfl1 intrathecal injectionmanchikanti et al . , 2012 prospective randomised blinded study120 pts , 213 injectionsbetamethasone 1 ml ( n = 60 ) fl3 subarachnoid punctures ( 1.4 % ) manchikanti et al . , 2012 prospective cohort study1450 injectionsnafl7 intravascular placement of needle ( 0.5 % ) 4 transient nerve root irritation ( 0.28 % ) 11 dural punctures ( 0.8 % ) 11 profuse bleeding ( 0.8 % ) 4 local haematoma ( 0.28 % ) 1 headache ( 0.07 % ) 2 facial flushing ( 0.13 % ) bartynski et al . ,2013 retrospective cohort study276 pts , 392 injectionmethylprednisolone acetate 80 mgfl1 dural puncture1 transient paraparesiscandido el al .2013 prospective randomised blinded study106 pts , l3s1methylprednisolone acetate 120 mgfl26 % discomfort and pain at the injection site18 % non - positional headache10 % nauseaevansa et al . , 2015 prospective randomised study120 pts , 120 injectionsmethylprednisolone acetate 80 mgfl ( n = 56 ) , us ( n = 56 ) 15 dizziness or pain at injection site or facial flushing1 intrathecal injection bl blind , ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial , us ultrasound complications reported with interlaminar lumbar epidural corticosteroid injections bl blind , ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial , us ultrasoundfourteen studies were identified that presented adverse effects following transforaminal esis ( table 3 ) . in contrast , no adverse events were presented by a number of other authors . the most common complication reported was increased pain , which was encountered in half of the patients . two prospective studies analysing a large number of transforaminal lumbar esis reported an incidence of intravascular penetration of between 7.4 and 7.9 % . the main difference was an 8.7 % rate of vasovagal episodes reported by karaman et al . . a similar rate was reported by ploumis et al . , although only 20 patients were included in that study . identified six intradiscal injections among 249 transforaminal esis , which represents an incidence of 2.4 % . a lower incidence of one in 402 injections was reported by candido et al . , although this was tenfold higher than after interlaminar esi . table2000 retrospective cohort study207 pts , 322 injectionseither betamethasone 912 mg or methylprednisolone 80 mgfl10 non - positional headaches ( 3.1 % ) 8 increased back pain ( 2.4 % ) 2 increased leg pain ( 0.6 % ) 4 facial flushing ( 1.2 % ) 1 vasovagal reaction ( 0.3 % ) 1 increased blood sugar ( 258 mg / dl ) in an insulin - dependent patient with diabetes mellitus ( 0.3 % ) 1 intraoperative hypertension ( 0.3 % ) ahadian et al . , 2011 prospective randomised study98 pts , 98 injectionsdexamethasone 4 , 8 or 12 mgfl1 pain at injection site5 vascular uptake6 paraesthesia during procedurekaraman et al . , 2011 prospective cohort study562 pts , 1305 injectionstriamcinolone acetonidefl97 vascular penetration ( 7.4 % ) 8.7 % vasovagal episodes5 transient erectile dysfunction ( 0.9 % ) 5 facial flushing ( 0.9 % ) mcgrath et al . ,2011 retrospective cohort study1667 pts , 3964 injectionsnafl42 increased pain6 numbness9 pain at injection sitemanchikanti et al . , 2012 prospective cohort study1310 injectionsnafl104 intravascular placement of needle ( 7.9 % ) 16 transient nerve root irritation ( 4.6 % ) 8 profuse bleeding ( 1 % ) 1 vasovagal ( 0.08 % ) 2 facial flushing ( 0.15 % ) cansever et al .2012 cohort study37 pts , 65 injectionstriamcinolone 40 mgct3 transient weakness14 increased low back pain2 low blood pressure post - injectionkoh et al . , 2013 rct53 ptstriamcinolone 20 mgfl1 burning at injection site ( 1.9 % ) manson et al . , 2013 retrospective cohort study91 pts , 106 injectionstriamcinalone 40 mgfl2 vasovagal episodeshong et al . , 2014 prospective cohort study239 pts , 249 injectionsdexamethasone 5 mg and mepivacaine 3 mlfl6 intradiscal injectionmanchikanti et al . , 2014 rct120 pts , 601 injectionsbetamethasone 3 mgfl28 intravascular infiltrations ( 4.6 % ) 9 nerve root irritations ( 1.5 % ) kraiwattanapong et al . ,2014 prospective cohort study38 pts , 72 injectionsmethylprednisolone 80 mgfl3 worsening of leg painploumis et al . , 2014 prospective cohort study20 pts , l4s1betamethasone 9 mgfl2 vasovagal episodes ( 10 % ) tauheed et al . , 2014 rct60 ptsmethylprednisolone 60 mgfl3 transient paraesthesia of nerve distribution ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled trial complications reported with transforaminal lumbar epidural corticosteroid injections ct computed tomography , fl fluoroscopy , na not available , pts patients , rct randomised controlled triala large number of case reports presenting rare adverse events following esis exist ( fig . the available literature has described deaths following esis . reviewing the available case reports , the most common and devastating complication was infarction of the spinal cord , cerebellum , brain and brainstem . infarctions could occur due to damage to the blood vessels , or either to vasospasm or an emboli from particulate matter associated with the corticosteroid injection . damage to the blood vessels could result in haematomas , and subdural and epidural haematomas have been reported . direct damage to the spinal cord by trauma or direct injection of esi medications into the cervical spinal cord has been also documented . such a complication can occur with an absence of pain being reported by the patient when the spinal cord structures were punctured . subdural and intrathecal spread or diffusion of the injected mixture of corticosteroids , anaesthetic and contrast dye could result in cauda equina and conus medularis syndromes , arachnoiditis , meningitis and temporary respiratory depression . furthermore , cases of pneumocephalus , pneumorrhachis and cerebrospinal fluid ( csf ) leak can occur . fig .2 reported major complications and approach used reported major complications and approach used infections and abscesses have been also reported following esi . with the exception of a fungal infection outbreak in the usa in 2012 , infection rates vary following an epidural injection , but , on average , are reported to be one in 60,000100,000 epidural injections . the documented outbreak in 2012 was possibly caused by a contaminated glucocorticoid product used for epidural and paraspinal injection . in single case reports , cases of meningitis , vertebral osteomyelitis , and spinal and paraspinal abscesses , staphylococcus aureus and methicillin - resistant s. aureus . blindness after esi has been reported multiple times . it has been hypothesised that this complication is caused by an abrupt rise in the csf pressure caused by the volume of the injected pharmaceutical agents . in the cervical spine , this complication can be the result of the administration of radio contrast agents administered in the intracranial vasculature . the patient s vision returned to normal within 1 year of follow - up in some studies , but permanent visual impairment in patients vision was reported by some authors . vaginal bleeding has been reported as a potential complication of esi . have retrospectively reviewed 8166 esi procedures and reported an incidence of 2.5 % ( n = 201 ; 197 patients ) for abnormal vaginal bleeding . of these women , 70 % were premenopausal and 30 % were postmenopausal . ovarian axis causing anovulatory cycles has been hypothesised to be the mechanism for this adverse effect . case reports have also presented other complications including iatrogenic cushing s syndrome , persistent hiccups , convulsions , reversible posterior leukoencephalopathy syndrome , epidural granuloma formation , subdural block , brown squard syndrome , herpes zoster outbreak , steroid myopathy and corticosteroid - induced psychosis following esi . spinal epidural lipomatosis is a rare condition of adipose tissue hypertrophy in the epidural space and has been reported to occur after esi . in addition , cardiopulmonary arrest following esi and anaphylaxis and other adverse events due to the epidural corticosteroid compounds can occur . complex regional pain syndrome and development of neuropathic pain following esi have also occurred . esis have been used for more than 60 years since lievre et al . reported the use of epidural hydrocortisone in a series of 20 patients . over the yearsthe number of epidural injections has increased by 106.3 % in the decade between 1997 and 2006 . currently , esis are the most common intervention performed for the management of chronic low back pain in the usa . indications for esi are not robust and the outcome could not be correlated with the extent of the underlying pathology , e.g. the degree of lumbar spinal stenosis , but could be determined by factors such as age , sex and the preceding opioid use . collectively , this systematic review contains data from more than 100,000 esis reported in prospective or retrospective studies . major events have been reported anecdotally and it is impossible to comment on their true incidence based on the available results in the literature . overall , the potential causes of adverse events could be categorised into three distinct categories : ( 1 ) direct damage to the blood vessels or adjacent anatomical structures during the procedure ; ( 2 ) intravascular administration of the injectate ; and ( 3 ) a local or systemic reaction including bacterial contamination . direct damage to the blood vessels or adjacent structure is an inherent risk for any injection , including esis . direct damage to the spinal cord by the needle and the injection of corticosteroids into the cervical spinal cord has been also documented in a very limited number of case reports . clinically significant haematomas derived from piercing or damage to the blood vessels can occur and the reported incidence for all epidurals is less than one in 150,000 . this complication is increased in patients with coagulopathy and patients on anticoagulant medications . inadvertent dural punctures can occur after esis and csf flashback is pathognomonic of this complication . other complications , including intracranial subdural haematoma after accidental dural puncture and cases of pneumocephalus , pneumorrhachis and csf leak , have been presented in case reports . intravascular injection of the corticosteroids , carrier and / or the local anaesthetic could account for the large majority of the serious adverse effects . the reported incidence of inadvertent intravascular injection with fluoroscopically guided tesi is reported to range from 9 % to as high as 32.8 % . furman et al . reported an incidence of fluoroscopically confirmed intravascular penetration of 19.4 % for cervical tesis , 8.1 % for lumbar tesis and 21.3 % for tesis at the s1 level . in addition , sullivan et al . suggested that intravascular uptake is twice as likely to occur in patients over rather than under 50 years of age . vascular embolic events from intra - arterial injection of particulate corticosteroids have been found to account for serious complications including spinal cord infarction , paraplegia and death . houten et al . presented three cases of paraplegia which ensued suddenly after instillation of the corticosteroid solution in the artery of adamkiewicz . it should be mentioned that intra - articular injections pose a higher degree of danger , while venous uptake has been considered benign . in terms of the injectate , medium - sized particles between 51 and 1000 m have the potential to enter and occlude a blood vessel . irrespective of the size , it has been suggested that when corticosteroid particles enter a blood vessel they could coalesce and precipitate , forming larger particles . the injection of the particulate corticosteroid methylprednisolone into the vertebral artery of four pigs resulted in permanent loss of consciousness , while the animals receiving dexamethasone and prednisolone recovered fully . . demonstrated that methylprednisolone and its non - particulate carrier can produce significant injury to the bloodthe authors also suggested that in addition to the cerebral microvasculature occlusion by the particulate corticosteroids , damage can occur via toxicity of the carrier or the corticosteroid . based on several observations that failed to highlight any difference in the efficacy of particulate and non - particulate corticosteroids , we would recommend the use of soluble non - particulant agents . a transient blockage of the neural conduction is expected ; however , the reported central canal , conus medularis and cauda equina syndromes must have an underlying cause , i.e. hematoma , infarct , etc . transient systemic reactions including headaches , vasovagal reactions and facial flushing have been reported ; these reactions occurred shortly after the esi and could represent a reaction to the injected anaesthetic agents and / or corticosteroids . it is rather unclear whether esis pose a long - term risk of certain conditions and whether a cumulative effect of prolonged exposure exists . if that is true , epidural corticosteroids could have similar systemic effects to that of long - term corticosteroids administered through other routes . for instance , a significant number of the patients with chronic back pain conditions are treated with repeated injections over prolonged period of time . corticosteroids are known to interfere with calcium homeostasis , reducing bone formation and increasing bone breakdown . osteoporosis and an increased fracture risk could theoretically occur ; however , the available literature does not support this theory . prospectively evaluated 100 patients receiving epidural injections and reported no change in bone mineral density . insulin resistance is another adverse effect associated with corticosteroid administration ; however , studies looking specifically at patients receiving esis did not find any changes in the fasting glucose levels . adrenal axis suppression has been demonstrated to occur after esis . . showed that following esi with dexamethasone a profound decrease in the serum levels of adrenocorticotropic hormone ( acth ) occurs . hypertension can also occur following esis ; a mean systolic blood pressure increase of 5 mmhg has been previously reported following esis . finally , corticosteroid administration represents a risk factor for wound complications postoperatively and poses an increased risk for infections . esis are frequently performed prior to spinal surgery , either as a disgnostic tool or for pain management , but their contribution to complications of such procedures is currently unknown . severe infections are rare after spinal injections and have an incidence of 0.10.01 % . the only exception is a fungal infection outbreak in the usa in 2012 . according to the centers for disease control and prevention , 25 deaths due to epidural corticosteroid - related meningitis ( many due to aspergillosis ) were identified : 337 patients were affected in 18 us states and 14,000 patients were probably exposed to contaminated corticosteroids . in the authors opinion , several recommendations can be made with the aim of minimise the incidence of major complications after esis . first , esis should be performed under fluoroscopic guidance and the needle position should be confirmed in at least two planes , typically anteroposterior and either an oblique or lateral plane . aspiration prior to the injection is specific but not sensitive at detecting intravascular needle placement , being unable to produce a flashback of blood in 74 % of cases in which the needle was ultimately determined to be intravascular . injection of contrast media is recommended and operators must be able to distinguish between intravascular , epidural and subdural contrast flow patterns . the use of a blunt needle and the suggestion that a small test dose of the medication should be inject initially has been proposed . dynamic live fluoroscopy was found to perform better than static intermittent fluoroscopy , which was found to miss 57 % of the intravascular injections . digital subtraction angiography can be used as a radiologic adjunct to identify vascular compromise during the injection . however , in a case report by chang et al . , an anaesthetic test dose and digital subtraction angiography performed twice did not prevent a catastrophic spinal cord infarction and the resultant paraplegia . it is under debate whether the transforaminal route poses a higher risk of serious complications when performed by an experience physician . given the lack of evidence , one could argue that it is reasonable to consider the transforaminal approach only when the interlaminar route has failed . finally , informed consent should be taken and the patient should be aware of the potential risk and benefits of this procedure . the survey of cervical injections conducted by scanlon et al . is the only manuscript that presents a high number of serious and fatal cases . possible mechanisms explaining these events include the intra - arterial injection of particulate corticosteroid or trauma causing embolisation to the distal basilar or vertebral arteries . despite the fact that the study presents the extreme end of potential complications , it is unclear what the true incidence of these events is . as previously mentioned , it would be of enormous educational interest to have further details regarding these events , especially details of the technique and imaging used as well as the training and experience of the physician . the warning issued by the fda regarding esis merits further discussion and analysis , and the use of corticosteroids for injections in the epidural space for spinal pain syndromesthe fda mentions that , despite their use , the effectiveness of esis has been challenged and could potentially result in serious adverse events including death , stroke and paralysis . in support of these arguments , the fda has published several case reports . major adverse events can occur with esis , but such events are rare , their true incidence is unknown and they have only been presented in case reports . for instance , none of the studies included in tables 1 , 2 and 3 presents such major devastating complications . conclusion stating that the fda s warning is an additional burden on patient access to pain - relieving treatments . should the fda s warning letter be replaced by an evidence - based educational guidance to safeguard the best clinical practice ? a large proportion of the available case reports and studies provide insufficient documentation , i.e. the approach used for esi , symptom duration , volume injected or even the number of injections . in addition , the majority of the studies report adverse effects incidentally as their main aim is to report the efficacy of the injections . furthermore , the available studies were heterogeneous with regards to the outcome measures , and in several manuscripts the surgical technique , corticosteroid dosage and the addition of other medications are not reported . it is of note that many studies did not look at or record the complications or adverse effects of corticosteroid exposure but present results from several pain and functional scores . therefore , it is possible that both the short - and long - term adverse effects of corticosteroid exposure remain unreported . esis are relatively safe ; however , although major complications of esis have been reported , their true incidence remains obscure . vascular penetration and administration of pharmaceutical agents intra - arterially could account for a large proportion of the adverse events reported . with accurate placement of the needle , use of non - particulate corticosteroids , live fluoroscopy , digital subtraction angiography and familiarisation of the contrast patterns on fluoroscopy these risks should be minimised . further research is required to shed more light on the best clinical practice for the use of esis and the true incidence of complications relating to them .\noutput:\n" }, { "from": "agent", "value": "background and objectiveepidural corticosteroid injections ( esis ) have been used for several decades and now represent the most common intervention performed for the management of back pain with a radicular component . however , several reports have presented devastating complications and adverse effects , which fuelled concerns over the risk versus clinical effectiveness . the authors offer a comprehensive review of the available literature and analyse the data derived from studies and case reports.methodsstudies were identified by searching pubmed medline , ovid medline , embase , scopus , google scholar and the cochrane library to retrieve all available relevant articles . publications from the last 20 years ( september 1994 to september 2014 ) were considered for further analysis . studies selected were english - language original articles publishing results on complications related to the technique used for cervical and lumbar esis . the studies had to specify the approach used for injection . all studies that did not fulfil these eligibility criteria were excluded from further analysis.resultsoverall , the available literature supports the view that serious complications following injections of corticosteroid suspensions into the cervical and lumbar epidural space are uncommon , but if they occur they can be devastating.conclusionsthe true incidence of such complications remains unclear . direct vascular injury and / or administration of injectates intra - arterially represent a major concern and could account for the vast majority of the adverse events reported . accurate placement of the needle , use of a non - particulate corticosteroid , live fluoroscopy , digital subtraction angiography , and familiarisation of the operator with contrast patterns on fluoroscopy should minimise these risks . the available literature has several limitations including incomplete documentation , unreported data and inherent bias . large registries and well - structured observational studies are needed to determine the true incidence of adverse events and address the safety concerns ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: diabetes mellitus , as the most prevalent metabolic disorder , is characterized by chronic hyperglycemia due to defect in insulin secretion by beta cells of langerhans islets or resistance against insulin action . more than 300 million people are suffering from diabetes mellitus all over the world and studies show that population aging , changes in lifestyle and improvement in detection techniques are most important factors in increasing the numbers of cases . the prevalence of type 2 diabetes mellitus ( t2 dm ) varies in different populations from less than 6 % in most populations to more than 50 % in pima indians . in 2013it was reported that in middle east region about 35 million people suffered from diabetes . the prevalence of diabetes has been estimated as 382 million people throughout the world while nearly 176 million of them seem to be still undiagnosed . diabetes mellitus can also cause complications in most of organs : heart , eye , kidney , and nervous system which has resulted in high economic cost and burden . a systematic review showed that between years 1996 and 2004 the prevalence of type 2 diabetes in iran was 24 % and the risk was 1.7 % greater in women . according to this report the prevalence of t2 dm in iran seems to be highest amongst developing countries . previous reports on total urban population of middle eastern countries show the prevalence of t2 dm as 3.4 % in sudan , 20 % in united arab emirates , 8.5 % in bahrain , and 12.1 % in india . type 1 diabetes mellitus ( t1 dm ) includes 510 % of diabetic patients . cellular - mediated autoimmune destruction of the beta - cells of the pancreas results in t1 dm . it classically occurs in juveniles and affected patients are dependent on insulin injection in their lifetime and are very prone to ketosis . vascular complications such as nephropathy , neuropathy , retinopathy , and cardiovascular disease may develop in these patients . the impact of genetic component appears to be stronger in t2 dm compared to t1 dm . gestational diabetes mellitus ( gdm ) is another type which is observed during pregnancy and the prevalence may range from 1 to 14 % in all pregnancies . mody ( maturity onset diabetes of young ) is monogenic form of diabetes comprised of several types with various features which is consisting of 15 % of patients diagnosed as t2 dm . the onset of this type of diabetes is normally before 25 years and its treatment is independent of insulin . mody in its different forms is inherited in autosomal dominant pattern and presents as a result of mutation in transcription factors genes including hnf4 ( hepatocyte nuclear factor ) , hnf1 , ipf1 ( insulin promoter factor ) , and neuro - d1 . there are also other types of diabetes which are considered as secondary to other conditions , for example , any damage to pancreas such as removal of pancreatic tissue , trauma , pancreatic carcinoma , and infection , or underlying diseases including endocrine diseases that alter different hormones secretion which are antagonist to insulin resulting in various clinical manifestations such as acromegaly , cushing 's syndrome , pheochromocytoma , glucagonoma , somatostatinoma , and diabetes . diabetes ( or carbohydrate intolerance ) is also found in increased frequency with a large number of genetic syndromes such as wolfram syndrome , which causes diabetes mellitus , diabetes insipidus , and other neurodegenerative disorders , melas ( mitochondrial myopathy , encephalopathy , lactic acidosis , and stroke ) which is presented with myopathy and encephalopathy caused by mitochondrial mutation , midd ( maternally inherited diabetes and deafness ) which causes diabetes , and ipex ( immune dysregulation , polyendocrinopathy , enteropathy , and x - linked syndrome ) which is x - linked and alters immune system and causes multiple endocrine problems . diabetes mellitus is a multifactorial disease with both environmental and genetic causes affecting its presence and incidence . genome wide association studies revealed the genetic heterogeneity of diabetes and the fact that difference in ethnicity can result in different susceptible genes associated with diabetes . studies on candidate genes related to diabetes revealed that several genes including pprag ( peroxisome proliferator - activates receptor gamma ) , irs1 and 2 ( insulin receptor substrate ) , kcnj11 ( potassium inwardly rectifying channel ) , and hnfa are associated with t2 dm . genome wide association studies ( gwas ) showed that many genes including calpain 10 and tcf7l2 ( transcription factor 7 - like 2 ) are associated with t2 dm . hhex ( hematopoietically expressed homeobox ) , slc30a8 ( solute carrier family 30 ( zinc transporter ) , member 8 ) , cdk2a / b ( cyclin - dependent kinase inhibitor 2a / b ) , and ig2bp2 ( insulin - like growth factor 2 ) are other genes which have been shown to be associated with t2 dm based on gwas . some of these genes are expressed in beta cells or involved in insulin secretion pathways . other candidate genes in association with t2 dm include ppar , ace ( angiotensin converting enzyme ) , mthfr ( methylene tetrahydrofolate reductase ) , fabp2 ( fatty acid binding protein - 2 ) , and fto ( fat mass and obesity associated gene ) . gwas was carried out in many populations including finnish , french , and american caucasians and showed different loci on most of the chromosomes associated with t2 dm . systematic review and meta - analysis studies also confirmed the association of some genes such as pgc - 1 ( peroxisome proliferator - activated receptor gamma coactivator - 1 ) and adiponectin with t2 dm . for example , insulin ( ins ) gene vntrs ( variable number of tandem repeats ) with a protective effect is a variants related to t1 dm . in addition ptpn22 ( protein tyrosin phosphatase ) , ctla4 , and il2ra genes have also been shown as candidates for t1 dm due to their role in t - cell signaling . studies have also confirmed the association between ifih1 , cyp27b1 , and clec16 , which are important in immune system and t1 dm . there is no inclusive information for genetic association studies of diabetes in middle eastern population including iranian population . in order to make a comprehensive approach , we aimed to collectively investigate and gather data for association between genetic variants and type 2 diabetes in iranian population in a systematic review study . this study is reported according to prisma ( preferred reporting items for systematic reviews and meta - analyses ) guideline . we systematically searched international web databases : google scholar , pubmed , scopus , and persian web databases ; iranmedex ; and magiran to investigate the association of genetic variants with diabetes and its complications in iranian population up to january 2014 . diabetes , diabetes ' complications , nephropathy , retinopathy , neuropathy , foot ulcer , and cad ( coronary artery disease ) and their mesh terms and persian equivalents with diabetes . at least three emails were sent to the corresponding author of articles which were not accessible as full text or had insufficient data . duplicate articles and multiple publications from the same population were excluded and the most relevant data were used for the investigation . we included all observational population - based studies 100 sample size , which were conducted as case - control , cohort , or cross sectional . according to who criteria , diabetes mellitus was defined as fbs 7 mmol / l ( 126 mg / dl ) or 2 h plasma glucose 11.1 mmol / l ( 200 mg / dl ) . in addition , we excluded animal studies , clinical trials , short communications , letters to editor , dissertations , in vitro studies , review articles , and population - based studies conducted in pregnant women . two researchers , se and mkh , independently reviewed title , abstract , and full text of each article to assess the eligible articles according to inclusion and exclusion criteria . inclusion and exclusion of articles were supervised by a third reviewer ( otm ) in case of conflicts . the following data were extracted and presented in an excel sheet : author ( s ) , year , genes and snps , patients ' characteristics ( sample size , age , and sex ) , city , study design , genotyping method , and significant association . six selected items from the strobe ( strengthening the reporting of observational studies in epidemiology ) checklist was used for quality assessment of the included studies and assessed separately for each included article . the below items were considered : ( a ) clearly define the outcome and association between gene variants and diabetes ; ( b ) give the eligibility criteria ; ( c ) present key elements of study design ; ( d ) report numbers or significance / nonsignificance statistically of outcome events ; ( e ) give characteristics of study participants ; and ( f ) describe the locations and relevant dates . all studies with quality score 3 were considered as high quality study and included in our systematic review . due to heterogeneity in genotyping techniques and also differences in genetic variants studied in assessed included articles performing a meta - analysis was impossible . a summary of the literature review process performed in this study is presented in a flow chart in figure 1 . in final step 88eligible studies were included in this study and assessed due to the inclusion / exclusion criteria . t2 dm was the most investigated type of diabetes ( 42 studies ) . among diabetes complications , diabetic nephropathy and cadthe least investigated complication was diabetic foot ulcer which was assessed only in one study . retinopathy and insulin resistance were also among the least investigated complications including 3 and 4 studies , respectively . all of the studies were performed on both genders except for one which was performed on males . all the studies in this subgroup including 12 studies were in a case control study design using pcr ( polymerase chain reaction ) , pcr - rflp ( restriction fragment length polymorphism ) , pcr - ssp ( single specific primer ) , and arms - pcr ( amplification refractory mutation system pcr ) method . in all studiesboth men and women were included and the overall 2519 subjects were under 40 years old . association of interleukins including il - 18 ( interleukin ) and il - 12 with t1 dm revealed that the 137c / g polymorphism of il - 18 had significant association with t1 dm ( p = 0.037 , p = 0.0001 ) while no significant relation was observed between 607a / c variant of this gene and t1 dm . investigating il - 12 also showed that there was a significant association between + 1188a / c polymorphism of this gene and t1 dm ( p = 0.035 ) . in 2 studies the association of + 49a / g variant of ctla - 4 ( cytotoxic t lymphocyte associated antigen 4 ) was investigated and it was revealed that there was a positive significant association between ag genotype and t1 dm ( p = 0.01 , p 0.001 ) . one of these studies also revealed that there was a negative relation between aa genotype and t1 dm . vitamin d receptor ( vdr ) was investigated in 2 studies . both of them assessed the association of foki , bsmi , apai , and taqi variants of vdr with t1 dm . in one study which was performed on 114 subjects , aa ( p = 0.003 ) , ff ( p = 0.008 ) and bb ( p = 0.014 ) genotypes were shown to be positively associated with t1 dm but no significant association was observed between taqi polymorphism and t1 dm . another study which was performed on 187 subjects showed no significant association between t1 dm and foki , bsmi , and apai . however tt genotype was observed to be more frequent in controls ( p = 0.007 ) and negatively associated with t1 dm . different polymorphisms of tap2 and their association with t1 dm were investigated in 191 subjects . other variants of tap2 ( transporter 2 atp - binding cassette ) including ala565thr , arg651cys , and ala665thr were not associated with t1 dm significantly . it was revealed that a3 allele had negative ( p = 0.025 ) and a5 had positive ( p = 0.001 ) significant association with t1 dm . association of some other genes including osteopontin ( rs1126772 polymorphism ) , integrin 4 ( rs1449263 polymorphism ) , cd44 ( rs8193 polymorphism ) , and tgf ( transforming growth factor ) ( + 915c / g polymorphism ) was also investigated in 2 studies and no significant relation was observed between these variants and t1 dm . in this categoryonly one study was found and the association of val255met polymorphism of hnf and diabetes was investigated in 101 subjects including mody subjects , their relatives , and healthy controls . the study was designed as a case control association study and pcr - rflp and direct sequencing was used for genotyping of variants . val255met mutation in this investigation was observed in mody subjects and their relatives but not in control group . in this subgroup 42 studies were assessed and all of them were designed as case control association studies except for one which was cross sectionally designed . in 33 studies , pcr - rflp was used for genotyping . in 5 of them pcr was used and the remaining studies pcr - sca , real - time pcr , arms - pcr , gap pcr , and csge ( conformation - sensitive gel electrophoresis ) sequencing as the genotyping method were applied . association between two polymorphisms of tcf7l2 including rs7903146 ( c / t ) and rs12255372 ( g / t ) was assessed in three studies . in one study investigating rs7903146 ( c / t ) in 466 subjects , significant difference in the frequency of cc and ct genotypeshowever in another study this polymorphism showed a positive significant association with tt genotype in t2 dm ( p = 0.008 ) . investigation of rs12255372 ( g / t ) polymorphism of tcf7l2 in another study showed that among 491 subjects there was a positive significant association between tt carriers and t2 dm ( p = 0.014 ) . investigatingthe association of calreticulin with t2 dm in 650 subjects showed two mutations , only in case group , 9 bp deletion of 397399 codons and g t mutation at ivsii - 142 . association of estrogen receptor and its pvuii ( pp , pp , pp ) and xbai ( xx , xx , xx ) polymorphism with t2 dm in two studies was assessed . in one study , the significant association of pvuii and xbai polymorphisms with t2 dm was observed ( p = 0.014 and p = 0.002 , resp . ) . in another studyit was revealed that pooled pp + pp and xx + xx male carriers have positive significant association with t2 dm ( p = 0.001 and p = 0.026 , resp . ) . association of pro12ala polymorphism of ppar with t2 dm was investigated in three studies . negative significant association of ala / ala genotype with t2 dm was observed in two studies ( p = 0.003 ) . ala / pro carriers were shown to be positively associated in one study and negatively associated in another study with t2 dm ( p 0.001 and p = 0.003 , resp . ) . however in the third study no significant association was observed between pro12ala polymorphism of ppar and t2 dm . association of different polymorphisms of apoai with t2 dm was investigated in two studies . in one study investigation ofit was shown that g - 75a polymorphism of apoai was not associated with t2 dm while a significant association was found between c +83 t polymorphism and t2 dm ( p = 0.028 ) . two studies assessed the association of 156g c polymorphism of cxcl5 with t2 dm . in one study positive significant association of gc carriers ( p = 0.006 ) and negative association of gg carriers ( p = 0.01 ) was found between diabetic patients and healthy controls and in another study positive significant associationwas found between gc or cc carriers and t2 dm ( p = 0.009 ) . adiponectin and its association with t2 dm were investigated in two studies . in one study , two variants including + 45t / g and 11391g / a were investigated but no significant relation was found between these two polymorphisms and t2 dm . however in another study investigating + 45t / g polymorphism of adiponectin , it was revealed that nonobese t2 dm subjects had significantly higher tt genotype ( p = 0.04 ) . in one study that investigated insulin receptor gene , the following mutations were found only in t2 dm : 511c a , 514t g , 586 , and 628t a on exon 2 , 694g c , 680g a on exon 3 , 1627a 2007c c / t on exon 9 , 2595c c / t and 2669g c / g on exon 14 , and 3471t a and 3516t g on exon 19 . other variants which had significant association with t2 dm included haptoglobin ( allele 2 - 2 ) , leptin ( g - 2548a polymorphism ) , paraoxonase 2 ( ser311cys polymorphism ) , gst ( glutathione - s - transferase ) m1 and gstm1 / gstt1 interaction , calpain - 10 ( snp ( single nucleotide polymorphism ) 43 ) , irs - 1 ( g972r polymorphism ) and irs - 2 ( g1057d polymorphism ) , vdr ( vitamin d receptor ) ( taqi polymorphism ) , kcnj11 ( e23k polymorphism ) , enos ( endothelial nitric oxide synthase ) vntr ( intron 4 a / b polymorphism ) , resistin ( 420c / g polymorphism ) , and ace ( insertion / deletion ) . in contrast to above variants , ctla4 ( + 49a / g polymorphism ) , hnf - 1 ( ala98val polymorphism ) , glp - 1r ( glucagon - like peptid 1 receptor ) ( thr149met polymorohism ) , slc30a8 ( arg325trp polymorphism ) , gstp1 ( ile105val polymorphism ) , glucokinase ( 30g / a polymorphism ) , sdf - 1 ( stromal derived factor -1 ) ( g801a polymorphism ) , apoe ( apolipoprotein e ) , enpp1 ( ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 ) ( k121q polymorphism ) , sumo4 ( small ubiquitin - like modifier 4 ) met55val polymorphism ) , mthfr ( c677 t polymorphism ) , ucp2 ( uncoupling protein 2 ) ( 866g / a polymorphism ) , 5httlpr , il - 4 ( 590c / t polymorphism ) , ifn - ( interferon ) ( + 874t / a polymorphism ) , ccr5 ( c - c chemokine receptor type 5 ) ( 32mutation ) , hfe ( hemochromatosis gene ) ( h63d , c282y , ptpn1 ( protein tyrosin phosphatase 1b ) / 51dela , 451a g , 467t c , 1023c a , 1045g a , 12863 bp del aca , 12919 bp del ctagactaa polymorphisms ) were not significantly associated with t2 dm . in this subgroup , three studies used pcr - rfl and one study used real - time pcr for genotyping . the studies assessed in this subgroup showed a positive association of tg carriers of + 45t / g polymorphism of adiponectin ( p = 0.032 ) and ala allele carriers of pro12ala polymorphism of ppar ( p = 0.036 ) with t2 dm . a positive significant association of ff carriers of vdr was also shown ( foki polymorphism ) ( p = 0.02 ) and negative association of 148insg carriers of ptpn1 ( 148insg polymorphism ) ( p = 0.041 ) with insulin resistance index . design of all 11 studies in this subgroup was case - control association study except one study which was designed as cross sectional . pcr - rflp was used in all of them for genotyping except in one study which used arms - pcr method . paraoxonase 1 ( 163t / a polymorphism ) was the only variant in this subgroup which was not significantly associated with atherosclerosis risk in t2 dm . investigation of another polymorphism of paraoxonase 1 ( q192r ) revealed that diabetics with cad had significant increase in rr genotype ( p 0.05 ) . investigating b1 and b2 alleles of cetp taqi b allele in 400 subjects showed that pooling of b1b1 + b1b2 and b1b1 genotypes had significant association with t2 dm and cad ( p 0.01 ) . on the other hand assessing the g894 t polymorphism of enos showed positive significant association between tg and tt carriers and cad ( p 0.05 ) . it was also shown that concomitant presence of nos3 t allele and cept b1 allele was significantly associated with t2 dm ( p = 0.004 ) and cad ( p = 0.002 ) . investigation of apolipoprotein e ( e2 , e3 , and e4 ) alleles showed the association of e2 and e4 alleles with cad ( p 0.001 ) . also it was shown that interaction of butyrylcholinesterase ( bche k ) and apolipoprotein e ( apoe ) was associated significantly with cad and diabetes . adiponectin + 276g / t and + 45t / g were significantly associated with cad ( p = 0.023 and 0.033 , resp . ) while investigating 16125a / 6a polymorphism of mmp - 3 ( matrix metalloproteinase 3 ) showed a significant association with cas ( coronary artery stenosis ) ( p = 0.008 ) . in addition a1166c polymorphism of at1r ( angiotensin i receptor ) and 420c / g polymorphism of resistin in diabetic patients with cad revealed significant association with diabetes , p = 0.01 and p = 0.009 , respectively . another study showed insertion ( i ) / deletion ( d ) polymorphism of angiotensin converting enzyme ( ace ) dd genotype was significantly associated with higher blood pressure ( p = 0.026 ) . factor v leiden ( g1691a polymorphism ) , prothrombin ( g20210a polymorphism ) , and mthfr ( methylenetetrahydrofolate reductase ) ( c677 t polymorphism ) were the variants which were not significantly associated with cad and t2 dm in this subgroup . all of 15 studies in this subgroup were designed as case - control association studies . in 7 studies , pcr - rflp was used for genotyping ; in four studies pcr was used and in 4 of them both pcr and pcr - rflp were used . studying the association of 163a / g polymorphism of sumo4 showed a positive significant association between aa carriers and diabetic nephropathy ( p 0.05 ) . studying the interaction of enos / 4a / b and g894 t revealed positive significant association between 4a or 894 t allele carriers and macro - and microalbuminuria ( p = 0.01 , p = 0.02 , resp . ) . it was observed that the interaction of enos ( g894 t polymorphism ) and ace ( i / d alleles ) was significantly associated with more frequent macroalbuminuria ( p = 0.035 ) . it has also been shown that interaction of enos ( g894 t polymorphisms ) and mthfr ( c677 t and a1298c polymorphisms ) , enos t / 1298 c , and enos t / 677 t carriers had positive significant association with macroalbuminuria . in addition significant association of enos gt + tt carriers with lipid profile ( p 0.05 ) was shown in this study . c677 t and a1298c polymorphisms of mthfr were also investigated in another study revealing that 677 t , 1298c , and 677t / 1298c carriers were significantly associated with macroalbuminuria ( p 0.001 ) . positive significant association when pooling ct + tt genotypes and 677t / 1298c was also found with microalbuminuria ( p 0.001 ) . investigating the interaction of mthfr ( a1298c , c677 t polymorphisms ) and ace ( i / d alleles ) showed a positive significant association of ace d / 677 t ( p = 0.035 ) and ace d / 1298c ( p = 0.012 ) genotypes with macroalbuminuria . ace ( i / d alleles ) polymorphisms were investigated in three studies . in one study positive significant association ( p 0.01 ) between dd carriers and progression but not development of albuminuria was observed . in another study in nephropathic subjects , association of dd carriers and t2 dm ( p = 0.006 ) butinteraction of ace ( i / d alleles ) with factor v leiden ( g1691a polymorphism ) was not significant . association of interleukins including il - 4 and il - 10 with diabetic nephropathy was also investigated in two studies . study of 592c / a polymorphism of il - 10 revealed positive significant association between cc carriers and nephropathy ( p = 0.001 ) and study of 590c / t polymorphism of il - 4 revealed positive significant association between ct carriers and nephropathy ( p 0.001 ) . other significant associations between variants and diabetic nephropathy included at2r ( angiotensin ii receptor ) ( 1332g / a polymorphism ) , vegf ( vascular epithelium growth factor ) ( + 405g / c polymorphism ) , and vdr ( taqi polymorphism ) . all of the 3 studies in this subgroup were conducted as case - control association studies . investigating null / positive genotype of gstm1 in a study , which used arms - pcr for genotyping , revealed that null genotype is significantly associated with diabetic retinopathy ( p 0.05 ) . this result was confirmed in another study by using multiplex pcr as genotyping , although no significant association between gstt1 and retinopathy was found in this study . investigating + 405g / c polymorphism of vegf also revealed positive significant association between gg carriers and diabetic retinopathy ( p = 0.005 ) . in this subgrouponly one study was found which was case - control designed and used arms - pcr for genotyping . in this study association of 7c / t and 2578c / a polymorphisms of vegf with diabetic foot ulcer ( dfu ) was investigated , and a positive significant association between aa carriers and dfu ( p = 0.03 ) was observed . but no significant association was found between 7c / t of vegf and dfu . diabetes mellitus is the eighth most frequent disease leading cause of death throughout the world and now ranks the fifth , following communicable diseases , cardiovascular disease , cancer , and injuries . type 2 diabetes is the most frequent type of diabetes mellitus . systematic review and meta - analysis studies have assessed the association between different genes and t2 dm . glutathione - s - transferase including gstmi , gstm1 , and gstp1 are important genes and their association with diabetes has been investigated in two meta - analysis studies . it was revealed that null genotype of both gstm1 and gstt1 could be as a risk factor for diabetes while no significant association was found between gstp1 and diabetes . these results are in line with our finding and confirming the association of the null genotype of gstt1 and gstm1 with t2 dm in iranian population . the relation between gstt1 and gstm1 and diabetic retinopathy has also been shown in iranian population . no association of c677 t polymorphism of mthfr gene was found in africans , asians , and caucasians . mthfr is a gene which is involved in dna methylation and synthesis and regulated folate activity . it has been reported that mutant homozygote and heterozygote of c677 t polymorphism of mthfr increase plasma homocysteine which is an important factor leading to diabetic nephropathy ( dn ) and , as a result , c677 t polymorphism of mthfr can be associated with the development of dn . in caucasians this association has also been observed . in iranian population , in line with other populations , no significant association was found between mthfr polymorphisms and t2 dm although significant association of 677 t and 1298c alleles with diabetic nephropathy was observed . interaction of two polymorphisms and also interaction of mthfr polymorphisms with other genes such as ace and enos showed an association with development of dn . interleukins especially il - 10 are shown to have significant association with t2 dm in different ethnic groups . significant association between 592c / a and 819c / t polymorphisms of il - 10 and t2 dm risk in africans was shown . also 1082a / g polymorphism of il - 10 seems to be a risk factor for t2 dm in asians but not in europeans and africans . in another studyit was reported that 1082gg genotype of il - 10 and 174cc genotype of il - 6 are as risk factors for t2 dm in egyptians . in our studyinvestigation of different polymorphisms of adiponectin and their association with t2 dm in a meta - analysis study revealed 11391g a and 11426a g polymorphisms of adiponectin as risk factor for t2 dm in europeans and 11377c g variant of adiponectin as risk factor of t2 dm in europeans and asians . it was also shown that + 45t g and + 276g t variants are not associated with t2 dm in europeans , africans , and asians . in contrast to previous studies , + 45t g and 11391g a polymorphisms were not associated with t2 dm in this study due to difference in genetic background . among candidate genes in association with t2 dm , tcf7l2 is one of the strongest genes related to diabetes . in a meta - analysis study after pooling all data of european , african , and asian populations , it has been revealed that rs12255372 polymorphism of tcf7l2 significantly increases the risk of t2 dm . however no data from iranian population as a type of asian population was included in this meta - analysis . in line with these data , in our study , we found a positive association between rs12255372 and rs7903146 variants of tcf7l2 and t2 dm . pro12ala polymorphism of ppar is found to be as a protective variant especially in asian population although the results were highly heterogeneous . in our studyin one study no association was found between this polymorphism and t2 dm in contrast with previous studies while in other studies protective effect of this polymorphism with t2 dm was confirmed in line with previous studies . these controversial data may be due to different ethnicity in different populations being studied in iran . type 1 diabetes mellitus is another type of diabetes in which hla ( human lymphocyte antigen ) , ir1r1 ( interleukin - 1 receptor type 1 ) , ctla - 4 , and vdr are some important genes studied in association with t1 dm . vdr is one of the most studied genes in relation to t1 dm due to its role in t - cell mediated autoimmune diseases . meta - analysis studies showed that bsmi and foki polymorphisms of vdr increased the risk of t1 dm in east and west asians , respectively . in our studywas shown to be associated with t1 dm while in another study no association was found . foki was not associated with t1 dm in our study in contrast to previous studies which might be due to difference in ethnicity and genetic background or insufficient clinical data . among diabetic complications , cad and dnmeta - analysis studies showed that rs2010963 and rs3025039 polymorphisms of vegf , 4b / a , t - 786c , and g894 t polymorphisms of enos and ace are associated with dn . in our study , 4a / b and g894 t polymorphisms of enos and ace were shown to be associated with dn in line with previous studies . in our studyrs2010963 polymorphism of vegf was also found to be associated with diabetic nephropathy which was in line with previous studies . the most investigated genes in association with cad include ppar , tcf7l2 , ace , tnf - , adiponectin , and irs1 . in our study , + 45t g and + 276g t polymorphisms of adiponectin were investigated and the significant association of these variants with cad was confirmed . overall it seems that more studies are needed to identify diabetes susceptibility genes in iranian population . investigation of candidate genes is one way to understand these genes , but the method with the least expenses and error is gwas which scans a set of loci in association with a disease in many people . gwas in different populations such as americans , caucasians , australians , west africans , and europeans revealed multiple loci in association with t2 dm . in asians especially in middle eastern countries , we reviewed five studies which investigated the association between enos , ace , mthfr , and factor v leiden and the interaction between them and diabetic nephropathy and reach a coherent result while gwas could be helpful and reduce time and other expenses . firstly , this systematic review , for the first time , assessed the association between genetic variants and diabetes in iranian population . moreover , the studies included in this systematic review were assessed for quality and selected as high quality ( scored 3 ) . for limitationsit should be considered that all included studies were observational , which does not allow reliable inferences about causality . moreover due to methodological heterogeneity , we were not able to pool the data and perform the meta - analysis . our study showed significant association between ctla - 4 , il - 18 , vdr , tap2 , il - 12 , and cd4 genes and t1 dm . the following genes showed significant association with t2 dm : haptoglobin , paraoxonase , leptin , tcf7l2 , calreticulin , er , ppar - 2 , cxcl5 , calpain - 10 , irs - 1 and 2 , gstm1 , kcnj11 , enos , vdr , resistin , insr , ace , apoa - i , adiponectin , and ptpn1 . in assessment of association between cad and diabetes in iranian population the following genes showed significant association : paraoxonase 1 , adiponectin , enos , cetp , at1r , resistin , mmp - 3 , bche k , apo e , ace . the following genes had significant association with diabetic nephropathy : enos , at2r , sumo4 , il - 10 , vegf , mthfr , ace , and vdr . the following genes had significant association with diabetic retinopathy : gstm1 and vegf and also vegf had significant association with diabetic foot ulcer . insufficient data might cause the conflicting results ; therefore gwas on defined population with large sample size is suggested as a more comprehensive approach answering many more questions .\noutput:\n" }, { "from": "agent", "value": "introduction . diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors . in this systematic review , we assessed the association between genetic variants and diabetes / its complications in studies with iranian populations . methods . google scholar , pubmed , scopus , and persian web databases were systematically searched up to january 2014 . the search terms were gene , polymorphism , diabetes , and diabetic complications ; nephropathy , retinopathy , neuropathy , foot ulcer , and cad ( coronary artery diseases ) ; and persian equivalents . animal studies , letters to editor , and in vitro studies were excluded . results . out of overall 3029 eligible articles , 88 articles were included . we found significant association between ctla - 4 , il - 18 , vdr , tap2 , il - 12 , and cd4 genes and t1 dm , hnf and mody , haptoglobin , paraoxonase , leptin , tcf7l2 , calreticulin , er , ppar - 2 , cxcl5 , calpain - 10 , irs - 1 and 2 , gstm1 , kcnj11 , enos , vdr , insr , ace , apoa - i , apo e , adiponectin , ptpn1 , cetp , at1r , resistin , mmp - 3 , bche k , at2r , sumo4 , il - 10 , vegf , mthfr , and gstm1 with t2 dm or its complications . discussion . we found some controversial results due to heterogeneity in ethnicity and genetic background . we thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in iranian populations ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: dialysis requires more self - management than any other medical treatment to control risk factors associated with increased mortality . a patient starting dialysis , aged 60 years , may be informed that they have a 50 % chance of surviving five years , but observational studies suggest this can be improved by controlling intake of fluids , salt , fat , phosphate , and potassium , attending regularly for dialysis , monitoring blood pressure , cholesterol , phosphate , and haemoglobin , and taking prescribed medication to control these factors , plus weekly injections to improve haemoglobin . few people are able to understand and manage all aspects simultaneously , and their relative importance is unknown . meaningful discussion between clinician and patient about these issues , and phosphate control in particular , is currently not possible and unsurprisingly adherence to prescribed regimens is poor . we will address the significance of one risk factor for mortality in dialysis patients serum phosphate to facilitate and inform future patient - clinician discussions and enhance the shared decision making process . serum phosphate increases in chronic kidney disease and by the time the patients are on dialysis , high serum phosphate is found in more than 40 % of dialysis patients and is linked with a 40100 % increased mortality risk in retrospective , observational studies .27 observational studies were included in a meta - analysis which examined the relationship between dysregulated mineral metabolism and all - cause or cardiovascular mortality or cardiovascular events in patients with chronic kidney disease ( ckd ) or end - stage renal disease ( esrd , which is when they need to start dialysis treatment ) . though there were limitations in the analysis noted by the authors due to the low number of studies included and the quality of the data obtained from them , a greater risk of all - cause and cardiovascular mortality was seen with elevated phosphate concentrations . the dialysis outcomes and practice patterns study ( dopps ) , a prospective cohort study in 25,588 patients with esrd receiving haemodialysis , showed an increased risk of cardiovascular mortality with serum phosphate concentrations of 5.15.5 mg / dl ( 1.61.78 mmol / l ) and an increase in all - cause mortality at serum concentrations over 6.0 mg / dl ( 1.94 mmol / l ) . it is recognised that such studies are useful for generating research hypotheses but can not definitively establish cause / effect relationships . consequently it is believed important to control phosphate , but whether this improves patient outcomes remains unknown , since no randomised interventional trials have been undertaken . dietary control and dialysis are insufficient to normalise phosphate , and tablets are required to bind phosphate in the gut . the available phosphate binders can be broadly classified into calcium containing phosphate binders like calcium carbonate and calcium acetate and non - calcium containing binders like lanthanum ( fosrenol trade name ) and sevelamer ( renvela and renagel trade names for sevelamer carbonate and sevelamer hydrochloride , resp . ) and aluminium containing and iron containing phosphate binders . this classification is important because several small interventional randomised controlled trials have looked at difference in clinical outcomes between calcium containing phosphate binders and the common non - calcium containing ones like lanthanum and sevelamer . jamal et al . published a meta - analysis of 11 such studies , 9 of them in dialysis patients , and compared outcomes between patients with chronic kidney disease taking calcium - based phosphate binders and those taking non - calcium - based binders . they concluded that non - calcium - based phosphate binders were associated with a decreased risk of all - cause mortality compared with calcium - based phosphate binders in patients with chronic kidney disease . multiple clinical trials have further shown an increase in coronary artery calcification with calcium - based binders compared to non - calcium - based binders . there is an increasing acceptance among clinicians that calcium containing phosphate binder is not optimum therapy and has resulted in greater use of non - calcium containing binders which are ten times more expensive than the calcium containing binders . a study of patients ' perspectives of phosphate binding medication identified gaps in understanding of the concept of phosphate control and the role of medication . even when binders are taken correctly , achieving normal phosphate levels is difficult , and more than 25 % of patients remain above the current opinion - based target range of 1.11.7 mmol / l , and more than 40 % are above the true normal limit of 1.4 , there is a significant gap between the recommendations and the serum phosphate concentrations achieved by patients in clinical practice . the important contributing causes to the lack of effective phosphate control are nonadherence to a low phosphate diet and to phosphate binder medication . despite the investment in expensive binder medication ( up to 3,000 per patient / per annum , 30 % of the 27000 prevalent dialysis patients in uk , works out to more than 24 m per annum ) and large pill burden ( up to 15 pills with meals daily in some cases ) with significant gastrointestinal side - effects , we do not know if lowering serum phosphate is of benefit . a review of all available evidence by the international kidney disease improving global outcomes ( kdigo ) expert group concluded , the extensive review exposed significant gaps in our knowledge robust studies of a large sample size addressing the following issues should be given priority : does lowering phosphateour trial will examine the feasibility of conducting such a study of large sample size , which we hope will ultimately answer the questions posed by kdigo . the primary endpoint is the percentage of study participants achieving , and being maintained within , the higher and lower target ranges for phosphate , over the duration of the maintenance phase of the study . the secondary endpoints are the following : percentage of greater manchester kidney physicians agreeing to enter patients into a study which includes a higher range group.percentage of eligible invited participants willing to be randomised into a study which includes a higher range group.percentage of participants achieving consistent control of serum phosphate in each group over a 10 - month maintenance period.drop - out rate from the study due to adverse events , kidney transplantation , intercurrent illness , and death . these numbers will inform the power calculation for the larger national study.pill burden per participant required to control serum phosphate.adherence to therapy.number of participants willing to participate in communicare patient support programme.mean symptom score assessed by pittsburgh dialysis symptoms index.incidence of major vascular events , defined as nonfatal myocardial infarction or any cardiac death , any stroke , or any arterial revascularisation excluding dialysis access procedures ( expected mortality of around 14 % per annum in patients on dialysis ) . percentage of greater manchester kidney physicians agreeing to enter patients into a study which includes a higher range group . percentage of eligible invited participants willing to be randomised into a study which includes a higher range group . percentage of participants achieving consistent control of serum phosphate in each group over a 10 - month maintenance period . drop - out rate from the study due to adverse events , kidney transplantation , intercurrent illness , and death . incidence of major vascular events , defined as nonfatal myocardial infarction or any cardiac death , any stroke , or any arterial revascularisation excluding dialysis access procedures ( expected mortality of around 14 % per annum in patients on dialysis ) . the design is a dual - centre , pan - manchester prospective randomised parallel group study , with titration to target ( 2 months ) and maintenance phase ( 10 months ) . the total number of participants planned is 100 at randomisation ( up to 300 at consent ) . the study will be conducted across two large renal units in greater manchester which cover a population of about 3.2 million . prevalent dialysis patients will be recruited from the renal units and their associated satellite dialysis units which give a target dialysis population of about 1100 patients with 900 patients on haemodialysis . documented approval has been obtained from appropriate ethics committee and the cmft research and development department . the study conforms to international conference on harmonization of good clinical practice guidelines and with the declaration of helsinki . written informed consent will be obtained from each patient before any study - specific procedure takes place . participation in the study and date of informed consent of patients will be documented appropriately in each patient 's files . safety monitoring committee is in place to review saes as is trial steering committee to review progress and trial management committee to oversee the conduct of the trial . the medical records of all the dialysis patients in the greater manchester area will be accessed by the study personnel that are also a part of the direct care team ( some study personnel will be members of the direct care team ) . a retrospective screening of their previous serum phosphate levels ( which would have been done as part of their routine monthly blood tests ) will be completed . patients with a mean level of 1.4 mmol / l over the past 3 months , and taking an oral phosphate binder , will be identified and flagged up . inclusion criteria are as follows : male and female patients aged 30 years or above , on dialysis for at least 6 months ( to ensure no recovery of renal function ) , and under the supervision across pan - manchester sites . patientsless than 30 years of age have a low rate of vascular events and will not be recruited.serum phosphate level of 1.7 mmol / l or greater after wash - out ( discontinuation ) of previous phosphate binding medication.able to achieve renal association standards for quality of dialysis on the most recent test of dialysis efficacy . this would be a urea reduction ratio of 65 % . able to communicate in english because communicare package ( the package is explained in treatments ) is currently available only in english.able to consent . male and female patients aged 30 years or above , on dialysis for at least 6 months ( to ensure no recovery of renal function ) , and under the supervision across pan - manchester sites . patientsless than 30 years of age have a low rate of vascular events and will not be recruited . serum phosphate level of 1.7 mmol / l or greater after wash - out ( discontinuation ) of previous phosphate binding medication . able to achieve renal association standards for quality of dialysis on the most recent test of dialysis efficacy . able to communicate in english because communicare package ( the package is explained in treatments ) is currently available only in english . exclusion criteria are as follows : living donor renal transplant planned in the next 12 months.serum parathyroid hormone greater than 800 pg / ml ( 85 pmol / l ) on 2 consecutive 2 - or 3 - monthly blood tests . such patients probably have uncontrolled hyperparathyroidism which adversely influences serum phosphate levels and needs treatment in its own right.known intolerance of both oral sevelamer and lanthanum carbonate.medical history that might limit the individual 's ability to take the trial treatments for the duration of the study ( e.g. , history of cancer other than nonmelanoma skin cancer or recent history of alcohol or substance misuse ) . living donor renal transplant planned in the next 12 months . serum parathyroid hormone greater than 800 pg / ml ( 85 pmol / l ) on 2 consecutive 2 - or 3 - monthly blood tests . such patients probably have uncontrolled hyperparathyroidism which adversely influences serum phosphate levels and needs treatment in its own right . medical history that might limit the individual 's ability to take the trial treatments for the duration of the study ( e.g. , history of cancer other than nonmelanoma skin cancer or recent history of alcohol or substance misuse ) . prior to randomisation , the number of potentially eligible participants will be identified ( medical records ) and each will be sent the participant information sheet with an invitation to attend a screening clinic appointment . written informed consent will be sought from those who attend the appointment and are willing to participate ( 3 weeks ) . they will undergo an assessment of adherence at baseline using modified basel assessment of adherence scale for immunosuppressives ( baasis ) . patients whose average serum phosphate is more than or equal to 1.7 mmol / l despite ongoing therapy with phosphate binders will be randomised . patients whose average serum phosphate is less than 1.7 mmol / l , and who are taking phosphate binders , will enter a 3 - to 5 - week wash - outperiod from their previous phosphate binder and receive standard dietary advice from a renal dietician . serum lipids will be measured and treated according to uk renal association guidelines with a statin and / or ezetimibe . equivalent lipid levels would be required in the larger definitive trial to exclude the possibility of this influencing mortality . this is because two non - calcium containing phosphate binders , sevelamer and colestilan ( bindren trade name ) , also reduce serum cholesterol . sevelamer has been observed to reduce absorption of advanced glycated end - products , bacterial toxins , and bile acids , suggesting that it may reduce inflammatory , oxidative , and atherogenic stimuli in addition to its lowering of serum phosphate . provided that serum phosphate level rises to greater than or equal to 1.7 mmol / l after wash - out , each participant will be randomised to either the lower range ( lrg ) or higher range ( hrg ) phosphate group . this minimises the possibility of an individual being randomised to hrg but whose phosphate level will not reach 1.7 mmol / l . those randomised to lrg will undergo a stepped approach to aid achievement of the lower range phosphate target . the treatment for each study visit is summarised in table 1 . during each of their dialysis sessions in the first week after randomisation , participants will be given access to , and encouraged to utilise , the communicare online patient adherence support programme . this comprises a patient questionnaire , developed by the london school of behavioural science , which highlights individual patient information needs and concerns related to taking phosphate binding medication . questionnaire results give participants access to online tailored , personalised ( but reproducible and standardised ) information orinfo bytes to help address the concerns they have about taking phosphate binding medication . the package also provides training for the study staff to enable them to discuss phosphate control knowledgeably with participants . there is a paper version of the communicare package which can also be used . the lrg participants will be able to access the communicare online support programme at any time but will be specifically encouraged to do so again during dialysis session in month 4 and month 8 . they will recommence oral phosphate binding medication with either lanthanum carbonate or sevelamer ( either carbonate or hydrochloride ) , titrated on a weekly basis with meals to achieve serum phosphate of 0.8 to 1.4 since sevelamer reduces serum lipid levels , those individuals taking a statin for cholesterol reduction may require dose adjustment . the dose adjustment of statin will be completed by the study clinicians according to their clinical judgement , with a view to maintaining the serum cholesterol according to the standards set by the renal association . this is a validated questionnaire which we have modified to reflect phosphate binders instead of immunosuppressants . this questionnaire has been validated in kidney transplant patients on immunosuppressive medications and in hiv patients who are on antiretroviral medications . both of these groups need to take their medications on a regular timely basis . this criterion applies to the administration of phosphate binders which need to be taken regularly and with each meal to be effective . all patients will have their adherence assessed at baseline ; only the patients randomised to the lrg will continue to have their adherence assessed once every 4 weeks . those randomised to hrg will recommence oral phosphate binding medication in the weeks following randomisation , with either lanthanum carbonate or sevelamer , titrated on a weekly basis to achieve a serum phosphate level of 1.82.4 mmol / l . the participants will have a range of licensed phosphate binding medication to choose from chewable tablets ( lanthanum fosrenol ) , tablets to be swallowed ( sevelamer renvela , renagel ) , and granules that can be mixed with water and consumed ( fosrenol , renvela ) as first - line therapy . changes to the phosphate binders and the cholesterol medications during the study will be documented in a drug dosing diary which will be carried by the patient . phosphate in all participants will be monitored on a monthly basis from week 8 onwards , with medication adjustments as necessary to maintain results within range . all haemodialysis patients have blood taken routinely for biochemical and haematological measurements on a monthly basis ; attempts will be made to ensure that the study blood tests coincide with the routine monthly blood tests ; this ensures a reduction in the number of additional blood tests required by this study during the maintenance phase . a blood sample will be collected at the consent visit , at randomisation , and every 12 weeks thereafter to measure the serum level of parathyroid hormone ( pth ) . all dialysis patients have this blood test once every three months as part of routine clinical care . efforts will be made to ensure that the study blood test coincides with their routine test to minimise the number of extra blood tests . participants will be asked to gift an extra 5 ml of blood with every blood sample collected for parathyroid hormone . this will be stored in the biobank at the renal research laboratories , manchester royal infirmary , for future biomarker analysis . all participants will complete the pittsburgh dialysis symptoms index again at month 6 and month 12 ( study end ) . oral vitamin d dosage will be altered if necessary to ensure good control of serum calcium pth . they will be commenced on one of the two non - calcium containing phosphate binders determined by their preference ( chewable , swallowed , and granules ) . the dosage of the medication will be increased once a week during the titration phase . the changes to drugs and dosages done as part of the study will be recorded in a drug dosing diary which the patient will carry . phosphate binders are prescribed in daily doses divided according to the estimated phosphate content of the meals . for some patients , this is three equal doses , whilst for others it might be two different daily doses . standard practice is for this advice to be given by the prescribing physician or by a renal dietician . the dosing schedule shown in table 3 is only a guide and the phosphate binders can be dosed according to clinician judgement . it is expected that many patients in the hrg will not require a phosphate binder . however , at any stage during the study , oral non - calcium containing phosphate binder will be introduced if the serum phosphate level exceeds the upper limit of 2.4 mmol / l . the intention would be to reduce and stabilise the phosphate level within the specified range of 1.72.4 mmol / l . table 4 outlines the titration regime , but if a patient 's serum phosphate exceeds 2.4 mmol / l for the first time during , for example , week 4 , then they should commence titration at that point . therefore this table describes titration steps rather than study weeks . the participants in both of the groups are allowed to switch their phosphate binding medication at any stage in the study to one of the other non - calcium containing formulations . they will then be changed to their trial phosphate binding medication of choice at a dose determined by the trial physicians . the target is to achieve the desired range of serum phosphate with a dose and combination that is convenient to the patient in order to encourage adherence . the dose of the study medications can be altered to maintain the serum phosphates in the desired range in the maintenance period on a monthly basis , according to the discretion of the study clinicians . no formal sample size calculation has been conducted given the exploratory and evaluative nature of the study . we will randomise 100 patients in total to the lower range group and higher range group . assuming an overall attrition rate of 25 % at 12 months , 75 patients will complete the data - monitoring period . this will be sufficient to allow the monitoring of logistical aspects of this study ( such as recruitment , randomisation , and attrition ) . detailed statistical evaluation will not be undertaken , and therefore the sample size is chosen to be representative of the manchester dialysis population ( 1100 in total ) . it will be large enough to address the outcome measures but small enough to facilitate timely recruitment and follow - up . we will be able toestimate a confidence interval for the proportion of patients achieving consistent control of serum phosphate in each group , estimate the major cardiovascular event ( including death ) rate and a confidence interval for this parameter , observe and record time - to - event data . estimate a confidence interval for the proportion of patients achieving consistent control of serum phosphate in each group , estimate the major cardiovascular event ( including death ) rate and a confidence interval for this parameter , observe and record time - to - event data . these calculations will help to inform the sample size calculation for a multicentre randomised controlled trial , for which mortality and cardiovascular event rate are expected to be the primary outcome measures but only if sufficient events are observed . we will also monitor and summarise recruitment and attrition rates and collect data on reasons for study withdrawal . table 5 gives a list of assessment measures used for the different endpoints in the study . this study will inform design of a large definitive trial of the effect of phosphate on mortality and cardiovascular events in dialysis patients , starting 2016/17 . if reduction of phosphate improves life expectancy , then both clinicians and patients will be better informed and will be able to address this issue more certainly and appropriately , despite current drawbacks of phosphate binding medication . the time , inconvenience , and expense associated with phosphate control would be justified . if there is no benefit to reducing phosphate to a prespecified range , then patients may be relieved of the burden of excessive binding medication and side - effects . savings from reduced prescriptions could be redirected to develop other methods believed to improve patients ' quality and quantity of life , for example , increased provision of home dialysis therapies , with benefits to nhs capital / revenue expenditure . a study which could definitively show a cause - effect relationship between serum phosphate levels and clinical outcomes like mortality and cardiovascular events will be a game - changer in the management of dialysis patients .\noutput:\n" }, { "from": "agent", "value": "background . retrospective , observational studies link high phosphate with mortality in dialysis patients . this generates research hypotheses but does not establish cause - and - effect . a large randomised controlled trial ( rct ) of about 3000 patients randomised 50 : 50 to lower or higher phosphate ranges is required to answer the key question : does reducing phosphate levels improve clinical outcomes ? whether such a trial is technically possible is unknown ; therefore , a study is necessary to inform the design and conduct of a future , definitive trial . methodology . dual centre prospective parallel group study : 100 dialysis patients randomized to lower ( phosphate target 0.8 to 1.4 mmol / l ) or higher range group ( 1.8 to 2.4 mmol / l ) . non - calcium - containing phosphate binders and questionnaires will be used to achieve target phosphate . primary endpoint : percentage successfully titrated to required range and percentage maintained in these groups over the maintenance period . secondary endpoints : consent rate , drop - out rates , and cardiovascular events . discussion . this study will inform design of a large definitive trial of the effect of phosphate on mortality and cardiovascular events in dialysis patients . if phosphate lowering improves outcomes , we would be reassured of the validity of this clinical practice . if , on the other hand , there is no improvement , a reassessment of resource allocation to therapies proven to improve outcomes will result . trial registration number . this trial is registered with isrctn registration number isrctn24741445 ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: regional anaesthesia ( spinal anaesthesia ) is widely used as a safe anaesthetic technique for both elective and emergency operations . shivering is known to be a frequent complication , reported in 40 to 70 % of patients undergoing surgery under regional anaesthesia shivering is a potentially serious complication , resulting in increased metabolic rate ; increased oxygen consumption ( up to 100 - 600 % ) along with raised carbon dioxide ( co2 ) production ; ventilation and cardiac output ; adverse postoperative outcomes , such as wound infection ; increased surgical bleeding ; and morbid cardiac events . it causes arterial hypoxemia , lactic acidosis , increased intraocular pressure ( iop ) , increased intracranial pressure ( icp ) ; and interferes with pulse rate , blood pressure ( bp ) and electrocardiographic ( ecg ) monitoring . shivering is very unpleasant , physiologically stressful for the patient undergoing surgery , and some patients find the accompanying cold sensation to be worse than the surgical pain . though the mechanism of origin of shivering is not clear , various hypotheses have been proposed to explain its occurrence . perioperative hypothermia is the primary cause , which occurs due to neuraxial anaesthesia - induced inhibition of thermoregulatory mechanism . shivering occurs as a thermoregulatory response to hypothermia or muscle activity with tonic or clonic patterns , and various frequencies have been noticed . however , in the postoperative period , muscle activity may be increased even with normothermia , suggesting that mechanisms other than heat loss with subsequent decrease in the core temperature contribute to the origin of shivering . these may be uninhibited spinal reflexes , sympathetic over - activity , postoperative pain , adrenal suppression , pyrogen release and respiratory alkalosis . moreover , shivering per se may aggravate postoperative pain , simply by stretching of surgical incision . there are various methods available to control shivering during anaesthesia , which include non - pharmacological methods and pharmacological methods using drugs which have anti - shivering properties . non - pharmacological methods using equipment to maintain normal temperature of the body are effective but expensive and lack practicality , while the pharmacological methods using drugs like pethedine , tramadol , clonidine , doxapram , katenserin , nefopam , etc . , are simple , cost - effective and easy to implement . the aim of this prospective double - blind randomized clinically controlled study was to clinically compare the efficacy , potency , haemodynamic effects , complications and side effects of clonidine with those of tramadol for control of shivering . after obtaining approval of the ethics committee and written informed consent , 80 american society of anaesthesiologists grade - l ( asai ) patients ( power of study , 70 % ) of either sex aged 18 to 40 years scheduled for elective abdominal , orthopaedic and gynaecological surgeries , e.g. , inguinal herniorraphy , abdominal and vaginal hysterectomy , k - nailing , dynamic hip screw ( dhs ) , under spinal anaesthesia with no prior pre - medication , were included in this prospective double - blind randomized clinically controlled study . patients with known hypersensitivity to clonidine and tramadol , known history of alcohol or substance abuse , hyperthyroidism , cardiovascular diseases , psychological disorder , severe diabetes or autonomic neuropathies and urinary tract infection ( uti ) were excluded . all patients who developed post - spinal anaesthesia intraoperative shivering were randomly allocated to two groups : group c ( n = 40 ) received clonidine 0.5 g / kg ( intravenously ) iv , and group t ( n = 40 ) received tramadol 0.5 mg / kg iv . anaesthesiology personnel who were not involved in the study made the trial preparations and recorded group randomization separately . the anaesthesiologists conducting the case and recording the data were unaware of the preparation administered . bupivacaine 0.5 % ( 10 - 15 mg ) at l3 - 4 or l4 - 5 interspace using 25 gauge quincke 's needle , and blockage up to t9 - 10 dermatome was achieved . all operation theatres in which the operations were performed maintained constant humidity ( 70 % ) and an ambient temperature of around 21c to 23c . oxygen was administered to all the patients of both groups at a rate of 5 l / min with face mask , and patients were covered with drapes but not actively warmed . preloading was not done in both the groups as we did not want intravenous fluid to influence the onset of shivering mechanism . standard monitoring of pulse rate was done , and non - invasive blood pressure ( nibp ) , oxygen saturation ( spo2 ) , body temperature ( axillary ) were recorded before the commencement of surgery and thereafter at every 5 minutes from the baseline ie subarachnoid block ( sab ) , for 1 hour ; and every 15 minutes , for the rest of the observation period . grading of shivering was done as per wrench , which is as follows : grade 0 : no shivering grade 1 : one or more of the following : piloerection , peripheral vasoconstriction , peripheral cyanosis with , but without visible muscle activity grade 2 : visible muscle activity confined to one muscle group grade 3 : visible muscle activity in more than one muscle group grade 4 : gross muscle activity involving the whole body patients who developed either grade 3 or grade 4 of shivering were included in the study . the attending anaesthetist recorded the time in minutes at which shivering started after spinal anaesthesia ( onset of shivering ) , severity of the shivering , time to disappearance of shivering ( in minutes ) and response rate ( shivering ceased after treatment in 15 minutes ) . duration of surgery was noted , and duration of spinal anaesthesia was recorded by assessing spontaneous recovery of sensory block using pin - prick method and observing spontaneous movements of limbs in the postoperative period . if the shivering did not subside by 15 minutes , the treatment was considered to be not effective . patients who did not respond or in whom recurrence of shivering occurred were treated with additional dose of clonidine ( 0.5 g / kg iv ) or tramadol ( 0.5 mg / kg iv ) in the respective groups , if required . side effects like nausea , vomiting , bradycardia ( 50 / min ) , hypotension ( 20 % of baseline ) , dizziness ; and sedation score were recorded . sedation score was assessed with a four - point scale as per filos : 1 : awake and alert2 : drowsy , responsive to verbal stimuli3 : drowsy , arousable to physical stimuli4 : unarousable drowsy , responsive to verbal stimuli drowsy , arousable to physical stimuli bradycardia , hypotension and vomiting were treated with atropine , mephenteramine and metaclopramide , respectively , in titrated doses when required . statistical analysis was done using suitable statistical software , and student t test and chi - square test were applied for the interpretation of results . a total of 80 patients were enrolled in the present study and were randomized into two groups of 40 each ( n = 40 ) , 57 of whom were male and 23 were female [ table 1 ] . both the groups were comparable with respect to age , sex , weight , duration of surgery , type of surgery , volume of intravenous fluid administered and the duration of spinal block . the mean age of the patients in group c was 30.033.80 years ; and patients in group t , 28.83.47 years ( p = .137 ) [ table 1 ] . demographic data of patients in the two groups shivering disappeared in 39 ( 97.5 % ) patients who received clonidine and 37 ( 92.5 % ) who received tramadol [ table 2 ] . both the drugs were found to be effective in reducing shivering . however , severity of shivering was unchanged in 1 ( 2.5 % ) patient of group c and 3 ( 7.5 % ) patients of group t. one patient in group c ( severity of shivering unchanged ) and 5 patients ( 3 - severity of shivering unchanged ; 2 - recurrence of shivering ) in group t were given rescue doses of clonidine or tramadol , respectively . six ( 7.5 % ) patients out of a total of 80 patients received rescue doses . post - spinal anaesthesia shivering and responses the mean interval between the injection of drug ( clonidine and tramadol ) and the complete cessation of shivering was 2.540.76 and 5.011.02 minutes , respectively ( p = .0000001 ) . time for onset of shivering and severity of shivering were not statistically significantly different between the two groups . however , the time interval between administration of drug after onset of shivering and disappearance of shivering was significantly shorter in the clonidine group [ table 2 ] ( p = .0000001 ) . there was no statistically significant difference with respect to heart rate , mean blood pressure , axillary temperature and oxygen saturation between the two groups . complication rates were significantly higher in group t than in group c [ table 3 ] . nausea , vomiting and dizziness were higher in group t [ nausea - 31 ; vomiting - 8 ; and dizziness - 22 ) than in group c. more patients of group c ( 10 patients ) were sedated than of group t ( 5 patients ) . complications in both groups bradycardia occurred in 2 patients of group c and 1 patient of group t. in group c , 3 patients suffered from hypotension , and 1 patient complained of dry mouth , both of which were not present in group t [ table 3 ] . regional anaesthesia , either central neuraxial block or peripheral nerve block , is a safe and very popular technique used for various surgeries . however , 40 % to 70 % of patients undergoing regional anaesthesia develop shivering , though it is also found to occur after general anaesthesia . the mechanism which leads to shivering afterregional anaesthesia is not very clear , but the probable mechanisms could be decrease in core body temperature secondary to sympathetic block ; peripheral vasodilatation ; increased cutaneous blood flow , which leads to increased heat loss through skin ; cold temperature of operation theatre ; rapid infusion of cold iv fluids ; and effect of cold anaesthetic drugs upon the thermosensitive receptors in the spinal cord . there are many non - pharmacological and pharmacological methods used to prevent heat loss and decrease shivering . non - pharmacological methods include radiant heat warmers , warming the operation theatre , blankets , warm iv fluids and using anaesthetic drugs at body temperature . the present study was designed to standardise these possible compounding factors , while reflecting the common practice in our institution . the factors that influence the occurrence of shivering , like temperature of iv fluids and drugs , were not tightly controlled , but this should not affect the validity of our study because the present study is focused on response to treatment used rather than incidence of shivering ; and by randomization , both groups were subjected to similar degrees of influence of these factors . pharmacological methods to treat shivering include pethedine , tramadol , doxapram , ketanserin , nefopam , alfentanyl , doxapram , etc . a limitation of this study is that we could not measure the core body temperature . for measurement of core body temperature , the probe needs to be put in the oesophagus or near the tympanic membrane . rectal temperature monitoring was a possibility but was not tried . in the present study , we compared the efficacy of clonidine and tramadol for treatment of shivering after spinal anaesthesia in patients undergoing various elective surgeries . clonidine exerts its anti - shivering effects at three levels : hypothalamus , locus coeruleus and spinal cord . at the hypothalamic level , it decreases thermoregulatory threshold for vasoconstriction and shivering , because hypothalamus has high density of 2 adenoceptors and hence is effective in treating the established post - anaesthetic shivering . it also reduces spontaneous firing in locus coeruleus a pro - shivering centre in pons . at the spinal cord levelclonidine is highly lipid - soluble and easily crosses the blood - brain barrier . due to these merits , interaction at the 2 adrenoreceptors at spinal and supraspinal sitestramadol is an opioid analgesic with opioid action preferably mediated via ( mu ) receptor with minimal effect on kappa and delta binding sites . the anti - shivering action of tramadol is probably mediated via its opioid or serotonergic and noradrenergic activity or both . in the present study , we found that clonidine is as effective as tramadol in treating post spinal anaesthesia shivering , but the time interval from the commencement of treatment to cessation of shivering is quite less with clonidine ( 2.540.76 minutes ) than with tramadol ( 5.031.02 minutes ) ( p = .0000001 ) . the response rate was also higher in the clonidine group than in tramadol group , but the difference was not statistically significant ( p = .03 ) . the complications were found to be higher in case of tramadol compared to clonidine . in the present study , similar differences were noted between the two groups in relation to vomiting and dizziness . in case of group c , 10 ( 25 % ) patients had sedation of grade 2 ; while in group t , it was 5 ( 12.5 % ) patients who had sedation . one patient of group c had dry mouth , which was not present in group t. two patients of group t had recurrence of shivering in postoperative period , while no patient in clonidine group suffered recurrence of shivering . these findings were similar to the findings of other researchers who compared clonidine with other drugs having anti - shivering properties . bradycardia occurred in 2 patients of group c , while 1 patient of group t suffered from bradycardia . hypotension occurred in 3 patients of group c. on overall analysis , higher complication rates were noted in group t patients compared to group c patients . it was noted in the present study that clonidine was quicker than tramadol in providing relief in shivering . zavaherforoush et al . compared clonidine with pethedine and fentanyl for treating post spinal anaesthesia shivering in elective lower segment caesarean section ( lscs ) and also found it to be offering better thermodynamics than pethedine . the present study also found that the patients who received clonidine were more sedated than the patients in the other group . in conclusion , both clonidine ( 0.5 g / kg ) and tramadol ( 0.5 mg / kg ) effectively treated patients with post spinal anaesthesia shivering , but tramadol took longer time to achieve complete cessation of shivering than clonidine , the difference being statistically significant . so we conclude that clonidine offers better thermodynamics than tramadol , with fewer side effects . the more frequent incidence of side effects of tramadol , like nausea , vomiting and dizziness , may limit it 's use as an anti - shivering drug . further studies are needed to compare the effectiveness of various drugs in the treatment of shivering in patients undergoing surgery under spinal anaesthesia .\noutput:\n" }, { "from": "agent", "value": "the aim of this study was to evaluate the efficacy , potency and side effects of clonidine as compared to tramadol in post spinal anaesthesia shivering . in this prospective double - blind randomized controlled clinical trial , 80 american society of anaesthesiologists grade - l ( asai ) patients aged between 18 and 45 years scheduled for various surgical procedures under spinal anaesthesia , who developed shivering were selected.the patients were divided into two groups : group c ( n = 40 ) comprised of patients who received clonidine 0.5 mg / kg intravenously ( iv ) and group patients who received tramadol 0.5 mg / kg iv . grade of shivering , disappearance of shivering , haemodynamics and side effects were observed at scheduled intervals . disappearance of shivering was significantly earlier in group c ( 2.540.76 ) than in group t ( 5.011.02 ) ( p = .0000001 ) . response rate to treatment in group c was higher ( 97.5 % ) than in group t ( 92.5 % ) , but the difference was not significant . nausea , vomiting and dizziness were found to be higher in group t ( p = 0.001 , 0.005 , 0.001 , respectively ) , while the patients in group c were comparatively more sedated ( sedation level , 2 ; group c , 25 % ) . we conclude that clonidine gives better thermodynamics than tramadol , with fewer side effects ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: this study was a two - arm parallel randomized controlled trial based at the diabetes antenatal clinic of the royal prince alfred hospital , camperdown , australia . with the exception of the study dietitian ( j.c.y.l . ) , who provided the dietary education , all study personnel and participants were blinded to dietary assignment . women aged 1845 years diagnosed with gdm by a 75 - g oral glucose tolerance test at 2032 weeks gestation , with an otherwise healthy singleton pregnancy , were eligible for the study . gdm diagnosis was based on the modified australasian diabetes in pregnancy society ( adips ) criteria : fasting blood glucose level ( bgl ) 5.5 mmol / l , 1 - h bgl 10.0 mmol / l , or 2 - h bgl 8.0 most women were tested at 2632 weeks , but testing occurred earlier in those at high risk . women who had special dietary requirements ( including vegetarianism / veganism ) , preexisting diabetes , or pregnancy achieved by assisted reproduction and those who smoked or consumed alcohol during pregnancy were excluded . a total of 482 women were approached between september 2008 and november 2010 , of whom 99 met the inclusion criteria and agreed to participate . the enrolled subjects were centrally randomized to study diet by computer - generated random numbers , stratified by bmi ( bmi 30 vs. 30 kg / m ) and weeks of gestation ( 28 or 28 weeks ) . participants received routine gdm care regardless of dietary assignment , including instructions to monitor bgl before breakfast and 1 h after meals . the treating endocrinologist ( t.p.m . or n.p . ) reviewed the subjects every 24 weeks prior to 36 weeks and then every week until delivery . insulin treatment was commenced if the mean fasting bgl or 1 - h postprandial bgl in the preceding week exceeded 5.2 and 7.5 mmol / l , respectively . at enrollment , demographic information , subjects were asked to recall their prepregnancy weight , were weighed , and were asked to complete a 3 - day food record ( including 2 weekdays and 1 weekend day ) at baseline and again at 3637 weeks gestation . a two - dimensional food model booklet was provided to the subjects to assist in portion size estimation . subjects were randomized to one of two healthy diets of similar protein ( 1525 % ) , fat ( 2530 % ) , and carbohydrate ( 4045 % ) content one with an lgi ( target gi 50 ) and the other with a high - fiber content and moderate gi , similar to the australian population average ( hf ) ( target gi 60 ) ( 1315 ) . both study diets provided all essential nutrients for pregnancy other than iron and iodine , which were supplemented as appropriate by the treating endocrinologist . the baseline 3 - day food diary provided information on baseline dietary composition and served as the basis of individualized dietary counseling . sample menus and their nutritional analyses are given in supplementary table a1 . subjects attended at least three face - to - face visits with the study dietitian , scheduled to coincide with regular antenatal visits . a 24 - h recall of all food and drink intake was conducted during each session to assess compliance . in the case of noncompliance , food sample baskets containing key foods for the assigned diet were provided to promote product recognition and dietary adherence . pregnancy outcomes , including birth weight , infant length , infant head circumference , and the need for emergency caesarean section , were obtained from the electronic medical records system . birth weight centile was calculated using a macro program for microsoft excel ( available from http://www.gestation.net ) that adjusted for ethnic differences ( 16 ) . the calculated birth weight centile was used to categorize the infant as small for gestational age ( birth weight 10th centile ) , normal , or lga ( birth weight 90th centile ) . ponderal index , an estimate of neonatal adiposity , was calculated as birth weight in kg infant length ( m ) . the study dietitian entered the food records into australian nutrition analysis software based on ausnut2001 ( foodworks professional 2009 ; xyris software , brisbane , australia ) . the gi of individual food items was assigned according to a published method ( 17 ) . dietary glycemic load ( gl ) was calculated as follows : gi available carbohydrate of each food in a day / 100 . dietary gi was calculated as follows : ( dietary gl / total daily available carbohydrate ) 100 . subjects were deemed compliant if their final dietary gi was 50 in the lgi group and 50 in the hf group . based on previous data , the study was designed to provide 80 % statistical power to detect an 260 g difference in birth weight , with 60 subjects in each group . recruitment was halted at 99 subjects because the sd in birth weight among the study population was smaller than expected . in the primary analysis , the observed sd of 416 g in birth weight provided 80 % power to detect a group difference of 246 g in birth weight or an 17 % point difference in birth weight centile . the primary analysis included all women randomized who attended at least one dietary education session but excluded those with preterm delivery ( 37 weeks ; n = 4 ; two from each group ) regardless of compliance . all statistical analyses were performed with spss ( version 19 ; ibm australia , st . results for continuous data are reported as mean sd or mean sem , and categorical data ( e.g. , need for insulin ) are reported as percentage . pearson test was used to test for differences between groups for categorical data , and continuous data were tested using one - way anova . a paired t test was used to assess within - group changes from baseline to final outcomes . the study was conducted according to the guidelines laid down in the declaration of helsinki , and all procedures involving human subjects / patients were approved by the human research ethics committee of the sydney south west area health service ( royal prince alfred hospital zone ) . women aged 1845 years diagnosed with gdm by a 75 - g oral glucose tolerance test at 2032 weeks gestation , with an otherwise healthy singleton pregnancy , were eligible for the study . gdm diagnosis was based on the modified australasian diabetes in pregnancy society ( adips ) criteria : fasting blood glucose level ( bgl ) 5.5 mmol / l , 1 - h bgl 10.0 most women were tested at 2632 weeks , but testing occurred earlier in those at high risk . women who had special dietary requirements ( including vegetarianism / veganism ) , preexisting diabetes , or pregnancy achieved by assisted reproduction and those who smoked or consumed alcohol during pregnancy were excluded . a total of 482 women were approached between september 2008 and november 2010 , of whom 99 met the inclusion criteria and agreed to participate . the enrolled subjects were centrally randomized to study diet by computer - generated random numbers , stratified by bmi ( bmi 30 vs. 30 kg / m ) and weeks of gestation ( 28 or 28 weeks ) . participants received routine gdm care regardless of dietary assignment , including instructions to monitor bgl before breakfast and 1 h after meals . the treating endocrinologist ( t.p.m . or n.p . ) reviewed the subjects every 24 weeks prior to 36 weeks and then every week until delivery . insulin treatment was commenced if the mean fasting bgl or 1 - h postprandial bgl in the preceding week exceeded 5.2 and 7.5 mmol / l , respectively . at enrollment , demographic information , family history of diabetes , and ethnicity were recorded . subjects were asked to recall their prepregnancy weight , were weighed , and were asked to complete a 3 - day food record ( including 2 weekdays and 1 weekend day ) at baseline and again at 3637 weeks gestation . a two - dimensional food model booklet was provided to the subjects to assist in portion size estimation . subjects were randomized to one of two healthy diets of similar protein ( 1525 % ) , fat ( 2530 % ) , and carbohydrate ( 4045 % ) content one with an lgi ( target gi 50 ) and the other with a high - fiber content and moderate gi , similar to the australian population average ( hf ) ( target gi 60 ) ( 1315 ) . both study diets provided all essential nutrients for pregnancy other than iron and iodine , which were supplemented as appropriate by the treating endocrinologist . the baseline 3 - day food diary provided information on baseline dietary composition and served as the basis of individualized dietary counseling . sample menus and their nutritional analyses are given in supplementary table a1 . subjects attended at least three face - to - face visits with the study dietitian , scheduled to coincide with regular antenatal visits . a 24 - h recall of all food and drink intake was conducted during each session to assess compliance . in the case of noncompliance , food sample baskets containing key foods for the assigned diet were provided to promote product recognition and dietary adherence . subjects provided blood samples at baseline and 36 weeks gestation . pregnancy outcomes , including birth weight , infant length , infant head circumference , and the need for emergency caesarean section , were obtained from the electronic medical records system . birth weight centile was calculated using a macro program for microsoft excel ( available from http://www.gestation.net ) that adjusted for ethnic differences ( 16 ) . the calculated birth weight centile was used to categorize the infant as small for gestational age ( birth weight 10th centile ) , normal , or lga ( birth weight 90th centile ) . ponderal index , an estimate of neonatal adiposity , was calculated as birth weight in kg infant length ( m ) . the study dietitian entered the food records into australian nutrition analysis software based on ausnut2001 ( foodworks professional 2009 ; xyris software , brisbane , australia ) . the gi of individual food items was assigned according to a published method ( 17 ) . dietary glycemic load ( gl ) was calculated as follows : gi available carbohydrate of each food in a day / 100 . dietary gi was calculated as follows : ( dietary gl / total daily available carbohydrate ) 100 . subjects were deemed compliant if their final dietary gi was 50 in the lgi group and 50 in the hf group . based on previous data , the study was designed to provide 80 % statistical power to detect an 260 g difference in birth weight , with 60 subjects in each group . recruitment was halted at 99 subjects because the sd in birth weight among the study population was smaller than expected . in the primary analysis , the observed sd of 416 g in birth weight provided 80 % power to detect a group difference of 246 g in birth weight or an 17 % point difference in birth weight centile . the primary analysis included all women randomized who attended at least one dietary education session but excluded those with preterm delivery ( 37 weeks ; n = 4 ; two from each group ) regardless of compliance . all statistical analyses were performed with spss ( version 19 ; ibm australia , st . results for continuous data are reported as mean sd or mean sem , and categorical data ( e.g. , need for insulin ) are reported as percentage . pearson test was used to test for differences between groups for categorical data , and continuous data were tested using one - way anova . a paired t test was used to assess within - group changes from baseline to final outcomes . the study was conducted according to the guidelines laid down in the declaration of helsinki , and all procedures involving human subjects / patients were approved by the human research ethics committee of the sydney south west area health service ( royal prince alfred hospital zone ) . the flow of subjects through the study is shown in supplementary fig . 1 . of the 99 subjects recruited , four delivered prematurely ( 37 weeks ) and three withdrew before the first dietary instruction session , leaving 92 subjects in the primary analysis . subjects in the lgi group had significantly higher 2 - h postload blood glucose levels ( lgi 8.61.2 mmol / l vs. hf 8.01.3 mmol / l ; p = 0.024 ) but were otherwise similar to those in the hf group . at baseline , both groups had a relatively lgi diet ( lgi 491 vs. hf 522 ) ( table 2 ) . at the end of the intervention ( 3637 weeks gestation ) , the diets were matched for macro - and micronutrients , but the lgi group had a significantly lower gi and gl than the hf group as per protocol ( both p 0.001 ) . compared with data at baseline , intake of fat , fiber , calcium , iron , zinc , and folatethe results were similar in the secondary analysis of compliers only except that compliers in the lgi group ( n = 30 ) had significantly decreased their gi , whereas those in the hf group ( n = 34 ) remained unchanged from baseline ( data not shown ) . subject characteristics data are mean sd except for ethnicity , family history of type 2 diabetes , and nulliparous , which are expressed as percentages . * p values calculated by one - way anova for continuous variables and pearson for categorical variables . baseline and end - of - intervention diet analysis * p values calculated by one - way anova to test for difference between groups . p values calculated by paired sample t test to test for difference compared with baseline . at the end of the intervention , biochemical parameters were similar between groups ( table 3 ) . the results were similar in the compliers - only analysis ( data not shown ) . in the primary analysis , there were no significant differences between groups in any of the pregnancy outcomes ( table 4 ) . fewer women in the lgi group gained an excessive amount of weight according to the american institute of medicine guidelines ( lgi 25 % vs. hf 42 % ; p = 0.095 ) . compliers in the lgi group appeared to gain less weight than those in the hf group ( lgi 11.20.9 kg vs. hf 13.71.0 kg ; p = 0.073 ) . there was no significant difference in fetal abdominal circumference at 3637 weeks gestation ( mean sem lgi 327.619.2 mm vs. hf 322.614.6 mm ; p = 0.186 ) . additional analyses with adjustments for ethnicity ( asian vs. caucasian ) , bmi ; oral glucose tolerance test results ; baseline characteristics including daily intakes of energy , monounsaturated fatty acid , polyunsaturated fatty acid , and sodium ; fasting bgl ; fasting insulin ; homeostasis model assessment of insulin resistance ; and total cholesterol did not change the lack of significance of the between - group comparisons . biochemical parameters at baseline and end of intervention homa2 - ir , homeostasis model assessment of insulin resistance . * p values calculated by one - way anova to test for difference between groups . p values calculated by one - way anova for continuous variables and pearson for categorical variables . contrary to our hypothesis , this randomized controlled trial of an lgi diet versus a conventional high - fiber diet found no differences in key pregnancy outcomes in gdm . average infant birth weight , birth weight centile , and ponderal index were within healthy norms in both groups . one explanation for the findings is that both groups of women achieved a relatively lgi diet , with only a modest 5 - point difference between groups . irrespective of dietary assignment , all had received early nutrition counseling in a group setting . thus , on enrollment , both groups were found to be consuming a diet with a lower gi than population norms . compared with routine care in another australian study ( 18 ) , both dietary interventions resulted in a lower prevalence of lga ( 9 vs. 22 % ) , macrosomia ( 4 vs. 21 % ) , and emergency caesarean section ( 16 vs. 20 % ) . hence , in the setting of intensive medical management of gdm , our findings suggest that both an lgi and hf diet produce optimal pregnancy outcomes . our findings increase the evidence supporting the safety and efficacy of an lgi diet in gdm . moses et al . ( 12 ) also found no significant differences in key fetal and obstetric outcomes between subjects who followed an lgi diet ( gi = 48 ) versus a higher - gi diet ( gi = 56 ) . however , unlike in the current study , they found that a significantly higher proportion of women in the higher - gi group met the criteria to commence insulin ( 59 vs. 29 % in the lgi group ) . in addition , almost one - half of the women in the higher - gi group who met the criteria for insulin commencement avoided insulin by switching to an lgi diet . their insulin treatment protocol , however , was different from that of the current study , in which more stringent criteria were used as the basis for insulin treatment . a recent canadian study ( 19 ) , in which women with gdm or impaired glucose tolerance monitored their own blood glucose levels , found that those who were randomized to an lgi diet versus those assigned to the conventional diet had a greater proportion of their 2 - h postprandial levels on or below the treatment target . although there was a tendency for higher birth weight in the control group , the study was a pilot and underpowered to detect a statistically significant difference . another explanation for our findings is the relatively normal weight of most of our subjects ( 68 % had a bmi 25 kg / m ) . it is possible that an lgi diet may be more effective among overweight and obese gravidas with higher degrees of insulin resistance and - cell deficiency ( 20 ) . ( 21 ) reported higher head circumference and a lower proportion of early delivery ( 38 weeks gestation ) in overweight and obese nondiabetic pregnant women assigned to a low gl diet . however , there was no significant difference in birth weight , ponderal index , or pregnancy weight gain , which are more sensitive to maternal glycemic control ( 22 ) . the lack of difference in our study may also relate to the timing and duration of the intervention . dietary instruction began at the start of the third trimester ( 29 weeks gestation ) and lasted , on average , 67 weeks . it is likely that maternal hyperglycemia during the first and second trimester will also drive excessive fetal growth . in a posthoc analysis of women who started dietary intervention before 25 weeks of gestation ( 10 from the lgi group and 5 from the hf group ) , those in the lgi group showed a tendency to lower birth weight ( lgi 3.20.2 kg vs. hf 3.50.1 kg ; p = 0.224 ) and lower birth centile ( lgi 45.311.0 vs. hf 57.512.2 ; p = 0.476 ) , suggesting that an earlier intervention may be beneficial . however , apart from a small number of high - risk women who are screened early , in most countries gdm screening occurs at 2628 weeks gestation ( 23,24 ) , which means that any intervention in gdm will be necessarily short . a more viable test of our hypothesiswould therefore be an appropriately powered study in women at high risk of developing gdm ( e.g. , women with a bmi 30 kg / m or previous gdm ) , starting on or before the start of the second trimester , to determine the effect of an lgi diet on both pregnancy outcome and risk of developing gdm . the failure to achieve the target gi of 60 in the hf group could reflect high recognition of the gi concept among australians diagnosed with diabetes , particularly among those with higher education ( in the current study , two of three subjects had a university degree ) . in the group education sessionconducted soon after diagnosis , all the women , irrespective of future dietary assignment , were encouraged to limit total carbohydrate to 180 g per day and to consume a greater proportion as fruit and dairy products changes which are likely to lower the gi of the overall diet . self - monitoring of blood glucose levels was also encouraged and may have provided feedback that discouraged consumption of high glycemic foods . finally , the use of data collected from medical record may be subject to inaccuracy , e.g. , birth weights were measured and entered by different staff , therefore biasing the result toward the null hypothesis . in conclusion , we found that both an lgi diet and a conventional high - fiber diet produced comparable pregnancy outcomes in women with gdm . both groups achieved a relatively low gi diet and had mean birth weight , birth weight centile , and pregnancy weight gain within population norms . an lgi diet appears to be a safe alternative to the traditional pregnancy diet for women with gdm and expands the range of dietary strategies that can be offered . further studies in overweight and obese individuals and earlier interventions in women with risk factors for gdm are warranted .\noutput:\n" }, { "from": "agent", "value": "objectivethe prevalence of gestational diabetes mellitus ( gdm ) is rising . there is little evidence to demonstrate the effectiveness of one dietary therapy over another . we aimed to investigate the effect of a low glycemic index ( lgi ) versus a conventional high - fiber diet on pregnancy outcomes , neonatal anthropometry , and maternal metabolic profile in gdm.research design and methodsninety - nine women ( age 2642 years ; mean sd prepregnancy bmi 24 5 kg / m2 ) diagnosed with gdm at 2032 weeks gestation were randomized to follow either an lgi ( n = 50 ; target glycemic index [ gi ] ~ 50 ) or a high - fiber moderate - gi diet ( hf ) ( n = 49 ; target gi ~ 60 ) . dietary intake was assessed by 3 - day food records . pregnancy outcomes were collected from medical records.resultsthe lgi group achieved a modestly lower gi than the hf group ( mean sem 47 1 vs. 53 1 ; p < 0.001 ) . at birth , there was no significant difference in birth weight ( lgi 3.3 0.1 kg vs. hf 3.3 0.1 kg ; p = 0.619 ) , birth weight centile ( lgi 52.5 4.3 vs. hf 52.2 4.0 ; p = 0.969 ) , prevalence of macrosomia ( lgi 2.1 % vs. hf 6.7 % ; p = 0.157 ) , insulin treatment ( lgi 53 % vs. hf 65 % ; p = 0.251 ) , or adverse pregnancy outcomes.conclusionsin intensively monitored women with gdm , an lgi diet and a conventional hf diet produce similar pregnancy outcomes ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: chronic hepatitis c ( chc ) is a major cause of chronic liver disease and affects 185 million people worldwide .1 the most serious complications of chc are high mortality from decompensated liver cirrhosis and hepatocellular carcinoma ( hcc ) .2,3 age and age at infection are two of the most important risk factors for the progression to liver cirrhosis during chronic hepatitis c virus ( hcv ) infection .4,5 patient age seems to have a greater effect than age at infection , and is especially significant for patients older than 65 years .6 many countries have aging cohorts of people with hcv infections because of previous peaks in the incidence of hcv infections .2,4 a sustained virologic response ( svr ) , achieved by interferon - based therapies , can slow the progression of liver fibrosis710 and reduce the development of hcc and liver - related mortality .1113 thus , antiviral treatments may provide the greatest benefit for elderly patients . however , the high prevalence of cirrhosis and comorbidities in elderly patients leads to higher rates of treatment discontinuation and dose reduction .14,15 in particular , the svr rate is lower in elderly patients than young patients due to their poor tolerance to treatment .15 thus , the decision of treatment for an elderly patient must consider the long - term benefits and the patient s life expectancy . few studies have examined the occurrence rate of liver cirrhosis after achieving svr in elderly patients with chc . the aspartate aminotransferase - to - platelet ratio index ( apri ) is a noninvasive marker that has been validated for the diagnosis of both significant fibrosis and cirrhosis .16,17 apri is a useful marker for the prognosis in chc patients . however , the prognostic value of apri in elderly patients for predicting the occurrence of liver cirrhosis is uncertain . the aim of this study was to evaluate the risk of the progression to liver cirrhosis after combined therapy consisting of pegylated interferon ( peg - ifn ) plus ribavirin ( rbv ) in elderly patients ( 65 years old ) with chc . patients with hcv infection who were aged 65 and underwent treatment with either peg - ifn -- 2a or peg - ifn -- 2b plus rbv from january 2005 to december 2011 were enrolled from the dalin tzu chi general hospital in this retrospective study . all the patients were positive for anti - hepatitis c antibody for 6 months , had alanine aminotransferase ( alt ) levels higher than the upper limit of normal ( uln ) , and had detectable serum hcv rna . patients with decompensated liver cirrhosis , malignant neoplasms , incomplete medical records , autoimmune diseases , hiv infection , neutropenia ( 1,500 neutrophils / ml ) , thrombocytopenia ( 75,000 platelets / ml ) , anemia ( 12 g hemoglobin / dl in females and 13 g / dl in males ) , or poorly controlled psychiatric diseases were excluded . fifty - three patients with compensated liver cirrhosis , five patients with hcc , 16 patients with posttreatment follow - up times 1 year , and six patients without complete medical records were excluded . there were 801 person - years of follow - ups , and the average follow - up time was 5.5 years ( standard deviation [ sd ] : 2.5 years , range : 1.112.3 years ) . this study was approved by the ethics committee of dalin tzu chi general hospital ( b10303008 ) , all patients provided written consent , and the local ethics committee approved the consent process . oral rbv plus subcutaneous peg - ifn -- 2a ( 180 g ; pegasys ; hoffmann - la roche , basel , switzerland ) or subcutaneous peg - ifn -- 2b ( 1.5 g / kg ; pegintron ; schering - plough corp . , the fixed duration ( 6 months ) without consideration of hcv genotypes is due to restrictions imposed by the reimbursement policy of the bureau of national health insurance in taiwan . the dose of oral rbv was 800 mg / day for patients who weighed 55 kg , 1,000 mg / day for patients who weighed 5575 kg , and 1,200 mg / day for patients who weighed 75 kg . dose adjustments of all drugs and administration of supplemental erythropoietin or blood transfusion were determined according to published practice guidelines .1820 the primary outcome was time to liver cirrhosis . all patients were given liver function tests ( serum aspartate aminotransferase [ ast ] , alt , total bilirubin , creatinine , hemoglobin , white blood cell count , and platelets ) , and abdominal sonography was performed at the gastrointestinal outpatient clinic at baseline , end of treatment ( 6 months ) , 24 weeks after the end of treatment , and every 36 months thereafter . liver cirrhosis and associated liver complications were evaluated every 36 months after the end of treatment . radiologic cirrhosis was defined as two documented ultrasonograms of liver cirrhosis ( included coarse liver echotexture with nodularity and small liver size ) combined with features of portal hypertension ( splenomegaly , ascites , hepatic encephalopathy , or varices ) .21 liver biopsy was an optional procedure and was performed in 108 patients ( 74.5 % ) at baseline with consent . hcv rna was quantified at baseline and at 24 weeks after the end of treatment . a diagnosis of fatty liver was based on results from a biopsy and / or abdominal ultrasound . other clinical factors , including diabetes mellitus , chronic hepatitis b , and alcoholism , were recorded by chart review . chronic hepatitis b was diagnosed if a patient had seropositivity for hepatitis b surface antigen for at least 6 months . the apri score was calculated as : [ ( ast / uln ) / platelet count ( 10 / l ) ] 100.22 the apri was used as a noninvasive maker for fibrosis . serum hcv rna was quantified at baseline and at 24 weeks after the end of treatment by use of real - time polymerase chain reaction , which had a detection limitation of 15 iu / ml .23 the threshold for discriminating low and high baseline hcv rna was 400,000 iu / ml .16 hcv genotyping was performed by melting curve analysis ( roche lightcycler ; biotronics tech corp . , lowell , ma , usa ) .24 svr was defined as undetectable hcv rna for at least 24 weeks after completion of the combined treatment . patients who were positive for hcv rna at week 24 after the end of treatment were considered non - svr . spss 19.0 for windows ( spss inc , chicago , il , usa ) was used for all statistical analyses . the chi - square test or fisherage , sex , diabetes , svr , other risks of hepatitis ( alcoholism , hepatitis b virus [ hbv ] coinfection , and fatty liver ) , hcv rna load , hcv genotype , and baseline apri score were considered as potential confounders for cirrhosis progression . in order to identify risk factors for cirrhosis , the proportional hazards cox regression model was used to control for those possible confounding factors , regardless of whether they were significant predictors in the univariate analyses .25 results were shown as hazard ratios ( hrs ) with 95 % confidence intervals ( cis ) . patients with hcv infection who were aged 65 and underwent treatment with either peg - ifn -- 2a or peg - ifn -- 2b plus rbv from january 2005 to december 2011 were enrolled from the dalin tzu chi general hospital in this retrospective study . all the patients were positive for anti - hepatitis c antibody for 6 months , had alanine aminotransferase ( alt ) levels higher than the upper limit of normal ( uln ) , and had detectable serum hcv rna . patients with decompensated liver cirrhosis , malignant neoplasms , incomplete medical records , autoimmune diseases , hiv infection , neutropenia ( 1,500 neutrophils / ml ) , thrombocytopenia ( 75,000 platelets / ml ) , anemia ( 12 g hemoglobin / dl in females and 13 g / dl in males ) , or poorly controlled psychiatric diseases were excluded . fifty - three patients with compensated liver cirrhosis , five patients with hcc , 16 patients with posttreatment follow - up times 1 year , and six patients without complete medical records were excluded . there were 801 person - years of follow - ups , and the average follow - up time was 5.5 years ( standard deviation [ sd ] : 2.5 years , range : 1.112.3 years ) . this study was approved by the ethics committee of dalin tzu chi general hospital ( b10303008 ) , all patients provided written consent , and the local ethics committee approved the consent process . oral rbv plus subcutaneous peg - ifn -- 2a ( 180 g ; pegasys ; hoffmann - la roche , basel , switzerland ) or subcutaneous peg - ifn -- 2b ( 1.5 g / kg ; pegintron ; schering - plough corp . , the fixed duration ( 6 months ) without consideration of hcv genotypes is due to restrictions imposed by the reimbursement policy of the bureau of national health insurance in taiwan . the dose of oral rbv was 800 mg / day for patients who weighed 55 kg , 1,000 mg / day for patients who weighed 5575 kg , and 1,200 mg / day for patients who weighed 75 kg . dose adjustments of all drugs and administration of supplemental erythropoietin or blood transfusion were determined according to published practice guidelines .1820 the primary outcome was time to liver cirrhosis . all patients were given liver function tests ( serum aspartate aminotransferase [ ast ] , alt , total bilirubin , creatinine , hemoglobin , white blood cell count , and platelets ) , and abdominal sonography was performed at the gastrointestinal outpatient clinic at baseline , end of treatment ( 6 months ) , 24 weeks after the end of treatment , and every 36 months thereafter . liver cirrhosis and associated liver complications were evaluated every 36 months after the end of treatment . radiologic cirrhosis was defined as two documented ultrasonograms of liver cirrhosis ( included coarse liver echotexture with nodularity and small liver size ) combined with features of portal hypertension ( splenomegaly , ascites , hepatic encephalopathy , or varices ) .21 liver biopsy was an optional procedure and was performed in 108 patients ( 74.5 % ) at baseline with consent . hcv rna was quantified at baseline and at 24 weeks after the end of treatment . a diagnosis of fatty liver was based on results from a biopsy and / or abdominal ultrasound . other clinical factors , including diabetes mellitus , chronic hepatitis b , and alcoholism , were recorded by chart review . chronic hepatitis b was diagnosed if a patient had seropositivity for hepatitis b surface antigen for at least 6 months . the apri score was calculated as : [ ( ast / uln ) / platelet count ( 10 / l ) ] 100.22 the apri was used as a noninvasive maker for fibrosis . serum hcv rna was quantified at baseline and at 24 weeks after the end of treatment by use of real - time polymerase chain reaction , which had a detection limitation of 15 iu / ml .23 the threshold for discriminating low and high baseline hcv rna was 400,000 iu / ml .16 hcv genotyping was performed by melting curve analysis ( roche lightcycler ; biotronics tech corp . , lowell , ma , usa ) .24 svr was defined as undetectable hcv rna for at least 24 weeks after completion of the combined treatment . patients who were positive for hcv rna at week 24 after the end of treatment were considered non - svr . spss 19.0 for windows ( spss inc , chicago , il , usa ) was used for all statistical analyses . the chi - square test or fisher s exact test was used for nominal variables . age , sex , diabetes , svr , other risks of hepatitis ( alcoholism , hepatitis b virus [ hbv ] coinfection , and fatty liver ) , hcv rna load , hcv genotype , and baseline apri score were considered as potential confounders for cirrhosis progression . in order to identify risk factors for cirrhosis , the proportional hazards cox regression model was used to control for those possible confounding factors , regardless of whether they were significant predictors in the univariate analyses .25 results were shown as hazard ratios ( hrs ) with 95 % confidence intervals ( cis ) . there were 64 males and 81 females , and the mean patient age was 69.13.3 years ( table 1 ) . eighty - nine of 145 patients ( 61.4 % ) were infected with hcv genotype - 1 , and 56 patients ( 38.6 % ) were infected with other hcv genotypes . ninety - five patients ( 65.5 % ) , including 45 with hcv genotype - 1 and 50 with other hcv genotypes , achieved svr . twenty - six patients ( 17.9 % ) did not complete the full 6 - month treatment , and the patients had mean treatment duration of 84 days . twenty - four patents did not accept complete treatment due to treatment side effect . among those patients , table 1 shows the baseline characteristics and treatment outcomes of patients who did and did not progress to liver cirrhosis . there were 801 person - years of follow - up data , and the average follow - up time was 5.5 years ( sd : 2.5 years , range : 1.112.3 years ) . during the follow - up ,27 patients ( 18.6 % ) developed liver cirrhosis , 12 patients developed hcc , three patients developed varices , two patients developed ascites , and one patient developed spontaneous bacterial peritonitis . one death that was unrelated to liver disease occurred during the follow - up period . the average age of patients with liver cirrhosis was 70.23.3 years , and 17 of these patients ( 62.9 % ) were females . among patients who progressed to cirrhosis ( n = 27 ) , 14 patients ( 51.9 % ) univariate analysis of patients who did and did not progress to cirrhosis indicated no significant differences in age , sex , diabetes , smoking , other risks of hepatitis ( alcoholism , hbv coinfection , and fatty liver ) , hcv rna load , hcv genotype , baseline apri , and svr . there was a trend of a higher baseline apri score in patients who progressed to liver cirrhosis compared with those who did not progress ( 2.11.2 vs 1.61.3 , p = 0.055 ) . table 2 shows the result of cox regression analysis with adjustment for age , sex , diabetes , other risks of hepatitis ( alcoholism , hbv coinfection , and fatty liver ) , hcv rna load , hcv genotype , and baseline apri . the results show a significant association between progression to liver cirrhosis and no svr ( hr : 3.39 , 95 % ci : 1.3128.761 , p = 0.012 ) . there was also a trend of an association between liver cirrhosis and low hcv rna load ( hr : 0.392 , 95 % ci : 0.1521.009 , p = 0.052 ) . there was no significant association between progression to liver cirrhosis and high baseline apri by cox regression ( adjusted hr : 1.285 , 95 % ci : 0.9211.791 , p = 0.14 ) . the risk of liver cirrhosis was significantly greater in patients without svr ( 3 - year cumulative incidence : 35.2 % , 95 % ci : 13.057.5 , p = 0.012 ) than in those with svr ( 3 - year cumulative incidence : 10.4 % , 95 % ci : 3.117.7 ) . decrease of progression to liver cirrhosis occurred in one patient for every four chc patients who achieved svr within 3 years . there were 64 males and 81 females , and the mean patient age was 69.13.3 years ( table 1 ) . eighty - nine of 145 patients ( 61.4 % ) were infected with hcv genotype - 1 , and 56 patients ( 38.6 % ) were infected with other hcv genotypes . ninety - five patients ( 65.5 % ) , including 45 with hcv genotype - 1 and 50 with other hcv genotypes , achieved svr . twenty - six patients ( 17.9 % ) did not complete the full 6 - month treatment , and the patients had mean treatment duration of 84 days . twenty - four patents did not accept complete treatment due to treatment side effect . among those patients , table 1 shows the baseline characteristics and treatment outcomes of patients who did and did not progress to liver cirrhosis . there were 801 person - years of follow - up data , and the average follow - up time was 5.5 years ( sd : 2.5 years , range : 1.112.3 years ) . during the follow - up , 27 patients ( 18.6 % ) developed liver cirrhosis , 12 patients developed hcc , three patients developed varices , two patients developed ascites , and one patient developed spontaneous bacterial peritonitis . one death that was unrelated to liver disease occurred during the follow - up period . the average age of patients with liver cirrhosis was 70.23.3 years , and 17 of these patients ( 62.9 % ) were females . among patients who progressed to cirrhosis ( n = 27 ) , 14 patients ( 51.9 % ) univariate analysis of patients who did and did not progress to cirrhosis indicated no significant differences in age , sex , diabetes , smoking , other risks of hepatitis ( alcoholism , hbv coinfection , and fatty liver ) , hcv rna load , hcv genotype , baseline apri , and svr . there was a trend of a higher baseline apri score in patients who progressed to liver cirrhosis compared with those who did not progress ( 2.11.2 vs 1.61.3 , p = 0.055 ) . table 2 shows the result of cox regression analysis with adjustment for age , sex , diabetes , other risks of hepatitis ( alcoholism , hbv coinfection , and fatty liver ) , hcv rna load , hcv genotype , and baseline apri . the results show a significant association between progression to liver cirrhosis and no svr ( hr : 3.39 , 95 % ci : 1.3128.761 , p = 0.012 ) . there was also a trend of an association between liver cirrhosis and low hcv rna load ( hr : 0.392 , 95 % ci : 0.1521.009 , p = 0.052 ) . there was no significant association between progression to liver cirrhosis and high baseline apri by cox regression ( adjusted hr : 1.285 , 95 % ci : 0.9211.791 , p = 0.14 ) . the risk of liver cirrhosis was significantly greater in patients without svr ( 3 - year cumulative incidence : 35.2 % , 95 % ci : 13.057.5 , p = 0.012 ) than in those with svr ( 3 - year cumulative incidence : 10.4 % , 95 % ci : 3.117.7 ) . decrease of progression to liver cirrhosis occurred in one patient for every four chc patients who achieved svr within 3 years . patients older than 65 years are often excluded in clinical trials of hcv therapies because they often have significant comorbidities and experience adverse effects during or after treatment . therefore , few studies have examined the progression of chc in elderly patients .6,14,15,2628 previous research indicated that the progression of chc to liver cirrhosis was associated with certain baseline host factors and time - dependent risk factors .2,3,29,30 the cumulative nature of fibrosis progression and the potential for more rapid progression in patients older than 40 years mean that cirrhosis is increasingly significant in elderly patients .2,5 in fact , previous research has documented that a longer duration of chc infection and advanced patient age are associated with more rapid progression of chc to liver cirrhosis .2,31 our findings support the rapid progression of liver cirrhosis in patients aged 65 years and older . in particular , the 3 - year cumulative risk of liver cirrhosis was 35.2 % in our elderly patients who had persistent viremia . previous studies examined the efficacy of peg - ifn plus rbv for treatment of chc in elderly patients .4,15,26,28,3235 although such patients have higher rates of dose reduction and adverse effects , some of them achieve svr .4,15,32,35 a recent meta - analysis indicated that the overall rate of svr in elderly patients was significantly lower than in young patients based on intention - to - treat analysis ( 42.0 % vs 60.1 % , p 0.00001 ) and per - protocol analysis ( 54.4 % vs 67.4 % , p = 0.002 ) .15 the rates of drug discontinuation and rbv dose reduction in elderly patients were significantly higher than in younger patients .15 the poor svr rate in elderly patients may be related to the high prevalence of liver cirrhosis and treatment intolerance .4,14,33 our study demonstrated the efficacy of peg - ifn plus rbv treatment in elderly patients . in particular , 65.5 % of patients overall achieved svr , and this included 50.6 % of those with hcv genotype - 1 and 89.3 % of those with other hcv genotypes . these data support the use of our treatment regimen in elderly patients with chc who do not have liver cirrhosis or hcc . furthermore , there were no deaths or severe treatment - related complications , and most patients who could not tolerate treatment stopped treatment near the beginning of the regimen ( mean treatment duration : 84 days ) . this suggests that the standard peg - ifn plus rbv treatment is safe in elderly patients if they are closely monitored . from our previous study , the patients who had absence of liver cirrhosis , low baseline hcv rna levels , high baseline alt level , no hcv genotype - 1 , or were treated with peg - ifn -- 2a were good responders to peg - ifn plus rbv treatments .36 thus , it seems that treatment will be effective in selected elderly patients with chc , such as those with good response predictors ( genotype 2/3 , low viral load , il28b - cc ) , good performance status , and without major concomitant diseases . previous long - term follow - up studies showed the benefits of svr in patients with chc .711 the achievement of an svr through interferon - based therapy slows the progression from chronic hepatitis to liver fibrosis710 and reduces the subsequent development of hcc and liver - related mortality .1113 these effects are universal and were stronger in patients with advanced fibrosis .11 a large - scale study that followed 1,386 patients with chc but not liver cirrhosis over 5 years reported that the annual incidence of liver cirrhosis in untreated patients and patients treated with interferon - based therapy ( n = 892 ) was 2.26 % and 1.11 % ( nonresponders : 1.99 % , sustained responders : 0.74 % ) , respectively .9 in addition , the 14.5 - year cumulative incidence of cirrhosis was significantly lower in sustained responders ( 4.8 % ) than in nonresponders ( 21.6 % , p = 0.0007 ) and in untreated patients ( 36.6 % , p 0.0001 ) . the present study showed that cirrhosis progressed rapidly and that an svr slowed the progression to fibrosis in elderly patients with chc . in particular , patients without svr had a significantly higher risk of liver cirrhosis than those with svr , and a significantly higher 3 - year cumulative incidence of liver cirrhosis than those with svr . these results suggest that suppression of hcv rna can dramatically reduce the risk of liver cirrhosis in elderly patients . a previous study reported that high apri score was associated with significant fibrosis or cirrhosis .22 our patients also had elevated apri scores ( mean sd : 1.71.3 ) , confirming the presence of advanced fibrosis at baseline and consistent with the rapid progression of fibrosis in elderly patients . in addition , there was a trend of a higher baseline apri score in patients who progressed to liver cirrhosis than those who did not progress ( 2.11.2 vs 1.61.3 , p = 0.055 ) . nonetheless , after adjusting for apri score by cox regression , svr remained the most important factor for progression to liver cirrhosis . antiviral treatments for chc have evolved since 2011 , and several new drugs , including direct - acting antivirals and host - targeted agents , are marketed or under clinical development . interferon - free regimens are expected to cure 90 % of patients with chc ,37 and the newly available drugs have fewer side effects than interferon - based regimens . however , the new hcv therapies are very expensive and have not been thoroughly evaluated in elderly patients . thus , additional research is needed to evaluate the cost - effectiveness of these new therapies in elderly patients . before adoption of the new therapies in elderly patients , the peg - ifn plus rbv regimen should continue to be used to prevent the rapid progression to cirrhosis . first , this was a retrospective observational study . some information such as age at infection , the number of patients who underwent therapy evaluation , the excluded patient number , and the reasons for excluding can not be obtained from this study . however , it is difficult to perform a prospective controlled trial in elderly patients , so our findings nonetheless provide important information regarding treatment decisions in this population . second , only 108 patients ( 74.5 % ) underwent liver biopsy at baseline , and we can not provide paired biopsy data . thus , most patients with cirrhosis were diagnosed using clinical criteria . however , our diagnostic criteria for cirrhosis included two documented ultrasonograms of liver cirrhosis with solid clinical end points ( splenomegaly , ascites , hepatic encephalopathy , or varices ) .9 although ultrasound is inaccurate in detecting the early stages of liver cirrhosis , combination of the morphologic finding can improve the performance of ultrasound to detect cirrhosis , reaching an accuracy of over 80 % .38 in conclusion , liver fibrosis progressed rapidly in elderly patients . an svr following peg - ifn combination treatment can reduce the risk of liver cirrhosis in elderly chc patients .\noutput:\n" }, { "from": "agent", "value": "objectivewe studied the effect of sustained virologic response ( svr ) after treatment with pegylated - interferon ( peg - ifn ) plus ribavirin on the development of liver cirrhosis in elderly patients with chronic hepatitis c ( chc ) . patients and methodsthis retrospective study enrolled 145 elderly chc patients ( aged 65 years ) who were treatment - nave and were treated with peg - ifn plus ribavirin for 6 months between january 2005 and december 2011 . abdominal sonography was performed and liver biochemistry was studied at baseline , at the end of treatment , and every 36 months thereafter . the development of liver cirrhosis and related complications was evaluated at the follow - ups . the aspartate aminotransferase - to - platelet ratio index was used as a noninvasive maker for fibrosis.resultsthe mean patient age was 69.13.3 years , and the average follow - up time was 5.5 years ( standard deviation : 2.5 years , range : 1.112.3 years ) . ninety - five patients ( 65.5 % ) achieved svr , and 26 ( 17.9 % ) discontinued treatment . twenty - seven patients ( 18.6 % ) developed liver cirrhosis after treatment . patients without svr had significantly greater risk of liver cirrhosis than those with svr ( hazard ratio [ hr ] : 3.39 , 95 % confidence interval [ ci ] : 1.3128.761 , p = 0.012 ) . the difference in 3 - year cumulative incidence of liver cirrhosis was 24.8 % greater for patients without svr ( 35.2 % , 95 % ci : 13.057.5 , p = 0.012 ) compared with those with svr ( 10.4 % , 95 % ci : 3.117.7 ) . there was a trend of a higher baseline aspartate aminotransferase - to - platelet ratio index score in patients who progressed to liver cirrhosis compared with those who did not progress ( 2.11.2 vs 1.61.3 , p = 0.055 ) , but the difference failed to reach significance by cox regression ( adjusted hr : 1.285 , 95 % ci : 0.9211.791 , p = 0.14 ) . conclusionan svr following peg - ifn combination treatment can reduce the risk of liver cirrhosis in elderly chc patients ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: radiofrequency catheter ablation has proven to be an effective treatment strategy for af . even though ablation is most effective treatment for af , it causes the inflammatory changes which are associated with the early af events ( eafes ) . other cardiac surgeries are also associated with early postoperative af ( poaf ) which occur in up to 30 % of patients undergoing coronary artery bypass surgery and 50 % after valvular surgery . cardiac surgery is becoming more common due to advances in technology and research , safe and easy to use technique and increase in a number of the older population . american and european task force have suggested that prevention of af is one of the important goals following cardiac surgery . despite ongoing improvements in the procedurethe cause of eafe remains unknown but may involve an inflammatory response due of thermal injury , pericarditis , or both . because eafe is responsible for a higher risk of late recurrence , it is of particular interest . corticosteroids has proven to be beneficial in reducing the inflammation and poaf incidence in few published studies , but benefits of corticosteroids are largely outweigh by the harm it cause , specifically in patients with hypertension and structural heart disease . that is why it is important to find the anti - inflammatory agent which is safe and efficacious . colchicine is used as antigout drug since a long time ; it has antiinflammatory efficacy and reduces the inflammation by inhibiting the microtubule polymerization . in the colchicine for the prevention of the postpericardiotomy syndrome ( copps ) trial , colchicine proved to be safe and efficacious in the prevention of postpericardiotomy syndrome following cardiac surgery by reducing the inflammation . because of antiinflammatory effect , it might be beneficial in reducing the eafe occurred mainly due to inflammation following cardiac procedures . due to the above mentioned reason , together with the limited antiinflammatory strategies available to prevent eafe following cardiac surgery , the clinical relevance of evaluating the possible antiinflammatory effect of colchicine specifically in cardiac surgery patient is even more important . we evaluated all the relevant studies published before april 2014 , and an inclusion criterion was the randomized clinical trial on pharmacological prevention of af following cardiac surgery and patients receiving colchicine therapy compared with placebo . the studies were searched by two independent reviewers to remove irrelevant reports and to identify multiple reports from the same study . disagreements were resolved by a discussion to make final decisions or by agreements of a third investigator , if necessary . studies were searched from the cochrane collaboration database of randomized trials , clinicaltrials.gov , cinahl , google scholar , pubmed , and scopus . in addition , all the abstracts from annual scientific session from american heart association , american college of cardiology , heart rhythm society and the european society of cardiology were electronically or manually searched . studies were excluded if they were not randomized controlled trial or if they were animal trial . from all the included studies baseline data , type of cardiac procedure , incidence of af following the colchicine dose versus placebo , preoperative af incidence and inflammatory cytokines blood level information were collected . of 48 citations retrieved , 17 studies assessing the effect of colchicine therapy on the incidence of af were identified . thirteen studies were excluded because they were editorial , review or early result of the included study . one study was excluded , because it was studying the late recurrence [ figure 1 ] . finally , three randomized studies were included for the analysis : one published study by deftereos et al . on effect of colchicine postpulmonary vein antrum isolation ( pvai ) , one published study by imazio et al . on effect of colchicine postcardiotomy , and one abstract by egami et al . presented at the american heart association 's annual scientific session studying the effect of colchicine on af post - pvai . selection process of studies included in the systematic review ( af = atrial fibrillation ; pvai = pulmonary vein antrum isolation ) . colchicine [ all fields ] ) and ( atrial fibrillation [ mesh terms ] or ( atrial [ all fields ] and fibrillation [ all fields ] ) or atrial fibrillation [ all fields ] ) imazio et al . assessed the association between colchicine and postcardiac surgery associated af in multi - center , double - blind , randomized study of the 336 patients ( average 65 years of age and 69 % male ) most of the patients were undergoing coronary artery bypass graft ( cabg ) ( 49.7 % ) and valvular surgery ( 27.3 % ) . only 19 ( 5.6 % ) patients had a previous history of af . colchicine was administered at 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month . the primary endpoint of the study was the incidence of poaf between day 3 and day 30 after the surgery . in 1 month , patients on colchicine had less incidence of af compared to control group ( 20 [ 12 % ] vs. 35 [ 21 % ] , p = 0.02 odds ratio [ or ] = 0.51 [ 0.28 , 0.92 ] ) . gastrointestinal ( gi ) side effects were similar between groups ( 16.5 % vs. 4.2 % , p = 0.08 ) . patients on colchicine had shorter overall hospital stay ( 24.28.9 , vs. 21.47.9 , p = 0.03 ) . most patients without poaf were on colchicine and beta - blocker preoperatively , had small la diameter ( 45 mm ) , undergoing cabg surgery and did not develop pericardial effusion . in multivariable analysis after adjusting for the la diameter 45 mm and preoperative beta - blocker , colchicine showed 48 % reduction in poaf ( heart rate = 0.52 , [ 0.28 , 0.96 ] , p = 0.036 ) . prospectively assessed the association between short duration of colchicine on reduction of eafe after pvai by randomizing 87 patients in colchicine ( n = 36 ) and placebo ( n = 51 ) group . the population had an average age of 64 years where 57 ( 65.5 % ) patients were males . in colchicine group , patients were treated with 0.5 mg / day colchicine for 2 weeks from the next day after catheter ablation . patients were followed - up at 48 h , 2 , 4 , and 12 weeks after the procedures and early recurrence was observed in 11 ( 30.6 % ) patients in colchicine group and 27 ( 52.9 % ) patients in control . in univariate logistic regression , patients on colchicine had 61 % less chance of developing af ( or = 0.33 [ 0.12 , 0.95 ] ) . patients were also subdivided by high vs. low left atrial epicardial adipose tissue ( la - eat ) volume and level of c - reactive protein ( crp ) was analyzed to study the effect of colchicine in both groups . in low la - eat volume group , colchicine showed a significant reduction in crp 2 days after the ablation but there was no significant difference in crp level for high la - eat group . deftereos et al . studied the effect of colchicine on prevention of early af recurrence after pvai by randomizing 161 patients with paroxysmal af undergoing pvai with 0.5 mg of twice daily colchicine versus placebo . colchicine was administered from day 1 ( the day of the ablation procedure ) at a dose of 0.5 mg twice daily . patients were followed - up for 3 months after pvai to detect the af recurrence . baseline characteristics were similar between the groups , and the average age was 62 years , and 115 ( 71 % ) of patients were male . af recurrence was observed in 27 ( 33.5 % ) patients in control and 13 ( 16 % ) patients in colchicine group ( or = 0.39 [ 0.16 , 0.96 ] , p = 0.001 ) ( log - rank p = 0.01 ) . furthermore , the authors studied the effect of colchicine on the inflammatory marker interleukin - 6 ( il - 6 ) and crp , where both markers were similar between groups at day 1 after the procedure but showed significant reduction at day 4 in the patients who were on colchicine . deftereos et al . also studied the safety of the colchicine in comparison to placebo where gi side effects were more common in patients who were on colchicine ( 13.6 % vs. 5 % ) . in multivariate analysis , colchicine significantly predicted the eafe prevention mainly by significant reduction in il - 6 and crp level . taken together , these clinical studies suggest a possible beneficial effect of colchicine therapy in preventing either incidence or early recurrence of af in patients undergoing a cardiac procedure . to provide an overall estimate of the effect of colchicine therapy in preventing eafe in patients undergoing cardiac surgery we performed a meta - analysis by including the publications selected above . the presence of heterogeneity among studies was evaluated with cochrane q test , and inconsistency was assessed with i test that describes the percentage of the variability in effect estimates that is due to heterogeneity : values of 25 % , 50 % , and 75 % correspond to low , moderate , and high heterogeneity ( i ) . publication bias was assessed using the egger 's test and displayed as a funnel plot of precision . statistical level of significance for the summary treatment effect estimate was two - tailed p 0.05 and analyzed by der simonian and laird random effect method . heterogeneity and publication bias were considered statistically significant at a two - tailed p 0.1 . the meta - analysis was performed by the review manager 5.2 ( the cochrane collaboration , 2011 ) . we evaluated all the relevant studies published before april 2014 , and an inclusion criterion was the randomized clinical trial on pharmacological prevention of af following cardiac surgery and patients receiving colchicine therapy compared with placebo . the studies were searched by two independent reviewers to remove irrelevant reports and to identify multiple reports from the same study . disagreements were resolved by a discussion to make final decisions or by agreements of a third investigator , if necessary . studies were searched from the cochrane collaboration database of randomized trials , clinicaltrials.gov , cinahl , google scholar , pubmed , and scopus . in addition , all the abstracts from annual scientific session from american heart association , american college of cardiology , heart rhythm society and the european society of cardiology were electronically or manually searched . studies were excluded if they were not randomized controlled trial or if they were animal trial . from all the included studies baseline data , type of cardiac procedure , incidence of af following the colchicine dose versus placebo , preoperative af incidence and inflammatory cytokines blood level information were collected . of 48 citations retrieved , 17 studies assessing the effect of colchicine therapy on the incidence of af were identified . thirteen studies were excluded because they were editorial , review or early result of the included study . one study was excluded , because it was studying the late recurrence [ figure 1 ] . finally , three randomized studies were included for the analysis : one published study by deftereos et al . on effect of colchicine postpulmonary vein antrum isolation ( pvai ) , one published study by imazio et al . on effect of colchicine postcardiotomy , and one abstract by egami et al . presented at the american heart association 's annual scientific session studying the effect of colchicine on af post - pvai . selection process of studies included in the systematic review ( af = atrial fibrillation ; pvai = pulmonary vein antrum isolation ) . colchicine [ all fields ] ) and ( atrial fibrillation [ mesh terms ] or ( atrial [ all fields ] and fibrillation [ all fields ] ) or atrial fibrillation [ all fields ] ) imazio et al . assessed the association between colchicine and postcardiac surgery associated af in multi - center , double - blind , randomized study of the 336 patients ( average 65 years of age and 69 % male ) most of the patients were undergoing coronary artery bypass graft ( cabg ) ( 49.7 % ) and valvular surgery ( 27.3 % ) . only 19 ( 5.6 % ) patients had a previous history of af . colchicine was administered at 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month . the primary endpoint of the study was the incidence of poaf between day 3 and day 30 after the surgery . in 1 month , patients on colchicine had less incidence of af compared to control group ( 20 [ 12 % ] vs. 35 [ 21 % ] , p = 0.02 odds ratio [ or ] = 0.51 [ 0.28 , 0.92 ] ) . gastrointestinal ( gi ) side effects were similar between groups ( 16.5 % vs. 4.2 % , p = 0.08 ) . patients on colchicine had shorter overall hospital stay ( 24.28.9 , vs. 21.47.9 , p = 0.03 ) . most patients without poaf were on colchicine and beta - blocker preoperatively , had small la diameter ( 45 mm ) , undergoing cabg surgery and did not develop pericardial effusion . in multivariable analysis after adjusting for the la diameter 45 mm and preoperative beta - blocker , colchicine showed 48 % reduction in poaf ( heart rate = 0.52 , [ 0.28 , 0.96 ] , p = 0.036 ) . prospectively assessed the association between short duration of colchicine on reduction of eafe after pvai by randomizing 87 patients in colchicine ( n = 36 ) and placebo ( n = 51 ) group . the population had an average age of 64 years where 57 ( 65.5 % ) patients were males . in colchicine group , patients were treated with 0.5 mg / day colchicine for 2 weeks from the next day after catheter ablation . patients were followed - up at 48 h , 2 , 4 , and 12 weeks after the procedures and early recurrence was observed in 11 ( 30.6 % ) patients in colchicine group and 27 ( 52.9 % ) patients in control . in univariate logistic regression , patients on colchicine had 61 % less chance of developing af ( or = 0.33 [ 0.12 , 0.95 ] ) . patients were also subdivided by high vs. low left atrial epicardial adipose tissue ( la - eat ) volume and level of c - reactive protein ( crp ) was analyzed to study the effect of colchicine in both groups . in low la - eat volume group , colchicine showed a significant reduction in crp 2 days after the ablation but there was no significant difference in crp level for high la - eat group . deftereos et al . studied the effect of colchicine on prevention of early af recurrence after pvai by randomizing 161 patients with paroxysmal af undergoing pvai with 0.5 mg of twice daily colchicine versus placebo . colchicine was administered from day 1 ( the day of the ablation procedure ) at a dose of 0.5 mg twice daily . patients were followed - up for 3 months after pvai to detect the af recurrence . baseline characteristics were similar between the groups , and the average age was 62 years , and 115 ( 71 % ) of patients were male . af recurrence was observed in 27 ( 33.5 % ) patients in control and 13 ( 16 % ) patients in colchicine group ( or = 0.39 [ 0.16 , 0.96 ] , p = 0.001 ) ( log - rank p = 0.01 ) . furthermore , the authors studied the effect of colchicine on the inflammatory marker interleukin - 6 ( il - 6 ) and crp , where both markers were similar between groups at day 1 after the procedure but showed significant reduction at day 4 in the patients who were on colchicine . deftereos et al . also studied the safety of the colchicine in comparison to placebo where gi side effects were more common in patients who were on colchicine ( 13.6 % vs. 5 % ) . in multivariate analysis , colchicine significantly predicted the eafe prevention mainly by significant reduction in il - 6 and crp level . taken together , these clinical studies suggest a possible beneficial effect of colchicine therapy in preventing either incidence or early recurrence of af in patients undergoing a cardiac procedure . to provide an overall estimate of the effect of colchicine therapy in preventing eafe in patients undergoing cardiac surgery we performed a meta - analysis by including the publications selected above . the presence of heterogeneity among studies was evaluated with cochrane q test , and inconsistency was assessed with i test that describes the percentage of the variability in effect estimates that is due to heterogeneity : values of 25 % , 50 % , and 75 % correspond to low , moderate , and high heterogeneity ( i ) . publication bias was assessed using the egger 's test and displayed as a funnel plot of precision . statistical level of significance for the summary treatment effect estimate was two - tailed p 0.05 and analyzed by der simonian and laird random effect method . heterogeneity and publication bias were considered statistically significant at a two - tailed p 0.1 . the meta - analysis was performed by the review manager 5.2 ( the cochrane collaboration , 2011 ) . we evaluated all the relevant studies published before april 2014 , and an inclusion criterion was the randomized clinical trial on pharmacological prevention of af following cardiac surgery and patients receiving colchicine therapy compared with placebo . the studies were searched by two independent reviewers to remove irrelevant reports and to identify multiple reports from the same study . disagreements were resolved by a discussion to make final decisions or by agreements of a third investigator , if necessary . studies were searched from the cochrane collaboration database of randomized trials , clinicaltrials.gov , cinahl , google scholar , pubmed , and scopus . in addition , all the abstracts from annual scientific session from american heart association , american college of cardiology , heart rhythm society and the european society of cardiology were electronically or manually searched . studies were excluded if they were not randomized controlled trial or if they were animal trial . from all the included studies baseline data , type of cardiac procedure , incidence of af following the colchicine dose versus placebo , preoperative af incidence and inflammatory cytokines blood level information were collected . of 48 citations retrieved , 17 studies assessing the effect of colchicine therapy on the incidence of af were identified . thirteen studies were excluded because they were editorial , review or early result of the included study . one study was excluded , because it was studying the late recurrence [ figure 1 ] . finally , three randomized studies were included for the analysis : one published study by deftereos et al . on effect of colchicine postpulmonary vein antrum isolation ( pvai ) , one published study by imazio et al . on effect of colchicine postcardiotomy , and one abstract by egami et al . presented at the american heart association 's annual scientific session studying the effect of colchicine on af post - pvai . selection process of studies included in the systematic review ( af = atrial fibrillation ; pvai = pulmonary vein antrum isolation ) . search criteria : ( colchicine [ mesh terms ] or colchicine [ all fields ] ) and ( atrial fibrillation [ mesh terms ] or ( atrial [ all fields ] and fibrillation [ all fields ] ) or atrial fibrillation [ all fields ] ) imazio et al . assessed the association between colchicine and postcardiac surgery associated af in multi - center , double - blind , randomized study of the 336 patients ( average 65 years of age and 69 % male ) . most of the patients were undergoing coronary artery bypass graft ( cabg ) ( 49.7 % ) and valvular surgery ( 27.3 % ) . only 19 ( 5.6 % ) patients had a previous history of af . colchicine was administered at 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month . the primary endpoint of the study was the incidence of poaf between day 3 and day 30 after the surgery . in 1 month , patients on colchicine had less incidence of af compared to control group ( 20 [ 12 % ] vs. 35 [ 21 % ] , p = 0.02 odds ratio [ or ] = 0.51 [ 0.28 , 0.92 ] ) . gastrointestinal ( gi ) side effects were similar between groups ( 16.5 % vs. 4.2 % , p = 0.08 ) . patients on colchicine had shorter overall hospital stay ( 24.28.9 , vs. 21.47.9 , p = 0.03 ) . most patients without poaf were on colchicine and beta - blocker preoperatively , had small la diameter ( 45 mm ) , undergoing cabg surgery and did not develop pericardial effusion . in multivariable analysis after adjusting for the la diameter 45 mm and preoperative beta - blocker , colchicine showed 48 % reduction in poaf ( heart rate = 0.52 , [ 0.28 , 0.96 ] , p = 0.036 ) . egami et al . prospectively assessed the association between short duration of colchicine on reduction of eafe after pvai by randomizing 87 patients in colchicine ( n = 36 ) and placebo ( n = 51 ) group . the population had an average age of 64 years where 57 ( 65.5 % ) patients were males . in colchicine group , patients were treated with 0.5 mg / day colchicine for 2 weeks from the next day after catheter ablation . patients were followed - up at 48 h , 2 , 4 , and 12 weeks after the procedures and early recurrence was observed in 11 ( 30.6 % ) patients in colchicine group and 27 ( 52.9 % ) patients in control . in univariate logistic regression , patients on colchicine had 61 % less chance of developing af ( or = 0.33 [ 0.12 , 0.95 ] ) . patients were also subdivided by high vs. low left atrial epicardial adipose tissue ( la - eat ) volume and level of c - reactive protein ( crp ) was analyzed to study the effect of colchicine in both groups . in low la - eat volume group , colchicine showed a significant reduction in crp 2 days after the ablation but there was no significant difference in crp level for high la - eat group . deftereos et al . studied the effect of colchicine on prevention of early af recurrence after pvai by randomizing 161 patients with paroxysmal af undergoing pvai with 0.5 mg of twice daily colchicine versus placebo . colchicine was administered from day 1 ( the day of the ablation procedure ) at a dose of 0.5 mg twice daily . patients were followed - up for 3 months after pvai to detect the af recurrence . baseline characteristics were similar between the groups , and the average age was 62 years , and 115 ( 71 % ) of patients were male . af recurrence was observed in 27 ( 33.5 % ) patients in control and 13 ( 16 % ) patients in colchicine group ( or = 0.39 [ 0.16 , 0.96 ] , p = 0.001 ) ( log - rank p = 0.01 ) . furthermore , the authors studied the effect of colchicine on the inflammatory marker interleukin - 6 ( il - 6 ) and crp , where both markers were similar between groups at day 1 after the procedure but showed significant reduction at day 4 in the patients who were on colchicine . moreover , inflammatory markers blood level was high in patients with recurrence . deftereos et al . also studied the safety of the colchicine in comparison to placebo where gi side effects were more common in patients who were on colchicine ( 13.6 % vs. 5 % ) . in multivariate analysis , colchicine significantly predicted the eafe prevention mainly by significant reduction in il - 6 and crp level . taken together , these clinical studies suggest a possible beneficial effect of colchicine therapy in preventing either incidence or early recurrence of af in patients undergoing a cardiac procedure . to provide an overall estimate of the effect of colchicine therapy in preventing eafe in patients undergoing cardiac surgery we performed a meta - analysis by including the publications selected above . the presence of heterogeneity among studies was evaluated with cochrane q test , and inconsistency was assessed with i test that describes the percentage of the variability in effect estimates that is due to heterogeneity : values of 25 % , 50 % , and 75 % correspond to low , moderate , and high heterogeneity ( i ) . publication bias was assessed using the egger 's test and displayed as a funnel plot of precision . statistical level of significance for the summary treatment effect estimate was two - tailed p 0.05 and analyzed by der simonian and laird random effect method . heterogeneity and publication bias were considered statistically significant at a two - tailed p 0.1 . the meta - analysis was performed by the review manager 5.2 ( the cochrane collaboration , 2011 ) . overall , 584 patients undergoing cardiac surgery were included , out of which 286 ( 48.97 % ) received colchicine and 298 ( 51.03 % ) received placebo . tables 1 and 2 summarize the study and population characteristics , respectively . after pooled analysis , colchicine was significantly associated with reduction in af events compared to placebo ( or = 0.44 [ 0.29 , 0.66 ] , p 0.001 ) [ figure 2 ] . although there was no significant publication bias , the numbers of included studies were limited [ figure 3 ] . in addition , pooled analysis was performed only for the study on the patients who underwent pvai and colchicine was associated with 62 % less chance of af events compared to placebo after pvai ( or = 0.38 [ 0.21 , 0.68 ] , p = 0.001 ) [ figure 4 ] . characteristics of the studies included in the meta - analysis baseline characteristics of study patients forest plot showing the odds ratio of early atrial fibrillation associated with colchicine use in each study and the overall or . square boxes denote or ; horizontal lines represent 95 % confidence interval funnel plot of the standard error of logarithm odds ratio against or , displayed as or . there is no presence of publication bias on visual estimation forest plot showing the odds ratio of atrial fibrillation associated with colchicine use in pulmonary vein antrum isolation study and the overall or . square boxes denote or ; horizontal lines represent 95 % confidence interval colchicine is associated with gastro intestinal side effect . out of three studies , imazio et al . reported gi side effects in 16 colchicine and 7 control patients and all the patient stopped the drug due to side effect . in deftereosmetanalysis was not performed for side effect as side effects were very few in included studies . overall , 584 patients undergoing cardiac surgery were included , out of which 286 ( 48.97 % ) received colchicine and 298 ( 51.03 % ) received placebo . tables 1 and 2 summarize the study and population characteristics , respectively . after pooled analysis , colchicine was significantly associated with reduction in af events compared to placebo ( or = 0.44 [ 0.29 , 0.66 ] , p 0.001 ) [ figure 2 ] . although there was no significant publication bias , the numbers of included studies were limited [ figure 3 ] . in addition , pooled analysis was performed only for the study on the patients who underwent pvai and colchicine was associated with 62 % less chance of af events compared to placebo after pvai ( or = 0.38 [ 0.21 , 0.68 ] , p = 0.001 ) [ figure 4 ] . characteristics of the studies included in the meta - analysis baseline characteristics of study patients forest plot showing the odds ratio of early atrial fibrillation associated with colchicine use in each study and the overall or . square boxes denote or ; horizontal lines represent 95 % confidence interval funnel plot of the standard error of logarithm odds ratio against or , displayed as or . there is no presence of publication bias on visual estimation forest plot showing the odds ratio of atrial fibrillation associated with colchicine use in pulmonary vein antrum isolation study and the overall or . square boxes denote or ; horizontal lines represent 95 % confidence interval colchicine is associated with gastro intestinal side effect . out of three studies , imazio et al . reported gi side effects in 16 colchicine and 7 control patients and all the patient stopped the drug due to side effect . in deftereosmetanalysis was not performed for side effect as side effects were very few in included studies . overall , 584 patients undergoing cardiac surgery were included , out of which 286 ( 48.97 % ) received colchicine and 298 ( 51.03 % ) received placebo . tables 1 and 2 summarize the study and population characteristics , respectively . after pooled analysis , colchicine was significantly associated with reduction in af events compared to placebo ( or = 0.44 [ 0.29 , 0.66 ] , p 0.001 ) [ figure 2 ] . although there was no significant publication bias , the numbers of included studies were limited [ figure 3 ] . in addition , pooled analysis was performed only for the study on the patients who underwent pvai and colchicine was associated with 62 % less chance of af events compared to placebo after pvai ( or = 0.38 [ 0.21 , 0.68 ] , p = 0.001 ) [ figure 4 ] . characteristics of the studies included in the meta - analysis baseline characteristics of study patients forest plot showing the odds ratio of early atrial fibrillation associated with colchicine use in each study and the overall or . square boxes denote or ; horizontal lines represent 95 % confidence interval funnel plot of the standard error of logarithm odds ratio against or , displayed as or . there is no presence of publication bias on visual estimation forest plot showing the odds ratio of atrial fibrillation associated with colchicine use in pulmonary vein antrum isolation study and the overall or . imazio et al . reported gi side effects in 16 colchicine and 7 control patients and all the patient stopped the drug due to side effect . metanalysis was not performed for side effect as side effects were very few in included studies . this is the first meta - analysis focusing on the efficacy of colchicine in preventing af postcardiac procedure . our result shows that colchicine reduces the early af nearly by 56 % compared to placebo . because eafe can lead to late recurrencecolchicine effectively reduces the inflammation , which is evidenced by reduction in blood level of inflammatory cytokines in two of the included study . in a study by deftereos et al . , there was a significant reduction in the blood level of crp and il - 6 after colchicine treatment , and this reduction was associated with less recurrence . study by egami et al . showed reduction in crp level after introduction of colchicine treatment . thus , from this meta - analysis , it is clear that the anti - inflammatory property of colchicine is benefiting in reduction of postcardiac surgery related af event . colchicine safety is still concern , because in the study by imazio et al . , patients on colchicine had significantly more gi side effects than placebo which leads to withdrawal of the patients from the study . in egamistudy , there were more side effects in the colchicine group but it was tolerable . major reason of lesser side effects in other two studies may be due to lower the dose of colchicine ( 0.5 mg vs. 1.0 ) . a recent multicenter trial by deftereos et al . studying long - term effect and quality of life effect of colchicine in prevention of af post - pvai showed that colchicine associated with significant reduction in af recurrence rate within 15 months after a single procedure , along with improvements in physical and psychological health - related quality of life scores . thus , side effects were tolerable and from the improvement in quality - of - life score , it is clear the benefit of elimination of af outweigh the adverse effect it causes . hence , side effect should be of little concern compared to elimination of af . major limitation of our study was the number of included studies were very few , and 2 of the study had pvai only as the cardiac procedure , which is the treatment of af . although pvai eliminates all the triggers causing af in paroxysmal patient , it is not 100 % successful and success can be variable depending on co - morbidity and inflammation caused by pvai which contribute to early recurrence and procedure failure . hence , chances of developing af are low in patients after pvai compared to other cardiac surgeries which is also evidenced by the or of imazio et al . another limitation is that egami et al . had presented the result at the conference , so we could not be able to determine other details like co - morbidity in that study which might influence the final results . . proved good criteria that colchicine should be given for 3 months based on significant elevation of crp for 3 months after af ablation , but more studies are needed to decide appropriate dose and timing of colchicine administration . although eafe predicts the late recurrence of af , it is likely that eafe could be due to failed ablation procedure rather than inflammation . in a study by deftereos et al . was confounded by beta blocker but it was not analyzed as confounder in studying the relationship between colchicine and af . while there was no information about antiarrhythmic in the study by egami et al . study might have missed the recurrences reported on first 2 days as colchicine was started at day 3 , so results could have been underestimated . despite several limitations colchicines role in preventing af after cardiac surgery , can not be disregarded . furthermore , colchicine is cheap , effective , and one of the very few antiinflammatory agents with minor side effect compared to other drugs like corticosteroids . furthermore , it reduces the hospital stay and life - threatening complications of cardiac surgery which reduces the overall cost and improves the quality - of - life . the results of our meta - analysis have to be interpreted as only hypothesis - generating , rather than conclusion - drawing . indeed , although the pooled treatment effect is quite impressive , with a reduction of more than 50 % of the risk of developing af , the small number of studies , with different clinical indications ( two for pvai and one for various cardiac surgery ) , different colchicine dosage and duration in each study and different intervals and length of follow - up make our results not definite , but worthy of further investigation . furthermore , in copps substudy , most of the af happened after non - cabg surgery so separate study is warranted for different cardiac procedures . thus , our results suggest that an appropriately designed randomized double - blind clinical trial testing the effectiveness of colchicine therapy in preventing af recurrence in a patients undergoing cardiac surgery would be warranted to determine the exact dosage and duration of colchicine treatment in preventing the af recurrence . the results of our meta - analysis have to be interpreted as only hypothesis - generating , rather than conclusion - drawing . indeed , although the pooled treatment effect is quite impressive , with a reduction of more than 50 % of the risk of developing af , the small number of studies , with different clinical indications ( two for pvai and one for various cardiac surgery ) , different colchicine dosage and duration in each study and different intervals and length of follow - up make our results not definite , but worthy of further investigation . furthermore , in copps substudy , most of the af happened after non - cabg surgery so separate study is warranted for different cardiac procedures . thus , our results suggest that an appropriately designed randomized double - blind clinical trial testing the effectiveness of colchicine therapy in preventing af recurrence in a patients undergoing cardiac surgery would be warranted to determine the exact dosage and duration of colchicine treatment in preventing the af recurrence . the results of our meta - analysis have to be interpreted as only hypothesis - generating , rather than conclusion - drawing . indeed , although the pooled treatment effect is quite impressive , with a reduction of more than 50 % of the risk of developing af , the small number of studies , with different clinical indications ( two for pvai and one for various cardiac surgery ) , different colchicine dosage and duration in each study and different intervals and length of follow - up make our results not definite , but worthy of further investigation . furthermore , in copps substudy , most of the af happened after non - cabg surgery so separate study is warranted for different cardiac procedures . thus , our results suggest that an appropriately designed randomized double - blind clinical trial testing the effectiveness of colchicine therapy in preventing af recurrence in a patients undergoing cardiac surgery would be warranted to determine the exact dosage and duration of colchicine treatment in preventing the af recurrence . colchicine may represent a novel strategy in preventing early af recurrence postcardiac procedures , by antiinflammatory action . the results of our meta - analysis suggest a striking reduction of af occurrence associated with colchicine use . this might have clinical and cost benefit in the prevention of af following cardiac surgery .\noutput:\n" }, { "from": "agent", "value": "objectives : inflammation is one of the predictors of atrial fibrillation ( af ) following surgical or interventional cardiac procedures . recent evidence suggests that colchicine may represent a new strategy to prevent af following cardiac procedures . this study aims to assess the antiinflammatory efficacy of colchicine in prevention of early af event ( eafe ) . materials and methods : we reviewed all available studies that assessed the effectiveness of colchicine therapy on the occurrence of af in patients undergoing cardiac procedures . meta - analysis was performed by random effect inverse variance - weighted method by entering af events and the total population from each study.results : after thorough review of the databases , we found three studies comparing colchicine and placebo which had eafe as the outcome . of 584 patients , 286 patients were on colchicine and 298 on placebo . all the three studies were randomized . after pooled analysis , colchicine was associated with significant reduction in af events compared to placebo ( odds ratio = 0.44 [ 0.29 , 0.66 ] , p < 0.001 ) . there was no statistical heterogeneity between included studies ( 2 = 0.45 , p = 0.80 , i2 = 0 % ) . conclusion : colchicine may prove beneficial in the prevention of af following cardiac surgery . further research is warranted ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: as noted above , most of the research on stressor controllability has been directed at understanding how uncontrollable stress produces its behavioral outcomes , such as poor escape learning and exaggerated fear / anxiety . the drn is the largest of the raphe nuclei and provides serotonergic ( 5 - ht ) innervation to much of the forebrain , as well as other structures . we originally studied the drn as a potential critical mediator of the behavioral effects of is because it projects to structures that are the proximate neural mediators of many of the behavioral sequelae of is , and elevated 5 - ht within these structures seemed to produce the appropriate behaviors . for example , the dorsal periaqueductal gray is a proximate mediator of escape behavior , and it is innervated by the drn . analogous neural arrangements existed for many of the other behavioral consequences of is , and so it seemed , a priori , as if the known behavioral consequences of is would occur if is were to differentially activate drn 5 - ht neurons . the drn has proved to have a complex subnuclear organization , with different regions of the drn receiving discrete sets of affrents and having different efferent projections . our work has implicated mid and caudal regions of the drn as being critical to is effects . all that needs to be noted here is that this work , as well as recent research from other laboratories , has delineated a 5 - ht system , projecting to a number of mesolimbic structures , that appears to be important in the mediation of anxiety - like behavior . we have argued that the changes produced by is are much more related to anxiety than depression , and so the argument that what is involved is an exaggerated 5 - ht response is not problematic . the most relevant findings are the following : ( i ) is produces a much greater activation of 5 - ht neurons in the mid and caudal drn than do exactly equal amounts and distributions of escapable tailshock ( es ) . this has been assessed both by an examination of fos in 5 - ht - labeled cells as well as measurement of 5 - ht efflux within the drn and projection regions of the drn15 with in vivo microdialysis ; ( ii ) this intense activation of 5 - ht neurons leads to the accumulation of high extracellular levels of 5 - ht within the drn . this high concentration of 5 - ht desensitizes / downregulates inhibitory somatodendritic 5 - ht1a receptors within the drn for a number of days ; ( iii ) 5 - ht1a desensitization / downregulation within the drn sensitizes drn 5ht neurons since this normal source of tonic inhibition is now reduced . thus , for a number of days , stimuli that normally produce little or no 5 - ht response now induce large 5 - ht activation . behavioral testing conditions such as escape training , fear conditioning , etc , now lead to exaggerated 5 - ht release in projection regions of the drn , the proximate cause of the behavioral outcomes . it is known that drn 5 - ht activity is a cause of the behavioral outcomes of is because lesion of the drn and selective pharmacological inhibition of 5 - ht drn neurons at the time of behavioral testing completely block the behavioral effects of is . in addition , pharmacological inhibition of drn 5 - ht activity at the time of is prevents the usual behavioral outcomes of is from occurring . finally , simply activating drn 5 - ht neurons , in the absence of any is , produces the same behavioral outcomes as does is . this focus on the drn is not meant to suggest that other structures are not involved . for example , the work of x weiss ( eg , ref 20 ) clearly implicates the locus coeruleus ( lc ) . however , the behavioral effects of is and other uncontrollable stressors must be mediated by a complex neural circuit , and the drn is likely but one , albeit critical , part of the circuit . we believe that the drn is a key integrative site on the efferent end of the circuit and receives inputs from multiple key structures . although the work summarized above clearly implicates the drn as a key site in the mediation of the behavioral effects of uncontrollable stress , the concept that it must be part of a more extended circuit naturally suggests the question of whether the drn ( or lc ) could be the structure that detects / learns / perceives whether a stressor is , or is not , under behavioral control . the drn is a small brain stem structure consisting of perhaps 30000 neurons in the rat . thus , it would appear to have neither the inputs required , nor the processing power , to compute whether a stressor is controllable or uncontrollable . the circuitry that performs this analysis must have available to it information concerning exactly when motor responses occur and when the stressor begins and ends . we thus determined inputs to the drn that mediate the effects of uncontrollable stress , and uncovered several ( locus coeruleus , lateral habenula , and likely the bed nucleus of the stria terminalis [ bnst ] ) . however , none were themselves sensitive to stressor controllability - they simply provided excitatory drive to the drn whenever a stressor was present , controllable or uncontrollable . in any case , the detection / computation of degree of control would seem likely to be a cortical function , and so it is of interest to inquire into which regions of cortex provide monosynaptic inputs to the drn . interestingly , the drn receives all , or virtually all , of its cortical inputs from infralimbic ( il ) and prelimbic ( pl ) regions of the medial prefrontal cortex ( mpfc ) . the mpfc is involved with mediating executive functions ; functions that are consistent with behavioral control detection . furthermore , the mpfc has been shown to be a key site in contingency learning as opposed to habit formation , a process very close to control learning . il and pl regions , which comprise the ventral mpfc ( mpfcv ) send excitatory glutamatergic projections to the drn . however , within the drn these pyramidal glutamatergic projections synapse preferentially onto yaminobutyric acid ( gaba ) - ergic interneurons that inhibit the 5 - ht cells . as would be expected from this anatomy , electrical stimulation of regions of the mpfcv that contain output neurons to the drn leads to inhibition of 5 - ht activity within the drn . the fact that activation of mpfcv output to the drn actively inhibits drn 5 - ht activity immediately suggests that if the mpfcv is indeed involved in control / lack of control detection , then perhaps it is really control that is the active ingredient , leading to mpfcv - mediated active inhibition of the drn when it is present . here the idea is that aversive stimulation per se drives the drn , and when the presence of behavioral control is detected by the mpfcv , the drn , and perhaps other stress - responsive limbic and brain stem structures ( see below ) are actively inhibited . in our first attempt to test the role of the mpfcv , we inactivated the mpfcv during exposure to is and es by microinjecting muscimol into the region . muscimol is a gaba agonist , and so inhibits the activity of cells that express gaba receptors , such as the pyramidal output neurons . inactivating the mpfcv did indeed eliminate the differential effects of controllability - that is , is and es now produced the same outcomes . however , mpfcv inactivation eliminated the is - es in a particular way the presence of control was no longer protective , and now es as well as is produced later escape learning failure and exaggerated fear conditioning . furthermore , es now activated the drn to the same degree as did is . inactivatingthe mpfcv did not make is better or worse ; it acted only in es subjects to eliminate the protective effect of control . it is important to note that muscimol microinjection did not retard the learning of the wheelturn escape response during es by the es subjects . that is , the es subjects turned the wheel and terminated the tailshocks , but did not benefit from the experience . this is in keeping with data indicating that the mpfc is not involved in the learning of habits or motor responses , but rather in more complex cognitive aspects of behavior . thus , when the mpfcv was inactivated the animals learned to turn the wheel , but this now did not lead to inhibition of the drn . the drn acted as if the stressor was uncontrollable , even though the rats turned the wheel and escaped normally ! the foregoing suggests that what is important is whether the mpfcv is activated during a stressor , not whether the stressor is actually controllable or not . to further test this idea , we directly activated the mpfcv during is and es . the mpfcv was activated by microinjection of the gaba antagonist picrotoxin , a procedure that has been shown to activate mpfcv output . ( figure 1 ) . shows the results of shuttlebox escape testing administered 24 hours after the es and is sessions , or home cage control treatment . escape trials terminated automatically after 30 sec if the subject failed to escape on that trial , and so group means near 30 seconds indicate that most of the rats in the group completely failed to escape . in vehicle - injected subjects , is interfered with later shuttlebox escape and es did not , as is typical . dramatically , is produced no interference with escape at all if the mpfcv was activated during the is with picrotoxin . these animals did not have a means to control shock during the initial stress experience , but simply activating the mpfc during the stressor protected them . importantly , the drn was now not activated - it responded as if the shock was controllable ( these data are not shown ) . in both humans and animals , an individual 's early or initial experiences with stressors can determine how that individual reacts to subsequent stressful life experiences . many years ago , it was reported that an initial experience with controllable shock blocks the typical behavioral effects of a later exposure to uncontrollable shock , even if the two experiences occur in very different environmentsthis immunization phenomenon is very different than the usual effects of control that have been studied . in the typical experiment , the presence of control blunts the impact of the stressor that is occurring at that time . however , in the immunization paradigm , an initial experience with control blunts the impact of an uncontrollable stressor occurring at a later period of time . this immunization phenomenon has not been studied at the neurobiological level . it is our hypothesis that there is plasticity in this system so that mpfcv activity becomes associated with or tied to the stressor or some aspect of the stress experience such as fear / anxiety ( see below ) . if this were so , then the mpfcv would become activated during the later uncontrollable stressor , thereby inhibiting the drn and protecting the organism from outcomes that depend on drn activation . during the past year we have begun to test this admittedly speculative hypothesis . ( figure 2 ) . shows the results of an experiment in which rats received either es , is , or hc treatment on day 1 , and is in a different environment 7 days later . either intra - mpfcv muscimol or vehicle microinjection preceded the day 1 treatment . as is evident , the experience of es 7 days before is completely blocked the behavioral effect of is . however , mpfcv inactivation during es blocked the ability of es to produce immunization . in a separate experiment , the mpfcv was inactivated at the time of the day 8 is rather than during es on day 1 . thus , mpfcv activity is necessary for immunization , both at the time of the initial experience with control and the later exposure to the uncontrollable stressor for protection to occur . the hypothesis being considered suggests that , as above , it is not control per se that is critical , but rather whether the mpfcv is activated during the initial experience with the aversive event . thus , we conducted an identical experiment to the one just described , but activated the mpfcv with picrotoxin during the day 1 stress session . es , of course , produced immunization . activating the mpfcv by itself , without the presence of a stressor ( p - hc / is ) did not confer protection against the effects of is . that is , the experience of uncontrollable stress actually protected the organism if the mpfcv was activated during the experience . finally , if it is true that after an initial experience with control now even is would activate the mpfcv , then the drn should be inhibited during is . ( figure 4 ) . shows extracellular levels of 5 - ht within the drn during is in animais that had received either is , es , or hc 7 days earlier . is produced a large increase in 5 - ht as usual , but this effect was virtually eliminated by prior es . here , this result is analogous to an illusion of control at the neurochemical level . clearly , an initial experience with control promotes resilience in the face of later aversive stimulation , and does so by activating the mpfcv . to this point we have focused on the interaction between the mpfcv and the drn , with control leading to protection against the effects of aversive events by increasing mpfcv inhibition of the drn . however , the mpfcv projects to other stressresponsive structures as well . the amygdala is a key site in the mediation of fear and anxiety its role in fear conditioning is well known , and fear conditioning has been argued to be a key process in the development of a number of anxiety disorders . the work of numerous investigators has suggested the following scenario ( see ref 35 for a review ) . inputs from neutral stimuli ( the conditioned stimulus [ cs ] , eg , a tone ) and aversive stimulation ( the unconditioned stimulus [ us ] , eg , a footshock ) converge in the lateral amygdala ( la ) where the association between the cs and us is formed by an amethyldaspartate ( nmda ) / longterm potentiation ( ltp ) - dependent process . expression of conditioned fear involves cs transmission to the la , connections from the la to the central nucleus of the amygdala ( ce ) either directly or indirectly via the basal nucleus , and then output connections from the ce to regions of the brain that are the proximate mediators of the specific aspects of fear responses ( autonomic , endocrine , and behavioral ) . this is an oversimplified scheme ( eg , 36 , 37 ) , but it nevertheless captures a large amount of data . in the present context , it is interesting to note that the mpfcv projects to the amygdala , and stimulation of the mpfcv has been reported to inhibit the increase in electrical activity in the la produced by an already conditioned fear stimulus , as well as the fear response to that stimulus , and to prevent the association between cs and us when they are paired . similarly , quirk et al found that mpfcv stimulation reduces output from the ce in response to electrical stimulation of input pathways to the ce , and milad et al found mpfcv stimulation to reduce fear responses produced by a fear cs . although the exact projections of the mpfcv to the amygdala responsible for the inhibition of fear conditioning and fear responses resulting from mpfcv stimulation are unclear , the mpfcv does project to the intercalated cell mass ( itm ) within the amygdala . these cells are almost all gabaergic , and project to the ce , providing an obvious pathway by which mpfcv activation could inhibit the ce . indeed , berretta et al found that stimulation of the mpfcv with picrotoxin increases fos expression in the gabaergic cells of the itm . the foregoing suggests that any factor that increases mpfcv output to the amygdala should reduce fear . we have reviewed research that suggests that behavioral control increases mpfcv output to the drn , thereby reducing drn - driven behavioral changes . perhaps this phenomenon is more general , and control also increases mpfcv output to the amygdala , thereby inhibiting ce function and fear . consistent with this possibility , it is already known that es leads to the conditioning of less fear to cues that are present than does is . however , the possibility being considered here makes an even stronger prediction . recall that an initial experience with es protected the organism against the effects of subsequent is , the argument having been that the original experience led the later is to now activate the mpfcv . if this were so , then an initial experience with es should actually interfere with fear conditioning conducted some time later in a different environment . to begin to explore these ideas , we first gave rats es or yoked is in wheel turn boxes , or hc treatment . a tone was paired with gridshock , and the level of conditioning to the tone and to the environmental context was measured 2 days later . the rats were simply placed in the fear conditioning chamber for 5 min and freezing assessed . to assess fear conditioned to the tone , the rats were placed in a novel chamber and freezing measured for 3 min . first , it should be stated that there was virtually no freezing at all on the conditioning day before the first footshock . thus , the freezing observed on the test day was the result of conditioning , not some aftereffect of the earlier is or es . the results for fear conditioned to the context are on the left . is 7 days before fear conditioning exaggerated fear conditioning , a result that was already known . the results for conditioning to the tone , shown on the right , were similar . these results are dramatic , as es is itself quite stressful and is not somehow negative stress . indeed , the es conditions used here produce a hypothalamo - pituitary - adrenal response that is as large as that produced by is . we know of no other position that would predict , or even explain , how exposure to a highly stressful event could retard the later development of fear . clearly , much more work is needed , but it may be that experiences of control produce resilience in the face of circumstances that induce fear . the amygdala is importantly involved in fear - related processes that go beyond the conditioning of fear to anxiety more generally it thus may be that experiences of control , and other circumstances that might activate the mpfcv , confer resistance to the development of anxiety . the general conclusion to be reached is that control is not detected or computed by brain stem structures such as the drn , but rather by circuitry within the mpfcv . stress or aversive stimulation per se would seem to activate structures such as the drn , with this activation then being inhibited by input from the mpfcv if behavioral control is present . primitive organisms possess only a limited behavioral capacity to deal with threats , and in such species adaptations and responses to threats are largely physiological in nature . for these types of species behavioral control and other methods of psychological coping are largely irrelevant , and so it may make sense that more primitive parts of the brain that are involved in responding to threats are themselves insensitive to dimensions such as behavioral controllability . as organisms became more complex , in which a threat can be dealt with behaviorally , it would be adaptive to inhibit or reduce the more physiological adaptive mechanisms since they can be costly in various ways . of course , higher regions of the brain such as the mpfc would have taken this function . it is also possible that a lack of control might weaken the inhibitory control exerted by the mpfc . the experiments discussed above were not well suited to detecting effects in this direction given possibleindeed , we have some evidence that uncontrollability might exert this sort of effect , but it is too preliminary to present . although our evidence is limited , it further suggests that initial experiences with stressors can bias the system such that the mpfcv responds to later stressors as it did to earlier stressors . if this plasticity proves to be real , then this would constitute a mechanism of resilience . the fear conditioning data presented above suggests that this mechanism may generalize broadly , with control over tailshock generalizing to fear conditioning . of course , there is no reason to believe that behavioral control is unique , and there are likely other aspects of experience that would activate mpfcv inhibition of stressresponsive limbic and brain stem structures . imaging studies of ptsd are especially illuminating in the present context , since they typically measure both amygdala and mpfc function . not surprisingly , ptsd patients show substantial amygdala activation to stimuli related to the events that caused the disorder . thus , combat veterans with ptsd show exaggerated amygdala activation to war scenes , relative to non - ptsd controls . interestingly , they also show exaggerated amygdala activity to fear stimuli unrelated to combat , such as fearful faces . however , ptsd patients have reduced mpfc activity in response to these stimuli , and this often correlates with the degree of disorder . it is possible that there is exaggerated amygdala activation in ptsd because there has been a loss of mpfc inhibition of the amygdala . many of the events that induce ptsd are ones over which the individual has little behavioral control not all of the individuals who experience these events develop ptsd , and it may be that earlier experiences with control or other forms of coping protect against the development of the disorder by biasing the mpfc to respond actively , thereby maintaining inhibition of the amygdala , and perhaps other stress - responsive structures .\noutput:\n" }, { "from": "agent", "value": "the degree of control that an organism has over a stressor potently modulates the impact of the stressor , with uncontrollable stressors producing a constellation of outcomes that do not occur if the stressor is behaviorally controllable . it has generally been assumed that this occurs because uncontrollability actively potentiates the effects of stressors . here it will be suggested that in addition , or instead , the presence of control actively inhibits the impact of stressors . at least in part this occurs because ( i ) the presence of control is detected by regions of the ventral medial prefrontal cortex ( mpfcv ) ; and ( ii ) detection of control activates mpfcv output to stress - responsive brain stem and limbic structures that actively inhibit stress - induced activation of these structures , furthermore , an initial experience with control over stress alters the mpfcv response to subsequent stressors so that mpfcv output is activated even if the subsequent stressor is uncontrollable , thereby making the organism resilient . the general implications of these results for understanding resilience in the face of adversity are discussed ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the world health organization currently recognizes cardiovascular disease ( cvd ) as the top cause of morbidity and mortality in the adult population worldwide , responsible for approximately 17 million deaths in 2008 , representing 48 % of global mortality from noncommunicable diseases , and with an estimated projection of 23.6 million yearly deceases by 2030 . venezuela depicts an aggravating scenario in this respect , as heart disease currently accounts for 21.36 % of total national mortality , propelling our country to one of the highest adjusted rates of cardiovascular mortality in latin america , with 104.2 deaths per 100,000 inhabitants during the 20032005 period . given the epidemic status cvd has reached worldwide and the profound impact it generates on public health systems at all levels , prevention strategies have become a first - line topic of scientific interest , particularly concerning risk factors and their involvement in the onset and development of disease . the third report of the expert panel on detection , evaluation and treatment of high blood cholesterol in adults ( atp iii ) categorizes cardiovascular risk factors as ( a ) nonmodifiable , such as age , gender , and ethnicity ; ( b ) modifiable , including diabetes mellitus , hypertension , dyslipidemia , and smoking ; and ( c ) emerging risk factors , encompassing triacylglycerides , homocysteine , and various inflammatory markers . an acute - phase reactant remains the most studied molecule from the latter category , exhibiting many properties which may intervene in atherogenesis . nonetheless , ongoing intense debate remains regarding its relative importance among other risk factors and its true impact on this process . indeed , evidence has suggested that crp may only potentiate vulnerability of the atheromatous plaque and formation of thrombi , rather than participate in the buildup of atheromas per se , highlighting the need for further research on crp . this review presents the molecular basis and currently known mechanisms for the involvement of crp in development and progression of atherosclerosis . crp was first described in 1930 by tillet and francis , named after its ability to precipitate and interact with phosphorylcholine residues of the c polysaccharide derived from teichoic acid within the cellular wall of streptococcus pneumoniae , as well as its ability to precipitate with calcium ions . although crp is classically considered an important regulator of the innate immune system and a paramount mediator of the acute - phase response , it has also been associated with various chronic inflammatory processes , such as certain rheumatologic conditions , cancer , and cvd . crp is a 206 - amino acid member of the short pentraxin family , alongside serum amyloid p component ( sap ) , with high phylogenetic conservation . pentraxins share a characteristic structure : five identical nonglycosylated globular subunits each of which is constituted by two - pleated sheets which are noncovalently associated and arranged in a symmetric cyclic pattern around a central pore , determining a pentameric , discoidal , and flattened configuration ( figure 1 ) . c - reactive protein is predominantly synthesized in the liver ( 1q23 .2 ) , typically within the transcriptional phase of the response to proinflammatory cytokines . il - 6 appears to be the main regulator , by promoting de novo synthesis of crp via upregulation of c / ebp and c / ebp , key transcription factors in this process . in addition , il - 6 signaling may be reinforced by il - 1 and tnf , both of which increase transcription rate of crp . serum crp levels have also been closely linked to signaling by proinflammatory cytokines released by visceral adipose tissue . indeed , both hypoadiponectinemia and hyperleptinemia , two adipokine disturbances common in subjects with obesity and insulin resistance , have been linked to increased hepatic production of crp , as well as augmented in situ synthesis of crp in vascular endothelial cells in hyperleptinemia . in thisregard , adipose tissue has been well characterized over recent decades as an endocrine organ , with important immunomodulatory roles through release of inflammatory messengers such as il - 1 , il - 6 , and resistin , among others , underlying the chronic inflammatory component of obesity . adipocyte dysfunction is the central phenomenon in this scenario , encompassing hyperplasia and hypertrophy of these cells due to lipid storage increase , which leads to hypoxia , rupture propensity , and ultimately proinflammatory adipokine secretion in this tissue . moreover , crp has been shown to be expressed in adipocytes in response to proinflammatory mediators , representing yet another link between obesity and chronic inflammation . following synthesis andrelease into circulation , serum crp levels tend to increase significantly 68 hours after initial stimulation , peaking at 2448 hours , with a half - life of approximately 19 hours . although the liver is the main site for production and release of crp , its mrna has been found in a myriad of extrahepatic sites , including adipose tissue , lungs , epithelial cells of renal cortical tubules , lymphocytes , and atherosclerotic lesions , in both macrophages and smooth muscle cells . numerous studies have focused on identifying other extrahepatic sources of crp production that may underlie the lower and more sustained crp concentrations which appear to predict cardiovascular risk ; these include findings of crp synthesis in coronary smooth muscle cells in response to inflammatory cytokines . crp has been described to adopt two different conformational forms : the native pentameric isoform ( pcrp ) and the monomeric isoform ( mcrp ) , which possess distinct antigenic , electrophoretic , and biological features ( figure 1 ) . although pcrp is the main form detected in serum and appears to be a very stable molecule , current evidence suggests that conformational subunits from pcrp can be dissociated , both in vitro and in vivo , into individual mcrp units . on the other hand , independent mcrp synthesisthe two main mechanisms for in vivo generation of mcrp may be summarized as follows.local expression : numerous studies report the presence of mcrp mrna in various extrahepatic tissues , including adipocytes , smooth muscle cells , and inflammatory cells within atheromatous plaques . recent in vitro studies support local expression , with the detection of mcrp mrna in u937 macrophages of atherosclerotic lesions . in addition , greater mcrp expression has been ascertained in atherosclerotic lesions of diabetics , in association with greater systemic inflammation . local dissociation : dissociation of pcrp into mcrp has been observed in membranes of apoptotic cells and activated platelets in atherosclerotic plaques , representing an important interface between innate and adaptive immunity , thrombosis , and atherogenesis . phosphatidylcholine molecules in the cell membrane of activated platelets appear to be important in this process , as this phospholipid is able to bind to circulating pcrp and induce its dissociation . in a primary step of this process , a hybrid intermediate molecule termed mcrpm is formed , exhibiting crp subunit antigenicity , yet retaining native pentameric conformation . this molecule rapidly detaches from cell membrane and finally dissociates in solution into mcrps , the final and most important form of mcrp . local expression : numerous studies report the presence of mcrp mrna in various extrahepatic tissues , including adipocytes , smooth muscle cells , and inflammatory cells within atheromatous plaques . recent in vitro studies support local expression , with the detection of mcrp mrna in u937 macrophages of atherosclerotic lesions . in addition , greater mcrp expression has been ascertained in atherosclerotic lesions of diabetics , in association with greater systemic inflammation . local dissociation : dissociation of pcrp into mcrp has been observed in membranes of apoptotic cells and activated platelets in atherosclerotic plaques , representing an important interface between innate and adaptive immunity , thrombosis , and atherogenesis . phosphatidylcholine molecules in the cell membrane of activated platelets appear to be important in this process , as this phospholipid is able to bind to circulating pcrp and induce its dissociation . in a primary step of this process , a hybrid intermediate molecule termed mcrpm is formed , exhibiting crp subunit antigenicity , yet retaining native pentameric conformation . this molecule rapidly detaches from cell membrane and finally dissociates in solution into mcrps , the final and most important form of mcrp . monomeric crp is scarcely found in circulation through common quantification methods , suggesting a predominance of local expression , such as that seen in normal vascular tissue . nonetheless , novel techniques , such as employment of monoclonal antibodies and rna aptamers for mcrp , allow for determination of nanomolar concentrations of this form , representing an important tool for further understanding the impact of mcrp in future research . to date , phosphatidylcholine remains the most important crp ligand , a phospholipid expressed in bacterial , fungal , and eukaryotic cells , particularly if these are necrotic or apoptotic , as well as in native and modified lipoproteins . the crp - binding sites for phosphatidylcholine are located on the lateral surfaces of each subunit and require binding of two calcium ions at specific hydrophobic pockets centered on phe66 , in an event known as calcium - dependent ligand binding . then , crp is able to interact with c1q , activating the classical pathway of the complement system . crp also has the ability to interact with other autologous ligands , such as modified and unmodified plasma lipoproteins , histones , chromatin , and small ribonucleoproteins , as well as extrinsic ligands , mainly somatic components of bacterial , fungal , and parasitic cell walls and membranes . furthermore , exposure to acidic environments , such as those found at inflammation sites , triggers conformational modifications in crp , revealing two additional binding sites within the intersubunit regions of crp , in the loop containing residues 115123 , although the specific amino acids implicated remain unelucidated . while the first site binds factor h , the second site may bind any structurally altered protein irrespective of its identity . alongside phosphatidylcholine , pcrp may also bind to phosphocholine and human complement factor h - related protein 4 ( cfhr4 ) until its dissociation into mcrp . release of the individual subunits permits exposure of previously hidden epitopes , which entail distinct antigenic features and are capable of activating platelets , polymorphonuclear leukocytes , monocytes , lipoproteins , and the complement system in vitro . regarding its receptors , this protein can be recognized by immunoglobulin g ( igg ) and fcr receptors , which are cell surface glycoproteins expressed in numerous cells , including macrophages , mast cells , platelets , and leukocytes , of both lymphoid lineage and myeloid lineage . depending on the affinity with which immunoglobulins bind to the receptor , the fcr receptors are classified either as high - affinity known as fcri ( cd64 ) or as low - affinity receptors , such as fcrii ( cd32 ) and fcriii ( cd16 ) . these may also be further classified by their encoding genes into three distinct subgroups : a , b , and c. the signal transduction mechanism triggered by these receptors depends on activation motifs ( itam ) or inhibition motifs ( itim ) located in tyrosine - based immunoreceptors , present in cytoplasmic portions or accessory chains . the fcriib is the only one of these receptors that contains an itim domain in its cytoplasmic portion , which allows it to negatively modulate the signaling cascade . pcrp can bind specifically to fcri in macrophages and to fcriia , in macrophages and platelets . on the other hand , mcrp isoform can only interact with the fcriii receptor , expressed primarily in platelets and endothelial cells ( table 1 ) . recent reports have commented on the crp - binding capacity of lectin - like oxidized low density lipoprotein receptor - 1 ( lox - 1 ) , confirmed through several methods , including immunofluorescence . this phenomenon has been linked to induction of complement activation , leukocyte infiltration , and modification of vascular response to vasodilators , representing a shared pathway for crp and oxidized ldl ( ldl - ox ) in endothelial dysfunction . crp has also been described to induce secretion of a soluble isoform of lox - 1 ( slox - 1 ) in classically activated macrophages and in macrophages derived from peripheral blood mononuclear cells of patients with acute coronary syndrome , in a process which appears to involve fcriia , tnf , and ros production . moreover , similar observations have been made in current smokers and patients with stable coronary disease . these observations outline possible clinical applications for lox - 1 , as a prognostic factor in acute coronary syndrome and as a potential pharmacological target , with a report describing reduced vascular toxicity induced by crp and lox - 1 following treatment with atorvastatin . inflammatory mechanisms play a fundamental role in all phases of atherosclerosis , from the initial recruitment of circulating leukocytes to the rupture of unstable plaques . among multiple inflammatory biomarkers , crp boasts the largest body of research supporting its role as an independent risk factor in the development of cvd , as it actively participates in atherogenesis by directly influencing processes such as activation of the complement system , apoptosis , vascular cell activation , monocyte recruitment , lipid accumulation , and thrombosis . both isoforms are involved in such processes : pcrp can generate inflammatory responses binding to the phosphatidylcholine on the exterior of ldl - ox and the surface of apoptotic cells , while mcrp is able to modulate platelet function inducing aggregation and contributes to atherothrombotic complications by promoting thrombosis ( figure 2 ) . the complement system is a set of enzymes and bioregulators with multiple biological activities , playing a key role in both innate ( alternative and lectin pathway ) and acquired ( classical pathway ) immunity . its proper activation is essential for defense against pathogens and elimination of apoptotic and necrotic cells . nevertheless , excessive or inappropriate activation of this system contributes to the pathogenesis of many chronic inflammatory diseases , including atherosclerosis . both crp isoforms have the ability to interact with c1q , activating the classical pathway . recent studies report the presence of crp mrna and depots with high concentrations of c1q , c3 , and c4 in atherosclerotic plaques , suggesting that crp may amplify and facilitate activation of the classical pathway , with the subsequent formation of the membrane attack complex ( mac ) . furthermore , activation of this pathway may contribute to the establishment and progression of atherosclerosis by inducing the proliferation of arterial smooth muscle cells and increased synthesis and secretion of il - 8 and monocyte chemotactic protein ( mcp - 1 ) . crp also participates in the activation of nuclear factor kappa b ( nf - b ) , a transcription factor present in rapid - response cells involved in immune and inflammatory reactions , increasing the production of cytokines , chemokines , adhesion molecules , growth factors , and immunoreceptors in several cell types within the atherosclerotic plaque . crp also exhibits affinity with members of the factor h protein family , providing binding sites for factor h in the mcrp isoform , to which it binds in a calcium - independent fashion . these proteins may facilitate recruitment of crp to the surface of necrotic cells , acting as soluble regulators of the alternative pathway of the complement system . excessive activity of this pathway leads to the presence of high circulating levels of c3a and c5a , potent anaphylatoxins involved in local inflammatory responses . in vitro studieshave shown expression of cr3 and cr5a in coronary artery atherosclerotic plaques , favoring chemotaxis of monocytes , mast cells , and lymphocytes , expression of endothelial adhesion molecules , release of tnf and il - 1 , and production of reactive oxygen species by macrophages located within the lesion . the fcr family includes major crp targets , expressed in numerous cells of the immune system , controlling activation , proliferation , phagocytosis , degranulation , and cytokine secretion , thus regulating local inflammatory processes , such as those occurring in atherosclerotic plaques . both crp isoforms can bind to fcri , fcriia , and fcriii , inducing conformational changes in their structures that trigger intracellular signaling cascades through their itam motifs . generally , this cascade would start with the sequential activation of a tyrosine protein kinase ( pkt ) of the src family , which phosphorylates tyrosine residues of this motif , followed by activation of syk tyrosine kinase . this would result in the recruitment of multiple signaling molecules , including other kinases such as protein kinase c ( pkc ) , extracellular signal - regulating kinases ( erk ) , mitogen activating protein kinases ( mapk ) , and phosphatidyl inositol -3-kinase ( pi3k ) , as well as phospholipase c ( plc ) , intracellular adaptation molecules , and second messengers such as calcium ( ca ) , diacylglycerol ( dag ) , and inositol -3-phosphate ( pi3 ) . however , recent evidence suggests that once bound to the fcriib receptor which has itim inhibitory intracellular domains in endothelial cells , crp starts a cascade characterized by the activation of phosphatases , such as ship - 1 , which then inactivate and regulate the signaling molecules previously described . recent reports suggest that pcrp may be a direct regulator of endothelial cell activation and dysfunction , by inducing the expression of intracellular adhesion molecules , vascular e - selectin , and monocyte chemoattractant protein - 1 ( mcp - 1 ) , which permits chemotaxis and binding of monocytes to endothelial cells during the early stages of atherogenesis . moreover , crp may drive human monocyte differentiation towards a proinflammatory m1 phenotype , mediated by fc receptors and the nf - b pathway , as well as inducing a shift in cytokine secretion patterns in m2 macrophages towards a m1 - like proinflammatory phenotype . additionally , in vitro studies indicate that crp at concentrations 10 g / ml is linked to a decrease in the synthesis of prostaglandin f - 1 , a stable metabolite of prostacyclin which regulates important endothelial processes such as vasodilation , platelet aggregation , and smooth muscle cell proliferation . similarly , crp may generate overexpression of angiotensin type 1 receptor ii ( atr - 1 ) through the mapk and nf - b pathways , favoring proliferation , remodeling , and migration of smooth muscle cells in atherosclerotic lesions . furthermore , crp isoforms play an important differential role in the modulation of endothelial progenitor cell ( epc ) proliferation . while pcrp appears to favor epc proliferation and induce primarily noninflammatory gene expression of these cells , mcrp does not seem to affect epc proliferation rate but rather induce upregulation of proinflammatory , interferon - responsive genes . ultimately , the dissociation of pcrp into mcrp may be viewed as a master switch for the focalization of the inflammatory processes involved in the formation of the atherosclerotic plaque : by binding to phosphorylcholine in the membrane of activated platelets , pcrp is able to localize its dissociation to the vicinity of the plaque , leading to an in situ accumulation of mcrp , which favors the further development of the plaque by all previously described mechanisms . metalloproteinases are proteolytic enzymes responsible for remodeling the extracellular matrix ( ecm ) , which have been implicated in the development and rupture of atherosclerotic plaques . in vitro and in vivo studieshave demonstrated crp to augment expression of metalloproteinase - 1 ( mmp - 1 ) and metalloproteinases 1 , 2 , and 9 via p38 - mapk , erk , and jnk signaling . nitric oxide ( no ) is a simple gas produced by a group of enzymes termed no synthases . these are widely distributed in several tissues , particularly in endothelial cells , where they mediate vasodilation and antioxidant and antithrombotic effects . in vitro and in vivo studiesindicate that crp may interfere with no synthesis by inhibiting endothelial nitric oxide synthase ( enos ) activity through various pathways , all of which ultimately lead to endothelial dysfunction . to this end , crp has been demonstrated to inhibit gtp cyclohydrolase 1 through the p38 kinase pathway ; this enzyme is the first step in the de novo synthesis of tetrahydrobiopterin , an important cofactor for enos . as a result , decreased tetrahydrobiopterin leads to decoupling of enos and depletion of no levels , favoring endothelial dysfunction . additionally , fc receptors , as well as cd32 and cd64 receptors , have been shown to mediate a decrease in the phosphorylation of enos in ser1177 and an increase in phosphorylation of thr495 , resulting in diminished enos activity . several reports indicate that inhibition of this enzyme may be mediated specifically by fcriib through the phosphatase 2a pathway , preventing bradykinin - and insulin - triggered phosphorylation of enos . yet another mechanism contributing to endothelial dysfunction involves modification of protein - protein interactions of enos with heat shock protein 90 ( hsp90 ) and caveolin - 1 , decreasing binding to the former and increasing binding to the latter , resulting in reduced enos activity . mcrp selectively binds to low density lipoprotein ( ldl ) and , in a lesser proportion , to very low density lipoproteins ( vldl ) , while pcrp interacts mainly with highly immunogenic forms of these lipoproteins , such as ldl - ox , enzymatically altered ldl ( e - ldl ) , and minimally modified ldl ( mmldl ) . microenvironmental ph at the inflammation site plays a key role in the binding of crp to lipoproteins , as the binding site for ldl - ox is only revealed after modifications in the structure of crp triggered by acidic milieus . furthermore , despite being able to bind e - ldl at physiological ph , acidic ph enhances affinity for this modified lipoprotein . this association is thought to lead to opsonization and subsequent phagocytosis of ldl - ox and , in consequence , formation of a characteristic component of atherosclerotic plaques : foam cells ( figure 3 ) . in vivo assayshave demonstrated that crp not only promotes uptake of ldl - ox but also stimulates accumulation of cholesterol esters in human macrophages . likewise , pretreatment with anti - cd32 , cd36 , and cd64 diminishes crp activity , suggesting involvement of both fc and scavenger receptors . lastly , although pcrp may exert some anti - inflammatory effects by binding mmldl and consequently attenuating monocyte activation , this property is lost when dissociated into mcrp , further highlighting the importance of this dissociation as a localized inflammation mechanism . each isoform appears to play distinct roles throughout the atherosclerotic process , and both are subjects of continuous study . effector role in atherosclerosis , in contrast to pcrp , which may be described as a facilitator in circulation , awaiting dissociation for focalization of proinflammatory effects to injured sites , such as atheromatous plaques . in this context , the only relation between pcrp and activated platelets seems to be its dissociation into mcrp on their surface , as only the latter favors thrombosis in this scenario by promoting platelet aggregation , surface p - selectin and cd63 exposure , and glycoprotein iib - iiia activation . likewise , mcrp induces expression of tissue factor in endothelial cells , favoring fibrinolytic resistance and endothelial dysfunction , and is also much more effective than pcrp at inducing chemotaxis and binding to integrin in macrophages , as well . indeed , current knowledge depicts mcrp to exhibit more deleterious actions than pcrp and seems to be more powerful regarding the effects they share in atherosclerosis , although further research may reveal novel aspects in the properties of both isoforms that may modify this outlook . the concept of atherosclerosis has long diverged from mere lipid deposition in arterial walls , towards the current notion that describes it as a complex chronic inflammatory process . in this scenario , crp may play an active role through a wide array of mechanisms , although primarily via activation of the complement system and metalloproteinases , and recruitment and activation of inflammatory cells . simultaneously , crp favors the establishment of a generalized chronic inflammatory state and in turn potentiating atherosclerosis . although mcrp appears to drive most of these effects , further research is required in order to differentially characterize the roles of crp isoforms . moreover , many epidemiological studies have shown an association between crp and cardiovascular risk , and its clinical utility is currently a topic of great debate , with novel proposals for scenarios where its evaluation may be useful , including the use of fractions of crp as a new element in the diagnostic workup of patients with acute coronary syndrome and the designation of crp as a potential therapeutic target given its exhaustive involvement in the pathophysiology of atherosclerosis . in this context , the results from the jupiter study offer some insight into this possibility , by ascertaining better health outcomes in patients with lower crp levels . thus , further experimental testing is required to elucidate its true involvement as a risk factor , as well as population studies exploring the epidemiologic behavior of crp .\noutput:\n" }, { "from": "agent", "value": "cardiovascular disease is the leading cause of morbidity and mortality in the adult population worldwide , with atherosclerosis being its key pathophysiologic component . atherosclerosis possesses a fundamental chronic inflammatory aspect , and the involvement of numerous inflammatory molecules has been studied in this scenario , particularly c - reactive protein ( crp ) . crp is a plasma protein with strong phylogenetic conservation and high resistance to proteolysis , predominantly synthesized in the liver in response to proinflammatory cytokines , especially il - 6 , il - 1 , and tnf . crp may intervene in atherosclerosis by directly activating the complement system and inducing apoptosis , vascular cell activation , monocyte recruitment , lipid accumulation , and thrombosis , among other actions . moreover , crp can dissociate in peripheral tissue including atheromatous plaques from its native pentameric form into a monomeric form , which may also be synthesized de novo in extrahepatic sites . each form exhibits distinct affinities for ligands and receptors , and exerts different effects in the progression of atherosclerosis . in view of epidemiologic evidence associating high crp levels with cardiovascular risk reflecting the biologic impact it bears on atherosclerosis measurement of serum levels of high - sensitivity crp has been proposed as a tool for assessment of cardiovascular risk ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in 2011 , the centers for disease control and prevention ( cdc ) assisted state and local health departments in an investigation of a cluster of wnv disease transmitted through solid organ transplantation ( 6 ) . the adult male donor had a history of cerebral palsy , seizures , and blindness . he was cared for at home and had outdoor exposure in a county with known wnv activity . in late summer , he had acute onset of fever and lethargy ; 2 days after symptom onset , a urinary tract infection was diagnosed , and he received oral antimicrobial drugs . after consent was obtained , solid organs ( i.e. , kidneys , lungs , and liver ) and tissues ( i.e. , skin , fat , muscle , tendon , and bone ) were procured 9 days after his illness onset . the donor s organs were transplanted into 4 recipients ; none of the donor tissues were transplanted . after wnv infection was detected in 1 of the organ recipients 10 days after transplantation , the donor s stored clinical samples ( i.e. , serum and spleen / lymph node homogenate ) were retrospectively tested for wnv ; this testing occurred within 5 weeks after transplantation . the donor s serum sample was positive for wnv igm , igg , and neutralizing antibodies by serologic testing but negative for wnv rna by nucleic acid amplification testing . subsequently , all 4 organ donor recipients were tested and had positive results for wnv rna . five weeks after the donor s death , frozen spleen / lymph node homogenate from the donor that had been used for human leukocyte antigen testing was sent from the transplant center to cdc , and initial wnv pcr testing was performed as part of the transplant - transmission investigation ( 7 ) . eight weeks after the donor s death , skin samples that had been treated in cryopreservative solution containing an antibiotic and unprocessed fat , muscle , tendon , and bone samples , all of which had been stored frozen at 70c at a tissue bank , were transferred to cdc . at cdc , the tissues remained frozen at 20c to 70c in individual double - wrapping and plastic bags and were handled and tested separately to reduce the risk for cross - contamination . rna was extracted from each 35 mm section of tissue by using a phenol - chloroform extraction method as described ( 8 ) , with the following modifications . tissue was homogenized in buffer rlt ( qiagen , valencia , ca , usa ) and digested with proteinase k for 15 min at 55c ; an additional 24 - h digestion at 40c was used for bone . rna samples were tested by using wnv - specific reverse transcription pcr ( rt - pcr ) targeting the nonstructural protein 1 ( ns1 ) , capsid , and premembrane genes ( 9 ) . , we injected homogenates from tissues positive by rt - pcr into vero e6 cells ; for cells with cytopathic effect , we confirmed the presence of wnv by rt - pcr , immunofluorescence , and electron microscopy . immunohistochemical ( ihc ) staining for wnv was performed on rna - positive tissues ( 10 ) . rt - pcr was performed 2526 weeks after the specimens were collected from the donor ; virus culture and ihc staining were performed 50 weeks after specimens were collected . wnv rna was detected in samples from the spleen / lymph node , skin , and fat associated with the tibia bone , as well as 1 of 2 muscle specimens , 1 of 4 tendon specimens , and 1 of 2 bone marrow specimens ( table ) . cytopathic effect was noted only in vero cells injected with the spleen / lymph node homogenate ; these cells were positive for wnv by rt - pcr , immunofluorescence , and electron microscopy . cytopathic effect was not observed in vero cells injected with skin , fat , muscle , tendon , or bone marrow . results of ihc staining of skin , fat , muscle , and bone marrow samples were negative for wnv antigens . * wnv , west nile virus ; rt - pcr , reverse transcription pcr ; ihc , immunohistochemical ; + , positive ; nt , not tested ; , negative . for spleen / lymph node homogenate , fat , tendon , muscle , bone marrow , and bone , a single sample was tested for wnv rna by rt - pcr . if positive , a second specimen was tested by rt - pcr , inoculated into vero e6 cells , and evaluated by ihc . for skin , after initial wnv rt - pcr was positive , 3 subsequent samples were tested for wnv rna by rt - pcr , inoculated into vero e6 cells , and evaluated by ihc . we identified wnv rna in spleen / lymph node homogenate , skin , fat , muscle , tendon , and bone marrow samples obtained postmortem from a donor associated with transmission of wnv through solid organ transplantation . however , infectious virus could not be cultured , and wnv antigens were not identified by ihc staining from any of the wnv rna - positive tissues . data on the detection of wnv in postmortem organs or tissues are limited . in a study published in 1954 , a total of 95 patients with terminal cancer were injected intramuscularly with wnv ( 11 ) . among 14 patients who died within 1 month after inoculation , virus was isolated postmortem from solid organs in 11 patients and , in 1 patient each , from skin , muscle , or connective tissue . in a more recent study of 6 patients with fatal mosquito - borne wnv encephalitis , wnv rna or antigenswere variably detected in solid organ samples from all patients , and wnv antigens were identified in skin samples from 1 patient ( 12 ) . however , 4 ( 67 % ) of these patients were severely immunocompromised transplant recipients ; of the 2 immunocompetent patients , 1 had wnv rna in brain , spleen , and kidney samples and 1 had wnv antigens only in brain samples . wnv has also been cultured from an antemortem skin biopsy sample from a patient with rare hemorrhagic manifestations of disease ( 9 ) . the tissues were stored frozen for almost 1 year before culture , which may have decreased the ability to isolate viable wnv , although virus was isolated from the spleen / lymph node homogenate . several tissues that are commonly transplanted with minimal processing ( e.g. , corneas , heart valves , and vascular grafts ) and that have been implicated in recent transmission of other viruses , such as hepatitis b and c ( 13,14 ) , were not procured or tested in our study . finally , although the specimens were stored , handled , and tested individually , false - positive results or cross - contamination can not be completely ruled out . although wnv rna was detected in unprocessed tissues obtained from the organ donor , the absence of viral antigen by ihc staining and failure to culture infectious virus from skin , muscle , and tendon suggests that the risk for wnv transmission may be lower for transplantation of these tissues than for transplantation of solid organs . further studies are needed to determine if infectious wnv can be recovered from and possibly transmitted by transplantation of postmortem tissues and , if so , to assess the period of risk and whether tissue processing would mitigate the risk ( 15 ) .\noutput:\n" }, { "from": "agent", "value": "we identified west nile virus ( wnv ) rna in skin , fat , muscle , tendon , and bone marrow from a deceased donor associated with wnv transmission through solid organ transplantation . wnv could not be cultured from the rna - positive tissues . further studies are needed to determine if wnv can be transmitted from postmortem tissues ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: surgical or subcutaneous emphysema ( presence and spread of air in subcutaneous or submucous tissues ) is a common finding in maxillofacial practice . it is also a frequent complication of trauma , surgery , endoscopy , endotracheal intubation and multitude of other conditions . although different sources are described , chest trauma remains the most frequent cause of subcutaneous emphysema following blunt or penetrating injuries . associated pneumomediastinum ( pm ) or mediastinal emphysema usually denotes a primary perforation of visceral organ such as trachea , esophagus , bronchus or an intraabdominal hollow viscus injury . subcutaneous emphysema is caused by the upward movement of gas to the subcutaneous areas through fascial planes ; the reverse pathway is very rare ( occurrence of pm after maxillofacial trauma ) . herein , we report an atypical case of mediastinal emphysema secondary to orbital floor fracture . a 45 - year - old nepalese male presented to the trauma room after facial trauma assault . he has been hit mainly to his face 2 days prior to the index admission . the patient complained of left - sided facial swelling and pain with chest pain and progressive difficulty in swallowing . initial vital signs showed blood pressure of 120/80 mmhg , a pulse rate of 92 beats / min and a respiratory rate of 26 breaths / min . on physical examination , left periorbital swelling and tenderness were observed . extraocular eye movements were intact in all directions and there was no sign of diplopia . by palpation of larynx , laryngeal skeleton was intact and the endolaryngeal examination revealed normal mucosal integrity . palpation revealed tactile crepitus over the left orbit , cheek , neck and thoracic wall . chest x - ray and head , neck and chest computed tomography ( ct ) confirmed the diagnosis and extension of pm ( figs 13 ) . ct revealed fracture of the floor of left orbit with soft tissue , fat herniation into left maxillary sinus roof , left orbital emphysema with no muscular entrapment . gas was observed in periorbital tissues , left temporal scalp , infratemporal fossa , left parapharyngeal space and left cheek . moreover , tissue planes in the neck revealed the presence of air particularly around the carotid vessels , in the posterior triangle and superior mediastinum ( pm ) around the thymus , trachea ( middle ) , left side of the aorta and anterior to the sternum . however , on auscultation , lungs were clear with and the laryngeal passages and trachea looked normal . figure 1 : different levels of head imagining showing fracture of the floor of the orbit and subcutaneous air . figure 3 : ct scan shows the extension of air from the face , neck and chest . different levels of head imagining showing fracture of the floor of the orbit and subcutaneous air . the patient was admitted for observation and started prophylactically on co - amoxiclav 1.2 - g intravenously twice daily to avert potential mediastinitis . the patient symptoms improved , while his emphysema initially increased , and follow - up ct with oral and iv contrast revealed no new changes . the fracture was treated conservatively ; the patient tolerated full diet with uneventful hospital course and was discharged on the third hospital day with out - patient follow - up . pm or the presence of air in the mediastinal space is a well - established event that might occur either spontaneously ( rare ) or due to severe post - traumatic thoracic - abdominal injury . moreover , procedures that involve trachea , bronchi , esophagus and natural facial planes might be involved in leakage of gas into the subcutaneous space of head and neck . described a path to the submandibular space via retropharyngeal space , and vascular sheaths within the neck to produce subcutaneous emphysema , pneumothorax and pneumopericardium . the authors also described the potential communication with peritoneum and retroperitoneal spaces to cause pneumoperitoneum and pneumoretroperitoneum . pm itself does not signify a morbid condition ( very rare linkage with airway compromise or tension ) , it is rather a marker of underlying illness or injuries . of note , tracheobronchial rupture , esophageal injury or perforation of a hollow abdominal viscus may cause free mediastinal air . so , the presence of pm particularly in the absence of associated lung injury and pneumothorax is taken as a red flag for these severe potentially lethal injuries . clinically , pm might be asymptomatic or may be associated with chest or neck pain , cough , vomiting , voice change or stridor , low - grade fever , respiratory distress and mechanical shock ( tension ) . huon et al . also reported neck pain , swelling and odynophagia to be the primary initial symptoms of spontaneous pm . clinical signs may include subcutaneous emphysema , crepitations or murmur ( precordial systolic crepitations and diminution of heart sounds ) . the diagnosis of occult pm and exclusion of associated aerodigestive injuries could be made by chest x - ray and ct scan . rezende - neto et al . reported occult pm in 6 % of blunt chest trauma cases confirmed by chest ct scan . although the investigators found higher injury severity score in occult pm cases , none of them had associated aerodigestive injuries . some authors recommended the use of a water - soluble contrast agent followed by a barium meal if the findings are normal in order to increase the sensitivity of the test . bronchoscopy is indicated if a tracheobronchial perforation is suspected , which may be observed occasionally following blunt chest trauma . these patients should be observed very closely for evolving fever and signs of worsening respiratory distress or systemic sepsis . a recent case report presented facial subconjuctival and subcutaneous emphysema after an orbital floor fracture . intravenous antibiotic prophylaxis might be administered to avert mediastinitis and forceful blow to the nose should be avoided until complete recovery . in the absence of clear guidelines forthe management of this rare entity clinical judgment and sound practices would be the guide for what is needed to do . this case report of mediastinal emphysema will be a basis for further clarification of this rare association and can guide future approach to similar cases regarding prognosis and management . this case report has been approved by the medical research center ( irb no. 13440 / 13 ) , hamad medical corporation .\noutput:\n" }, { "from": "agent", "value": "pneumomediastinum ( pm ) is mainly an atypical finding among traumatic neck or thoracic injury patients . moreover , pm secondary to isolated orbital floor fracture remains a rare event which is infrequently associated with severe complications such as mediastinitis , airway obstruction and pneumothorax . herein , we report an atypical case of mediastinal emphysema consequent to orbital floor fracture along with review of the literature ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 20 - year - old woman visited the neurology clinic for generalized stiffness and frequent falling episodes secondary to tactile stimuli . she was born at term , and her antenatal and birth history were not remarkable . there was no developmental delay or neurologic deficit ; however , her parents had noticed sudden falling events since she was five years old . in response to unexpected tactile stimulation , she felt her body become rigid for a few seconds , which resulted in injurious falling down events with spared consciousness . she usually kept indoors and walked cautiously in order to avoid unexpected falling accidents . in childhood , the frequency of her falls was approximately four or five times per year , but after her teenage years , the frequency decreased to once or twice per year . her father and older sister had similar symptoms ( figure 1a ) . on physical examinationwhole exome sequencing with genomic dna extracted from peripheral blood identified a heterozygous missense mutation c. 896g a ( reference sequence : nm_001146040.1 ) in glra1 . no mutations were found in other genes known to cause familial hyperekplexia , such as glrb , slc6a5 , gphn , and arhgef9 . the change in the patient s glra1 sequence alters the arginine codon at 299 to a glycine codon ( p.arg299gln ) . the same mutation was also found in her sister , who was symptomatic ; however , we could not perform a genetic study on her parents . clonazepam was administered at a dose of 0.5 mg per day , which resulted in an improvement in the startle response . hyperekplexia , known as a hereditary startle disease , is characterized by an exaggerated startle response and neonatal hypertonia . this disorder is a rare neurogenetic condition , but it is potentially treatable . the symptom spectrum can vary from an exaggerated startle response to infantile apnea spells and even injurious falls . a previous case study reported a possible association with sudden infant death syndrome . in patients with hyperekplexia , no abnormalities are observed on routine blood tests , urinalysis , brain imaging studies , or eeg . hyperekplexia could be misdiagnosed as epilepsy , cerebral palsy , anxiety disorder , or conversion disorder and therefore can be mistreated . early diagnosis and treatment are important , as they not only prevent injuries but may also influence the quality of life of a patient . to conduct a systematic review of the literature regarding hyperekplexia cases caused by mutation in the glra1 gene , we retrieved articles from the pubmed database using the keywords hyperekplexia and glra1 , english and hyperekplexia and case , english . clinical features , ethnicity , types and locations of mutations and mode of inheritance , as obtained from the retrieved literature , are summarized in table 1 . most patients showed neonatal hypertonia ( 76 % ) and an exaggerated startle response ( 73 % ) . most patients ( 64 out of 66 cases with the nose - tapping test ) exhibited a hyperactive brainstem reflex , which was found with the nose - tapping test . exaggerated head retraction reflexes in response to the nose - tapping test indicate exaggerated brainstem reflexes and provide an important clue to diagnose hyperekplexia . the patients also suffered from severe complications , such as developmental delay ( 16.8 % ) and apnea spells ( 20.7 % ) . external abnormalities , such as umbilical ( 13.9 % ) and inguinal hernia ( 11.2 % ) , hip dislocation ( 6.8 % ) and club foot ( 1.9 % ) , were not uncommonly observed ( figure 1c ) . these findings are consistent with a previous case series that is not included in our analysis . clinical features that helped differentiate hyperekplexia from epilepsy included unexpected stimulus - inducing falling accidents , short episodes lasting only a few seconds , and spared consciousness , with no other abnormal movements accompanying the event . cautious gait , face lacerations and family history may be helpful for differentiating hyperekplexia from conversion disorder . frequent falls were observed in 39.8 % of cases for which information was available , and cautious gait was reported infrequently ( 4 % ) . data regarding falls and gait might have been biased by patients age , and therefore , there is a potential for missed information . six out of 161 reviewed patients exhibited a wide - based and stiff gait due to considerable fear of an unexpected falling event , and two patients lacked confidence in outdoor environments , resulting in impaired social behavior . presentation of a cautious gait resulting from unexpected falling episodes might be an indication of hyperekplexia . clonazepam , which enhances gaba - gated chloride channel function and presumably compensates for defective glycine - gated chloride channel function , has been considered the first choice for the treatment of hyperekplexia . antiepileptic drugs , including carbamazepine , phenytoin , valproate , and vigabatrin , have also been used for treatment . in this review ,60 out of 70 cases ( 85.7 % ) showed good response to clonazepam , which is similar to a previous study . among genes causing familial hyperekplexia , glra1 is the most common causative gene , accounting for 80 % of hereditary cases . our patients carried a heterozygous mutation , p.arg299gln , which was inherited in an autosomal dominant fashion . missense mutation of the arginine at codon 299 , which was previously reported as codon 271 , is the most common ( table 1 , figure 1d ) . both autosomal dominant and recessive inheritance have been reported in familial hyperekplexia caused by glra1 mutation . our analysis showed that dominant inheritance ( 73.9 % ) was 3-fold more commonly reported than recessive inheritance ( 26.1 % ) . interestingly , most dominantly inherited mutations were located between codons 290300 of the glra1 gene ( figure 1d ) . distribution of ethnicity in the reviewed hyperekplexia cases was caucasian ( 42 % ) , asian ( 33 % ) , turkish ( 14 % ) , arabic ( 8 % ) , and african ( 3 % ) ( figure 1e ) . in a genotype - ethnicity correlation , 8 asian families ( including isolated cases ) and 7 caucasian families demonstrated the p.arg299gln mutation of the glra1 gene . these findings support the notion that the arg299 amino acid site is vulnerable to hyperekplexia in ethnically disparate cases .\noutput:\n" }, { "from": "agent", "value": "familial hyperekplexia , also called startle disease , is a rare neurological disorder characterized by excessive startle responses to noise or touch . it can be associated with serious injury from frequent falls , apnea spells , and aspiration pneumonia . familial hyperekplexia has a heterogeneous genetic background with several identified causative genes ; it demonstrates both dominant and recessive inheritance in the 1 subunit of the glycine receptor ( glra1 ) , the subunit of the glycine receptor and the presynaptic sodium and chloride - dependent glycine transporter 2 genes . clonazepam is an effective medical treatment for hyperekplexia . here , we report genetically confirmed familial hyperekplexia patients presenting early adult cautious gait . additionally , we review clinical features , mode of inheritance , ethnicity and the types and locations of mutations of previously reported hyperekplexia cases with a glra1 gene mutation ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the analysis of tree rings typically involves measuring the distance between ring boundaries , comparing measurements between cores and checking for errors . while the fastest way to measure tree rings is to measure prepared cores or stem discs directly ( e.g. , with the lintab system [ frank rinn , heidelberg , germany ] ) , this method is very time - consuming if rings are sometimes indistinct , in which case it becomes necessary to compare and re - measure the original cores ( levani , 2007 ) . here , measuring digitized images that can be re - analysed easily is an advantage . several programs are available to measure tree rings on digital images , differing in cost and capacitywhile the more upmarket programs provide many extras , they may not be optimal for all purposes . for instance , in tropical tree rings , which are difficult to identify and cross - date , it is useful to compare cores on several images that can be scrolled up and down individually to search for matching features , but windendro and lignovision can open only one image at the time ( table 1 ) . writing completely new software for the analysis of tree - ring images for some specific needs tends to be too complex or time - consuming for most researchers . however , different programs are available that are able to perform part of the task necessary , such as image analysis , detrending or graphical presentations . if these programs can run macros in a common environment such as visual basic for applications ( vba ) , they can be linked to exchange data or commands even if their programming languages differ . compared to writing new software it then becomes relatively easy to produce versatile and flexible software for specific applications such as tree - ring analysis . i here present simple procedures to measure and evaluate digitized cores , combining existing programs via vba macros . while the software was designed to help with the analysis of tropical tree rings that are difficult to date , the first macro , with only about 160 lines of effective code , is simple to change and features such as graphic presentation and simple statistical evaluation can be modified in excel without any code - writing . the macros combine sigmascan pro , a program for image analysis , excel , a spreadsheet program with simple graphic and statistic features , and r , a powerful open - source statistical package . it was developed and tested with sigmascan pro 5.0 ( systat software inc . , chicago , usa ) , excel 2003 ( microsoft inc . , redmont , usa ) and r 2.9.0 ( r development core team , 2009 , http://www.r-project.org ) on a pc with windows xp as well as on a mac with windows xp . some technical details are given in the following chapters , the full source code with comments can be seen by opening the macro in excel . many researchers produce images from sanded increment cores with a high - end desktop scanner , but obtaining images with a microscope and stitching adjacent parts of a core together is also an option ( levani , 2007 ) . the image resolution needs to balance the amount of detail required and the size of the image files , a resolution of 12002400 dpi is almost always sufficient and substantially less ( 300600 dpi ) is sufficient for samples with clear ring boundaries . sigmascan supports a large range of image formats , including bmp , jpeg , pcx , tga , tif and psd , b / w as well as colour images . the size of the image as well as the number of images open at the same time are basically limited by computer memory , but should not be unnecessarily large to avoid slow performance . open the image with sigmascan and use the overlay draw mode of sigmascan ( mode overlay draw mode ) to mark ring boundaries with a dot . an overlay in sigmascan is a layer placed onto the original image but stored in a separate file , so that the original image is not modified . since only one overlay ( the standard is green ) is needed to mark ring , four other colours can be used to mark additional features or write comments to the image . the size of the dot can be set in tools cursor / pen size , 59 pixel is mostly useful , depending on the image size and how easily the marks should be visible . dots on successive ring boundaries should be approximately along a straight line , which is best achieved by following the rays from bark to pith . if this is not possible because the core does not exactly follow the rays from bark to pith , start a new line along a different ray by placing a second dot on the same ring boundary ( see arrows in fig . 2 and details in the next chapter ) . when all ring boundaries have been marked , save and close the file , the overlay with the ring boundaries will be saved in a separate file with the extensionopen tr r in excel ( click activate macros when asked ) and check that in the sheetsetup the directory of the image files , the outer year and the calibration ( in pixels per mm , e.g. , 94.5 for a resolution of 2400 dpi ) are correct . put the name of the image files ( including the extension but excluding the directory ) in the third row of the sheet ( via extra macro macros or alt - f8 ) . the detrended series are written below the cell with the filename , the raw data to the sheet raw , pearson correlation coefficients and gleichlufigkeit to the sheetnames and general layout of excel sheets should not be changed unless users also modify the code in the macro that addresses these sheets . the name of the excel file ( tr r ) can be changed as required . the raw - data measurement does not require r , so the program will run with excel and sigmascan alone . however , for detrending and the calculation of the correlation coefficient and gleichlufigkeit ( eckstein and bauch , 1969 ) r routines are called , and it is recommended to install r ( http://www.r-project.org ) and rexcel ( http://rcom.univie.ac.at/ ) as well . for users familiar with r , this provides a seamless interface to a powerful and increasingly popular statistics and graphics software . alternatively , excel can be used for graphic display and simple statistics , or data can be exported and used in other tree ring software . special export formats such as heidelberg or tuscon that some tree ring programs require are currently not provided . after running the macro , ring boundaries are tagged with the year ( see fig . 1 in the manual ) . this annotation is saved in a separate file and will be shown when the image file is opened in sigmascan the next time . depending on the project and how complex cross - correlation turns out to be , users will validate the first dating by comparing the graphs of detrended series or by using correlation coefficients and gleichlufigkeit . the sheetdetr shows the pearson correlation and gleichlufigkeit with the mean series , the sheet cor has cross - correlations between each two series . when cross - correlation indicates error in dating or problematic rings , images are compared in sigmascan . a major advantage compared to other available software is that various images of different cores can be opened at the same time and compared by scrolling individual images up and down so that matching tree rings can be aligned . this is a substantial advantage when identifying ring boundaries is difficult and detailed anatomical comparisons between cores are necessary . when dots marking ring - boundaries are changed and the excel macro is run , graphs and correlations in excel are updated automatically . the number of files open at the same time is limited by the computer 's memory , but more than six to eight is not of much use given the size of even a large screen . sigmascan is a flexible package for image analysis and sigmascan pro can be programmed with a specific macro language . in order to measure tree ringsit is only necessary to mark ring boundaries on images and to measure the distance between boundaries . in sigmascan imagescan be drawn on in five different colour - coded overlays , which are stored in separate files and do not modify the image . thus the distance between two points , positioned on ring boundaries along the radius , yields the ring width . points marking rings can be placed along a line following the rays , which will generally not be a completely straight line . if required one can also draw a straight line with a different colour and place boundaries exactly along this line . since only one overlay is used to mark ring boundaries , other colours can be used for annotations . a typical core does not follow exactly the radius to the pith , and it is thus not possible to measure all rings along one single straight line or ray . to start a new line , if the angle between three successive points is lower than a user - defined threshold ( 160 was found to be useful ) , the program records a new line with the first point assumed to be on the same ring boundary as the last point of the previous line . the angle ( gamma ) between successive points is calculated with the code below , where x0 - y0 , x1 - y1 , x2 - y2 are the x and y positions of three consecutive points . sometimes cores are broken and the gap between two pieces needs to be excluded . if marked by short lines ( anything longer than 20 pixels ) along the gap boundaries , this is recognized as a gap and will be subtracted from the distance between the two boundaries next to the gap . running the macro measures ring widths , recognizing new lines and gaps , and will mark the rings with the year . the above procedure will work in sigmascan alone , however , to evaluate and compare the measurement of several cores requires graphics , which are very limited in sigmascan . thus the data are written to an excel spreadsheet where any graphic is immediately updated and the macro is called from within excel . we found it useful to plot ring - widths of several cores together with a mean curve , as well as the pearson correlation ( r2 ) and gleichlufigkeit ( gl ) between a measured core and the mean or standard curve , to indicate where cores cross - date well and where a likely error may have occurred . if the cell with the filename is marked in excel , starting the macro loads the image , measures distances , writes year - tags to the image and writes the results to the excel spreadsheets . thus a series of images whose filenames are written to a line in the spreadsheet can be measured quickly , updating tables and graphs immediately without the need to copy and paste results . r is code - based and it has been possible to link r with other programs such as c++ or vba previously . the recent release of rexcel ( baier and neuwirth , 2008 ) provides an easy link between r and excel , which combines the power of r with the comfort of a widely used spreadsheet and enables , for instance , to call r functions from the spreadsheet or to exchange data between r and excel . rexcel requires additional programs to function , which can be installed with the free package randfriends ( http :\\ \\ rcom.univie.ac.at ) . several published ( bigler , 2005 ; bunn , 2008 ) and many unpublished routines for tree - ring analysis are available in r and adapting statistical or graphic functions is relatively straightforward . in the macro , the algorithm for detrending was borrowed from dplr ( bunn , 2008 ) . alternatively , detrend can be called directly with the option to select one of several ways of detrending . linking sigmascan , excel and r provides the advantage that simple or more complex steps in tree - ring analysis can be automated and run immediately following measurement without the need of exporting and importing data in specified formats . for instance , a few lines of code calculate and copy the detrended series to the spreadsheet . in the coderuns r code from the vba macro and getarray copies values from r to excel . in principle , the statistical and graphic analysis of tree ring series can be run entirely in r without the need of a spreadsheet . apart from the fact that more people are familiar with excel than r and may find it easy to adapt a spreadsheet with graphs to their need , an important advantage of excel is that dependencies between cells are constantly monitored and the value of a cell or a graph is updated as soon as the value of another cell it depends on is changed . with rexcel r functions can be called directly from an excel cell . for instance , the first line of the sheet detr calculates the correlation coefficient ( r2 ) of the correlation between an individual series and the mean series ( or any other series selected by the user ) . a correlation coefficient could also be calculated with excel , but there is no excel function for the gleichlufikeit ( gl ) , which is often used to evaluate the correlation between ring series . to calculate gl , an r function glwas written to the sheet setup and this function is called from the second line of the sheet detr . sometimes this is rather unimportant , sometimes the distance to the pith needs to be know to estimate the age of the tree . this can be done by looking at the curvature of the inner rings ( duncan , 1989 ) , but measuring ring - width as described above allows to estimate the missing distance to the pith without any extra measurements . if ring boundaries are marked along straight lines parallel to the rays , the extension of these lines should intersect at the pith . typically , the first lines will be parallel to the core and the last lines will be almost perpendicular , passing the pith at a certain distance . of course ringsare neither perfectly circular nor will marked ring - boundaries be on a perfect line , thus more than two lines are very unlikely to intersect at a single point ( fig . however , a good estimate is obtained by selecting the three innermost lines but one , calculating the three points where pairs of these lines intersect , and taking the mean distance from these points to the innermost marked ring . currently , the distances of the three points where lines intersect are written to the spreadsheet eval . ring boundaries are defined by various anatomical characteristics such as vessel size , wood density or the distribution of cell types that can be easy to recognize by an experienced eye but are often hard to detect automatically . an important exception is conifer wood , where , due to the uniform cell type , the main defining feature is wood density , with denser latewood generally reflected in darker colours . thus , plotting the darkness from the bark to the pith will show regular changes with an increase from lighter early - wood to darker late - wood followed by an abrupt drop in darkness with the new early - wood . sigmascan measures the intensity ( greyscale ) of pixels along user - defined lines , together with the x and y position of the points along the line . the width of the line can be set , so that typically the intensity at any point will not be a single pixel but the average of all pixels across the line . in the current simple version of the macro autodetection , ring boundaries are detected as an abrupt change from high to low intensity , defined as the steepest negative slopes in the intensity - curve from bark to pith . to reduce noise , the greyscale curve is first smoothed , with the degree of smoothing and the slope of the greyscale that defines a transition being set by the user . to evaluate results , a graph in rshows the original , the smoothed and the first order differential of the greyscale curve with identified boundaries marked ( fig . sobel filters and more sophisticated edge detectors have been used to automatically identify tree rings ( conner et al . , 1998 ; this was not included in the autodetection macro as we want to retain the information on greyscales . however the potential to do this is shown in a small third macro ( filter ) that reduces noise , applies a sobel - filter for the detection of vertical edges , copies highlighted pixels to an overlay , removes edges that are 5 pixels , and copies the overlay onto the original picture ( fig . the program was written in part to optimize an image analysis system for the requirements of our project , in part because of the high costs of some specialized software ( table 1 ) . i did not intend to expand the options for statistical evaluation of results , as routines are being developed in r and can be included at any time . of the three software packages required , r is free and excel is installed on most computers . sigmascan is used in many academic departments , but is not free and has not been updated or expanded for the last years . free image analysis software is available , but to my knowledge not ( yet ) suitable for the application described . scionimage ( http://www.scioncorp.com/ ) is a windows - version of the popular nih image for mac ( http://rsb.info.nih.gov/nih-image/ ) and can also be linked to other programs using visualbasic . embimage ( http://www.bioconductor.org/packages/devel/bioc/html/ebimage.html ) is a free image processing and image analysis toolkit for r. in both cases it appears currently not possible to interactively mark or draw onto image using overlays that do not modify the image . if such features become available , modifying the macros to run on a free platform should be straightforward . i appreciate feedback from users and will try to provide support , add some useful features and update the manual to include upcoming questions . if the program is found useful , however , it is hoped that others will contribute additional useful features . the program was written in part to optimize an image analysis system for the requirements of our project , in part because of the high costs of some specialized software ( table 1 ) . i did not intend to expand the options for statistical evaluation of results , as routines are being developed in r and can be included at any time . of the three software packages required , r is free and excel is installed on most computers . sigmascan is used in many academic departments , but is not free and has not been updated or expanded for the last years . free image analysis software is available , but to my knowledge not ( yet ) suitable for the application described . scionimage ( http://www.scioncorp.com/ ) is a windows - version of the popular nih image for mac ( http://rsb.info.nih.gov/nih-image/ ) and can also be linked to other programs using visualbasic . embimage ( http://www.bioconductor.org/packages/devel/bioc/html/ebimage.html ) is a free image processing and image analysis toolkit for r. in both cases it appears currently not possible to interactively mark or draw onto image using overlays that do not modify the image . if such features become available , modifying the macros to run on a free platform should be straightforward . i appreciate feedback from users and will try to provide support , add some useful features and update the manual to include upcoming questions . if the program is found useful , however , it is hoped that others will contribute additional useful features .\noutput:\n" }, { "from": "agent", "value": "i present a new software that links a program for image analysis ( sigmascan ) , one for spreadsheets ( excel ) and one for statistical analysis ( r ) for applications of tree - ring analysis . the first macro measures ring width marked by the user on scanned images , stores raw and detrended data in excel and calculates the distance to the pith and inter - series correlations . a second macro measures darkness along a defined path to identify latewood earlywood transition in conifers , and a third shows the potential for automatic detection of boundaries . written in visual basic for applications , the code makes use of the advantages of existing programs and is consequently very economic and relatively simple to adjust to the requirements of specific projects or to expand making use of already available code ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the technology of assisted reproduction aims at achieving oocyte fertilization by incubation of cumulus - intact oocytes in the presence of a defined number of motile spermatozoa ( conventional in vitro fertilization , ivf ) or by injection of single spermatozoa into denuded , cumulus - free oocytes ( intracytoplasmic sperm injection , icsi ) . both procedures are followed about 16 to 20 hours later by the so - called pronucleus check . here , successful and normal fertilization is identified by the appearance of two pronuclei ( pn ) in the ooplasm and detection of two polar bodies in the perivitelline space , whereas the presence of more than two pn is considered to be associated with genetic disorders , mostly triploidy . consequently , these multipronuclear oocytes are excluded from further cell culture and embryo transfer . in contrast , recommendations on the treatment of oocytes displaying only one pronucleus are accompanied by greater uncertainty . in case of parthenogenetic activation , one should expect the formation of a haploid embryo with exclusively maternal chromosomes and therefore transfer should be cancelled . if , however , the pn had appeared asynchronously or underwent an undetected fusion , diploid biparental and transferable embryos may be available . in fact , a few pregnancies have been reported after transfer of embryos developing from monopronuclear oocytes . the frequency of monopronuclear oocytes among all pronuclear stages has reached 7.7 % after ivf and 5.0 % after icsi in a large study evaluating more than 6,000 cells for each technique . information on the chromosomal constitution of the resulting embryos appears to be of clinical interest particularly in rare cases without regular formation of two pn . the present report therefore summarizes pertinent data , reviews possible mechanisms of origin of a single pronucleus , and tries to deduce recommendations for handling affected oocytes during assisted reproduction . the literature search for this review is based on pubmed and scopus and includes results found until the end of january 2014 . single pronucleus , monopronuclear , monopronucleus , single pronucleated , unipronucleate , unipronuclear , one - pronuclear , and single - nucleated , each in combination withif specific data were excluded from the compilation of results , the reasons have been explained in the corresponding section . the cited studies have examined different developmental stages , including monopronuclear oocytes , zygotes , and embryos up to the blastocyst . it should be noted that a monopronuclear female gamete ( figure 1 ) will undergo breakdown of the pronuclear membrane after dna replication and hence the pronucleus will disappear comparable to the situation in normally fertilized bipronuclear oocytes . the next stage is the zygote though , strictly speaking , this description does not apply to parthenogenetically activated cells because a zygote is defined to result from the union of two haploid gametes and should therefore always contain a diploid chromosome set . however , the common nomenclature has been maintained in the present review because some zygotes indeed turned out biparental diploid ( see section 3 ) . for cytogenetic analysis , the above - mentioned developmental stages were frequently incubated in the presence of chemicals that block mitosis , for example , colcemid . the cells were then fixed on glass slides and the chromosomes were stained in order to establish karyotypes or allow at least chromosome counting . some zygotes that developed from monopronuclear oocytesthis project had been approved by the ethical committee of the university of ulm and details of our technique have been described elsewhere . briefly , we used a mixture of podophyllotoxin and vinblastine instead of colcemid , a gradual fixation air - drying method and homogeneous giemsa staining of the chromosomes . fluorescence in situ hybridization ( fish ) is another approach to examine cells that had been fixed on a glass slide . the method can be applied to interphase nuclei and therefore preceding exposure to colcemid is not necessary . the most frequently used dna probes are those for chromosomes x , y , 18 , and 13/21 . fish has been applied to intact developmental stages but also to single biopsied cells from embryos . isolated the karyoplast , that is , the nucleus with a small amount of cytoplasm from the remaining cytoplast in monopronuclear oocytes to analyze them separately . in one instance , van der heijden et al . presented a technique based on the asymmetrical distribution of histone modifications in male and female pn . histones are dna - associated proteins and determination of the presence of methylated lysine residues at a certain position of the n - terminal tail of histone h3 by a specific antibody allows distinguishing paternal and maternal chromatin because only the latter will be stained . the method yielded information on the haploid or diploid state of monopronuclear zygotes and the parental origin of the pn but aneuploidy could not be assessed . relevant information on the genetic constitution of monopronuclear oocytes and resulting developmental stages has been outlined in table 1 according to their origin ( conventional ivf or icsi ) . the data provided by balakier et al . for cleavage stages have been excluded because of the low number of analyzable cells in each category ( four embryos , one morula , and two blastocysts ) . the investigation of munn et al . was not considered because the authors themselves admitted that the applied technique would not allow clear distinction of monosomy and haploidy or trisomy and triploidy . moreover , these authors stated that an x result by pcr could be either a haploid cell , a female diploid cell , or a trisomic or triploid female cell . from the study of lim et al . the number of cells analyzed by fish ( n = 14 ) was low and subdividing them further ( ivf or icsi , zygotes or embryos ) would have yielded very small groups without providing additional information . the study of campos et al . was excluded because diploid - aneuploid and haploid - aneuploid cases could not be distinguished . further difficulties encountered when trying to classify the results particularly concern cleavage stages with a larger number of analyzable blastomeres . these often show a coexistence of diploidy , haploidy , polyploidy , and superimposed numerical chromosome abnormalities . presenting details would have been too confusing and therefore the cytogenetic terms chosen for table 1 ( haploid , diploid , and other ) are simplifications . in other words , the categoriesdiploid and haploid also contain cells with deviations from the respective exact chromosome count of 46 or 23 . for instance , the diploid - aneuploid embryos and blastocysts listed by liao et al . have been counted as diploid . concerning the study of mateo et al . , it was decided to classify diploid - mosaic cells as diploid , haploid - mosaic cells as haploid , and the remainder as carryingsince the main intention of the present review was to differentiate fertilized from unfertilized cells , this subjective approach appeared justifiable . the possible biparental origin of diploid cells was not considered in table 1 but will be addressed below . the genetic constitution of monopronuclear oocytes and zygotes obtained after ivf has been examined in three studies and it was shown that 37.5 % to 86.7 % of the cells were diploid ( table 1 ) . this incidence is conspicuously different from the range of 0 % to 30.3 % detected in monopronuclear cells produced by icsi ( , own unpublished results ) . , both applying conventional cytogenetics to uncleaved zygotes , failed to reveal a case of diploidy . in our material , 4 out of 18 haploid cells ( 22.2 % ) carried a chromosomal aberration ( hypo - or hyperhaploidy , see table 2 ) , whereas macas et al . here , it should be noted that cytogenetic investigations of monopronuclear zygotes are surprisingly scarce in view of the fact that these cells can inform about the total incidence of aneuploidy arising from female meioses i and ii . finally , 15 out of the 18 zygotes ( 83.3 % ) examined by us showed prematurely condensed sperm chromosomes comparable to the patterns found in unfertilized oocytes , indicative of correct sperm insertion into the ooplasm during icsi . as shown in table 1 , eight studies investigated the chromosomal constitution of embryos or blastocysts after ivf . icsi - derived embryos or blastocysts were included in five reports . according to these data , the incidence of diploid ivf embryos varies between 13.0 % and 80.5 % and is again considerably lower after icsi with rates between 2.2 % and 37.5 % . whereas all six ivf blastocysts examined by otsu et al . were diploid or diploid mosaics , only three of eight ( 37.5 % ) icsi - derived blastocysts analyzed by mateo et al . however , it is evident that both observations are based on a low number of cases . the results of liao et al . had to be considered separately because the origin of the embryos ( ivf or icsi ) was not specified . nevertheless , an important point in their study is that the rate of diploidy increases from 38.9 % in early cleavage stages to 78.0 % in blastocysts . as soon as a monopronuclear oocyte undergoes further development into a diploid zygote or even an embryo , it should be ascertained whether the diploid condition was actually caused by fertilization ( = biparental or heteroparental diploidy ) or by specific mechanisms giving rise to uniparental diploidy , for instance , endoreduplication of the haploid female chromosome set . regarded the presence of two chromatin domains with a nonuniform staining pattern as proof of a biparental origin . according to this approach , all 39 diploid ivf zygotes andall 10 diploid icsi zygotes were classified as biparental because male and female chromatin were detected . more common , however , is to determine the presence of a y - chromosome as evidence for sperm penetration . after conventional ivf , a minimum of 40 % of diploid embryos had a y - chromosome but this incidence even reached 66.7 % both in isolated karyoplasts and in blastocysts . after icsi , the frequency of diploid embryos with a y - chromosome ranged from 16.7 % to 52.2 % . mateo et al . found a y - chromosome in 19/54 ( 35.2 % ) icsi embryos but these data could not be included in table 3 because it was not clear whether mosaic haploid embryos were involved . finally , it should be added that 15/31 ( 48.4 % ) complex mosaic ivf embryos and 12/16 ( 75.0 % ) complex mosaic icsi embryos revealed a y - chromosome . the latter authors also reported one diploid icsi embryo with a yy - chromosome constitution . taken together , these figures support the former statement by munn et al . who , having found a y - chromosome in 41 % ( 9/22 ) of the embryos , suggested that approximately 80 % may have originated from fertilized eggs . the authors arrived at this value by doubling the percentage of y - bearing embryos because it is assumed that x - and y - spermatozoa participate equally in fertilization . with this formula in mind , some of the data shown in table 3 suggest an even higher incidence of biparental diploidy that may reach nearly 100 % independent of ivf or icsi , whereas uniparental diploidy in cleavage stages arising from monopronuclear oocytes appears to be an exception . up to now , the transfer of embryos that developed from monopronuclear ivf oocytes resulted in one pregnancy with unknown outcome , the birth of two healthy children and one biochemical pregnancy , and the birth of a normal healthy boy . moreover , even the birth of normal twin boys following transfer of a single embryo has been reported . in contrast , only barak et al . achieved the birth of a normal healthy boy after round spermatid injection accompanied by formation of one pronucleus . it should also be mentioned that a diploid ( 46 , xx ) human embryonic stem cell ( hesc ) line could be derived from a monopronuclear icsi zygote , whereas another group established 33 hesc lines . the latter authors who did not indicate the origin of the monopronuclear oocytes ( ivf or icsi ) obtained a diploidy rate of 97 % ( 32/33 ) and only one abnormal ( 47 , xy , +16 ) cell line . in contrast to these successes , petignat et al . described a twin pregnancy combining a complete hydatidiform mole and normal pregnancy that had to be terminated . this pregnancy occurred after transfer of two embryos , one obtained from a normally fertilized oocyte with two pn and the other from a monopronuclear oocyte . the authors hypothesized that the oocyte with one pronucleus gave rise to the hydatidiform mole and emphasized the danger of transferring the corresponding embryos . the underlying mechanism in this peculiar case would involve fertilization by a haploid spermatozoon with subsequent chromosome duplication or fertilization by a diploid spermatozoon , always accompanied by failed formation of the female pronucleus . this annotation shows that it must be clarified which mechanisms are responsible for the different genetic compositions , particularly haploidy and diploidy . haploidy is generally attributed to parthenogenesis , gynogenesis , or androgenesis and these terms have been explained in detail elsewhere . briefly , parthenogenesis means the development of an embryo from an oocyte without any intervention of a male gamete . the same is true in the case of gynogenesis but here the oocyte has been stimulated by a spermatozoon to undergo the second meiotic division . androgenesis also starts with oocyte activation by a spermatozoon but the female genome will be genetically inactivated or completely extruded and only the male genome is involved during subsequent development . about 45 % of monopronuclear ivf zygotes showed signs of sperm penetration and the authors surmised that , in oocytes without visible sperm heads or nucleus - like structures , the sperm chromatin might have undergone complete disintegration or extrusion to form observed but undefined extra bodies . thus , the incidence of sperm penetration could even be higher . more data are available for monopronuclear icsi zygotes . here , intact sperm heads or decondensed sperm chromatin was found in 76 to 86.5 % of examined cases . our own unpublished results of 83.3 % are in good agreement with these figures . in one study , a male origin of the single pronucleuswas determined in only 4 % of the examined oocytes due to the presence of a sperm tail and it was assumed that the entire maternal chromatin had been extruded into a polar body ( pb ) or did not succeed in forming a pronucleus . oocytes in which the meiotic spindle can not be detected at the time of icsi appear to be more susceptible to formation of a single male pronucleus . assessing histone methylation patterns in uncleaved zygotes , van der heijden et al . arrive at different figures . in their study , only paternal chromatin was found in 24.2 % of icsi zygotes and in 4.4 % of ivf zygotes . these authors concluded that complete extrusion of the maternal chromatin during formation of the second pb might be a quite frequent event . it remains to be determined whether the applied detection methods are responsible for the varying rates of male pn reported by kovacic and vlaisavljevic and van der heijden et al . for icsi zygotes . in the discussion on causative mechanisms , icsi could indeed be regarded as a separate phenomenon because it involves both a mechanical stimulus and participation of a spermatozoon that is inserted into the ooplasm . most probably , however , a sperm factor activates the oocyte and then sperm chromatin decondensation stops , whereas female pronucleus formation proceeds normally . taken together , most of the available data support the opinion that the majority ( ~ 80 % ) of haploid monopronuclear oocytes and resulting embryos are produced by gynogenesis and that parthenogenesis or androgenesis is less common . an asynchronous appearance of pn is the first possibility to explain the existence of biparental diploidy in embryos that develop from monopronuclear oocytes . for instance , staessen et al . performed a second observation of 312 single - pronucleated oocytes 4 to 6 hours after the initial assessment and detected a second pronucleus in 25 % of these cases . the authors concluded that a single observation of an oocyte with one pronucleus does not allow differentiating between asynchrony of pronuclear development and parthenogenetic activation . since delayed formation of the second pronucleus may not be a rare event , monopronuclear oocytes should therefore be rechecked after some hours . consequently , a proportion of diploid embryos could have arisen from fertilized oocytes in which the asynchronous pronuclear formation had been overlooked . however , how does diploidy arise if definitely only one pronucleus persists during the whole observation period ? a solution is offered by the concept of pronuclear fusion that has been put forward by levron et al . . these authors suggested that monospermic diploid monopronuclear zygotes may be formed by a fusion of the paternal and maternal genomes during syngamy , most probably by very early enclosure in a common pronuclear envelope rather than by fusion of pronuclear membranes at a later stage . it was further assumed that sperm penetration close to the metaphase plate of the oocyte might predispose to this modified fertilization process . pronuclear fusion was not observed in an investigation using time - lapse video cinematography but the number of examined oocytes ( 43 with formation of pn ) appears too low for definite conclusions . whereas levron et al . did not address the question whether fused pn possibly show an increase in size , otsu et al . differentiated between large ( 2934 m ) and small ( 2326 m ) pn . only some oocytes ( 6/34 ) from the group with larger pn were able to reach the blastocyst stage and these blastocysts were diploid or diploid mosaic . suggested that larger pn might be a product of pronuclear fusion before nuclear membrane breakdown . in contrast , others could not demonstrate a correlation between pronuclear size and chromosomal constitution and also denied the existence of pronuclear fusion at a later stage . the only possibility for formation of a diploid heteroparental pronucleus would consist in an irregular membrane formation enclosing maternal and paternal genomes . prior to these investigations , however , tesarik and mendoza had reported that oocytes injected with spermatids may develop two pn that later fuse to form a syngamy nucleus . it is currently not clear whether the described phenomenon is restricted to the use of sperm precursor cells for injection . further confirmatory observations are rare and spermatid injections have apparently been abandoned during the past years . obviously , there is a need for more basic research concerning the dynamics of pronuclear development , fusion events , and pronuclear size . comparable to cases of asynchronous pronuclear formation , embryos resulting from fertilization and early fusion of the genomes or later pronuclear fusion should reveal a diploid , 46 , xx or 46 , xy chromosome constitution . an embryo within this category can carry a diploid 46 , xx genome which is exclusively composed of female chromosomes as soon as a diploid oocyte starts to cleave without participation of a male genome . if on the other hand the genome is exclusively derived from the male gamete , the following chromosome complements can occur in embryos : 46 , xy ( first meiotic nondisjunction during spermatogenesis ) and 46 , xx or 46 , yy ( second meiotic nondisjunction ) . in each case , a diploid spermatozoon would fertilize an oocyte and cleavage would commence without participation of the female genome . as already mentioned above , staessen and van steirteghem detected one diploid icsi embryo with two y - chromosomes . this observation can be explained by a failed formation of the female pronucleus and development of a diploid male pronucleus due to injection of a diploid spermatozoon . alternatively , however , injection of a haploid spermatozoon might have been accompanied by suppression of the female and endoreduplication in the male pronucleus . endoreduplication has been reported to affect not only single chromosomes but also complete chromosome sets and may in the latter case contribute to the development of triploidy if it occurs in one of the two pn of a regularly fertilized oocyte . it is therefore conceivable that endoreduplication in a monopronuclear oocyte produces uniparental diploid embryos but clear evidence for this assumption is lacking . nonextrusion of the second pb has been discussed as another mechanism that may cause uniparental diploidy in embryos arising from monopronuclear oocytes . in such cases , the 23 oocyte chromosomes should separate into single chromatids but all 46 chromatids will remain within the ooplasm , become enclosed by a pronuclear membrane , and undergo dna replication , thus restoring a diploid female chromosome set . this concept has been described as one of the mechanisms for diploid parthenogenesis but it appears questionable in view of the findings for tripronuclear icsi oocytes . here , it is generally accepted that nonextrusion of the second pb leads to two individual haploid female pn and not to a single diploid female pronucleus . more data are therefore needed to verify a participation of the second pb in producing monopronuclear diploid oocytes and embryos . from these considerations , it becomes evident that a variety of mechanisms can influence the genetic composition of zygotes and embryos obtained from monopronuclear oocytes . in addition , mitotic nondisjunction of single chromosomes or whole chromosome sets may occur in cleavage stages and thus explain the observation of polyploid , mosaic , complex , and chaotic cases . from the preceding compilation of published results , two important points can be condensed : ( a ) monopronuclear oocytes are able to develop into embryos with variable chromosomal constitutions and ( b ) the majority of diploid embryos obviously result from a fertilization event . first , monopronuclear oocytes should be rechecked after the first assessment of pronuclear formation to detect delayed appearance of a second pronucleus . if this is not the case , one may follow sultan et al . who recommended that embryos developing from monopronuclear ivf oocytes may be replaced , whereas those obtained after icsi would not be suitable . nowadays , however , the frequently used transfer of blastocysts may provide an additional option . as discussed by feenan and herbert , human parthenotes are capable of cleaving to the 8 - cell stage but they rarely seem to develop up to the blastocyst ( table 1 ) . added that , besides haploidy , autosomal aneuploidy and polyploidy were eliminated in blastocysts and they concluded that blastocyst formation would be a useful indicator for normal fertilization and chromosomal constitution . thus , monopronuclear ivf and icsi oocytes in which the single pronucleus persists after a second assessment might be used for transfer when they are able to reach the blastocyst stage and when no other embryo is available . of course , each institution will have to clarify whether this approach should be accompanied by adequate counselling on potential genetic risks and written consent of the patients and whether a preimplantation genetic diagnosis could be offered . finally , though mateo et al . discourage from the use of diploid - mosaic blastocysts , it should be considered that a high rate of aneuploidy and mosaicism even occurs in high quality embryos derived from normally fertilized icsi oocytes . therefore , the implantation potential of such embryos and possible mechanisms of self - correction of abnormal chromosome complements are topics of future research . another important question may concern the epigenetic status of fertilized monopronuclear oocytes , particularly whether the interaction between paternal and maternal chromatin is disturbed when they are prematurely enclosed within one pronuclear envelope . oocytes in which a single pronucleus persists might be considered for transfer if they reach a good - quality blastocyst stage but this remains an individual decision of the ivf laboratory . more data on the morphologic quality , developmental ability , and genetic constitution of affected embryos are undoubtedly needed before a general consent can be achieved that should include recommendations on counselling of the patients and the role of preimplantation genetic diagnosis . the incidence and significance of early pronuclear fusion events or an immediate enclosure of paternal and maternal chromatin within a single pronuclear envelope might be an interesting topic of future research , particularly in view of genetic and epigenetic implications .\noutput:\n" }, { "from": "agent", "value": "the assessment of oocytes showing only one pronucleus during assisted reproduction is associated with uncertainty . a compilation of data on the genetic constitution of different developmental stages shows that affected oocytes are able to develop into haploid , diploid , and mosaic embryos with more or less complex chromosomal compositions . in the majority of cases ( ~ 80 % ) , haploidy appears to be caused by gynogenesis , whereas parthenogenesis or androgenesis is less common . most of the diploid embryos result from a fertilization event involving asynchronous formation of the two pronuclei or pronuclear fusion at a very early stage . uniparental diploidy may sometimes occur if one pronucleus fails to develop and the other pronucleus already contains a diploid genome or alternatively a haploid genome undergoes endoreduplication . in general , the chance of obtaining a biparental diploid embryo appears higher after conventional in vitro fertilization than after intracytoplasmic sperm injection . if a transfer of embryos obtained from monopronuclear oocytes is envisaged , it should be tried to culture them up to the blastocyst since most haploid embryos are not able to reach this stage . comprehensive counselling of patients on potential risks is advisable before transfer and a preimplantation genetic diagnosis could be offered if available ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: children with autism spectrum disorders are characterized not only by their core deficits , impairments in social interaction and communication and repetitive stereotyped behaviors ( apa , dsm - iv - tr 2000 ) , but they also suffer from many comorbid features such as anxiety , depression , adhd and behavioral problems ( e.g. leyfer et al . . an important distinction , however , is the presence of comorbid symptoms versus comorbid disorders . for a full clinical picture of a childit is valuable to be informed with respect to his / her comorbid symptoms but often additional treatment options are more likely to be offered when a dsm - iv disorder is classified . while several studies have examined comorbid psychiatric symptoms in children with asd ( e.g. gadow et al . 2005 ; kim et al . 2000 ) , studies that have examined the presence of comorbid psychiatric disorders are less common , particularly using standardized diagnostic interviews . we have identified ten of those studies ( table 1 ) . in these studies , rates for at least one comorbid disorder vary between 63.3 % ( amr et al . in addition , studies differ with respect to the most common disorder that is found , and rates for each specific disorder vary considerably ( table 1 ) . table 1summary of studies that have examined the prevalence rates ( % ) of psychiatric comorbid disorders in children with asd using ( semi - ) structured diagnostic interviewsfirst authoryearage rangeasd subtype and ( sub ) sample sizepsymdddyssocsadsphgadocdagopanadhdoddcdamr2012411ad ( n = 55 ) ; pdd - nos ( n = 5 ) 63.313.3 nrnr8 .340.010.055.0 nrnr31 .6 nr23 .3 de bruin2007612pdd - nos ( n = 94 ) 80.910.62.111.78.538.35.36.46.41.144.737.29.6 gjevik2011618ad ( n = 47 ) ; as ( n = 12 ) ; pdd - nos ( n = 12 ) 71.81.41.47.00.030.90.09.8 nrnr30 .94.22.8 leyfer2006517aut ( n = 109 ) 73.010.1 nr7 .511.944.32.437.2 nr0 .030.67.0 nrmattila2010916as ( n = 27 ) ; hfa ( n = 23 ) 74.06.0 nr4 .02.028.0 nr22 .04.02.038.016.02.0 mukaddes2010616as ( n = 37 ) 96.729.0 nr5 .42.713.05.432.0 nr5 .445.05.45.4 mukaddes2010620as ( n = 30 ) ; hfa ( n = 30 ) 94.021.71.713.313.353.310.036.7 nr1 .765.031.71.7 simonoff20081014aut ( n = 62 ) ; other asd s ( n = 50 ) 70.80.90.529.20.58.513.48.27.910.128.228.13.2 witwer2010617as ( n = 16 ) ; aut ( n = 17 ) ; pdd - nos ( n = 26 ) nr14 .813.116.414.867.224.64.9 nrnr91 .875.449.2 wozniak1997nraut ( n = 42 ) ; pdd - nos ( n = 24 ) nr53 .09.09.017.019.020.016.028.04.074.055.013.0 the bold values were used to visually illustrate the most common ( top - 3 ) comorbid disordersad autistic disorder , adhd attention deficit hyperactivity disorder , ago agoraphobia , as asperger s syndrome , aut autism , cd conduct disorder , dys dysthymic disorder , gad generalized anxiety disorder , hfa high functioning autism , mdd major depressive disorder , nr not reported , ocd obsessive compulsive disorder , odd oppositional defiant disorder , pan panic disorder , pdd - nos pervasive developmental disorder not otherwise specified , psy at least one comorbid psychiatric disorder is present , sad separation anxiety disorder , soc social anxiety disorder , sph specific phobiamost common comorbid psychiatric disordersecond most common comorbid psychiatric disorderthird most common comorbid psychiatric disorder summary of studies that have examined the prevalence rates ( % ) of psychiatric comorbid disorders in children with asd using ( semi - ) structured diagnostic interviews the bold values were used to visually illustrate the most common ( top - 3 ) comorbid disorders ad autistic disorder , adhd attention deficit hyperactivity disorder , ago agoraphobia , as asperger s syndrome , aut autism , cd conduct disorder , dys dysthymic disorder , gad generalized anxiety disorder , hfa high functioning autism , mdd major depressive disorder , nr not reported , ocd obsessive compulsive disorder , odd oppositional defiant disorder , pan panic disorder , pdd - nos pervasive developmental disorder not otherwise specified , psy at least one comorbid psychiatric disorder is present , sad separation anxiety disorder , soc social anxiety disorder , sph specific phobia most common comorbid psychiatric disorder second most common comorbid psychiatric disorder third most common comorbid psychiatric disorder factors that might be relevant to consider for their influence on comorbidity rates are gender , age and intelligence quotient ( iq ) . no significant gender differences in the rates of comorbid disorders were found in the study of simonoff et al . ( 2010 ) found that psychiatric comorbidity was more common in primary school - aged children with asd compared to secondary school - aged children . mixed results have been found for comorbidity and its relation with iq : in the study of simonoff et al . ( 2011 ) , iq was not associated with psychiatric comorbidity , while in the study of witwer and lecavalier ( 2010 ) children with an iq below 70 had fewer psychiatric symptoms compared to children with an iq above 70 . alternatively , children with asd and an iq below 70 may have poorer language skills to communicate ( psychiatric ) symptoms or internal feelings ( to their caregivers ) , which could contribute to such findings . child psychiatric disorders can be roughly divided into two main groups : internalizing and externalizing ( or disruptive behavior ) disorders . internalizing disorders are characterized by behaviors and emotions that are directed inwards and include mood disorders ( e.g. major depressive disorder , dysthymic disorder ) and anxiety disorders ( e.g. separation anxiety disorder , social anxiety disorder , obsessive compulsive disorder , specific phobia ) . externalizing disorders are characterized by behaviors and emotions directed outwards and include adhd , oppositional defiant disorder ( odd ) and conduct disorder ( cd ) . since adhd seems the most commonly reported comorbid disorder in children with asd ( table 1 ) , it is important to ( 1 ) explore differences and similarities between children with asd and children with adhd , and ( 2 ) to compare the prevalence of comorbid psychiatric disorders across those clinical groups . one study compared children with adhd alone , children with asd + adhd and children with chronic multiple tic disorder + adhd and found similarities as well as differences in comorbidity of symptoms among groups ( gadow et al . similarities for all groups were found for odd and cd symptoms , whereas differences between groups were found for anxiety symptoms . children with asd + adhd were generally rated to have more severe anxiety symptoms compared to the other groups . in addition , green and colleagues compared 20 adolescents with aspergers syndrome to 20 adolescents with cd and also found adolescents with aspergers syndrome to have more anxiety - related symptoms ( green et al . 2000 ) . to conclude , several studies have examined psychiatric comorbid disorders by using structured diagnostic interviews in children with asd , however , comparative studies between asd and other clinical groups ( such as adhd ) on comorbid psychiatric disorders are rare . examining comorbidity in clinical samples is important because they may influence the symptoms of the primary diagnosis ( e.g. anxiety symptoms may exacerbate asd - symptoms ; wood and gadow 2010 ) and may affect treatment plans and outcomes ( matson and nebel - schwalm 2007 ) . furthermore , knowing which comorbid disorders are ( more ) likely to exist in a particular clinical sample , may lead to ( early ) screening activities and ( the development of ) prevention programs . therefore , the current study aims to examine comorbid disorders in children with asd and to compare them to a group of children with adhd . in addition , the relation between comorbidity and age , and between comorbidity and iq , was explored ( gender was not examined because of power issues ) . all children were referred to a general outpatient mental health center in maastricht , the netherlands . in total 80 children , aged 718 , and their parent ( s ) participated : 40 children had a primary dsm - iv - tr classification of asd , and 40 children had a primary dsm - iv - tr classification of adhd ( based on a multi - disciplinary consensus diagnosis , see procedure ) . no standardized measures were used to confirm the primary diagnosis . however , we are confident about the reliability of the asd classification since in another sample of children with asd , partly from the same outpatient mental health care center , the agreement between a clinical dsm - iv - tr classification of asd and an asd classification based on the autism diagnostic interview - revised ( adi - r ; lord et al .1994 ) was excellent ( 97.8 % ; van steensel , bgels and de bruin , submitted ) . in addition , the kid - scid ( hien et al . 1994 ; dutch translation by dreessen et al .1998 ) was used to assess psychiatric comorbid disorders of which one is adhd . for 36 out of the 40 children ( 90 % ) classified as having adhd , it was decided not to exclude these children because after disclosure of the kid - scid results these children still received a dsm - iv based diagnosis of adhd as established by the multi - disciplinary team based on other diagnostic criteria ( e.g. the cognitive profile on the wechsler intelligence scale for children - revised , wisc - r ( wechsler 1974 ; van haasen et al .1986 ) , the ratings on the child behavior check list , cbcl ( achenbach 1991 ) , and / or the impairment of attention problems for those children in daily functioning ) . of the children with asd , 28 ( 70.0 % ) were diagnosed with pdd - nos and 12 children were diagnosed with aspergers syndrome ( 30.0 % ) . of the adhd sample ,23 children were classified as having adhd - combined type ( 57.5 % ) , nine as having adhd - inattentive type ( 22.5 % ) and five as having adhd - hyperactivity type ( 12.5 % ) . for three children ( 7.5 % ) , dsm - iv - tr classification of adhdwas postponed ( i.e. a formal diagnosis of adhd was not received because families dropped out ) . however , we decided not to exclude those three children from the study because they all met dsm - iv criteria of adhd based on the kid - scid . the asd sample consisted of 36 boys and four girls with a mean age of 11.10 years ( range = 818 years ; sd = 2.82 ) . the adhd sample consisted of 37 boys and three girls and had a mean age of 11.13 years ( range = 717 years ; sd = 2.85 ) . no group differences were found for gender , x ( 1 ) = 0.157 ; p = .692 , or age , f ( 1 , 78 ) = 0.002 ; p = .969 . for a summary of the education level and cognitive functioning of both groups , no differences between groups were found for primary education level , x ( 1 ) = 0.005 ; p = 1.00 , secondary education level , mann - whitney u = 43.50 ; p = .260 , or level of cognitive functioning , mann whitney u = 487.50 ; p = .371 . table 2education level and cognitive functioning of the asd and adhd sampleasd ( n = 40 ) adhd ( n = 40 ) n % n % schoolprimary ( elementary ) special25 .025.0 regular2870 .02665.0 secondary special12 .5410.0 low level12 .512.5 moderate level37 .537.5 high level37 .537.5 vocational low level12 .512.5 moderate level00 .000.0 high level12 .500.0 cognitive functioning ( iq ) 506925.000.07079410.037.5808900.0512.5901101640.01127.5111120922.51127.512113037.500.013037.500.0 iq data not available37 .51025.0 schools in the netherlands are divided in primary , secondary and vocational schools . secondary and vocational schools are split into three education levels : low , moderate and high . special education is viewed as a separate category ; however , all levels ( low - moderate - high ) may be present . after graduation , transfers are possible ( 1 ) from a lower to a higher level within secondary or vocational schools and ( 2 ) from a secondary to a vocational school with the same level education level and cognitive functioning of the asd and adhd sample schools in the netherlands are divided in primary , secondary and vocational schools . secondary and vocational schools are split into three education levels : low , moderate and high . special education is viewed as a separate category ; however , all levels ( low - moderate - high ) may be present . after graduation , transfers are possible ( 1 ) from a lower to a higher level within secondary or vocational schools and ( 2 ) from a secondary to a vocational school with the same level the kid - scid ( hien et al . the kid - scid is based on the widely used adult scid with the questions adapted for applicability to children ( and with additional childhood disorders ) . the adult scid has demonstrated acceptable reliability and validity levels ( e.g. basco et al . 2000 ; lobbestael et al . 2011 ; spitzer et al . 1992 ; williams et al . 1992 ) . in addition , several studies support the validity and reliability of the kid - scid ( matzner 1994 ; matzner et al . kappa values for the test retest reliability of the kid - scid were found to range from .63 to .84 for the disruptive behavior disorders ( kappa was .84 , .63 , and .84 for adhd , odd , and cd respectively ) and from .44 to 1.0 for the anxiety disorders ( kappa was 1.0 , .66 , and .44 for social anxiety disorder , separation anxiety disorder , and post - traumatic stress disorder , respectively ) ( matzner et al . in addition , kappa values for the inter - rater reliability were 1.0 for disruptive behavior disorders , .63 for anxiety disorders , and .76 for the diagnosis of a current major depressive disorder ( trimbremont et al . the symptom is rated as : ( 1 ) absent , ( 2 ) possibly present , or ( 3 ) present . both child and parent ( s ) provide answers and the interviewer combines the information of all respondents to rate aif the required number of symptoms is met ( i.e. the dsm - iv symptom - criterion is met ) , the interviewer asks about other dsm - criteria ( such as at what age symptoms emerged or whether symptoms cause interference with daily activities ) . finally , a kid - scid diagnosis is obtained when all dsm - iv criteria are met . in the present study , information was obtained from parent ( s ) and child and the following sections of the kid - scid were administered : disruptive behavior disorders ( adhd , odd and cd ) , mood disorders ( major depressive disorder and dysthymic disorder ) and anxiety disorders ( separation anxiety disorder , social anxiety disorder , specific phobia , generalized anxiety disorder , obsessive compulsive disorder , panic disorder , agoraphobia , post - traumatic stress disorder , and anxiety disorder not otherwise specified ) . dsm - iv classification of asd or adhd was established by a multi - disciplinary team of psychologists , therapists , social workers and child psychiatrists , and was based on clinical evaluations . clinical evaluations included for example interviews with parent ( s ) and child , observations of child - parent interaction , school observations , diagnostic assessments ( e.g. wisc - r , wechsler 1974 ; van haasen et al . approval was given by the medical - ethical committee , and participants signed informed consent . the kid - scid was part of the intake procedure in the outpatient mental health center and was administered by psychologists who had multiple years of experience with the assessment and treatment of children with psychiatric disorders . in addition , the interviewers were trained by the translators of the kid - scid who themselves were extensively trained in the use of the adult scid . first , the overall comorbidity rate as well as the rates for internalizing and externalizing comorbid disorders in children with asd and adhd were compared using chi - square analyses . if this test reached significance , then additional chi - square analyses were conducted to explore group differences within the internalizing ( mood / anxiety disorders ) or externalizing ( odd / cd ) disorders . in addition , the relation between comorbidity and age and between comorbidity and iq was explored with spearman s rho . considering the explorative nature of the research questions , alpha levels were set at .05 for all analyses . all children were referred to a general outpatient mental health center in maastricht , the netherlands . in total 80 children , aged 718 , and their parent ( s ) participated : 40 children had a primary dsm - iv - tr classification of asd , and 40 children had a primary dsm - iv - tr classification of adhd ( based on a multi - disciplinary consensus diagnosis , see procedure ) . no standardized measures were used to confirm the primary diagnosis . however , we are confident about the reliability of the asd classification since in another sample of children with asd , partly from the same outpatient mental health care center , the agreement between a clinical dsm - iv - tr classification of asd and an asd classification based on the autism diagnostic interview - revised ( adi - r ; lord et al .1994 ) was excellent ( 97.8 % ; van steensel , bgels and de bruin , submitted ) . in addition , the kid - scid ( hien et al . 1994 ; dutch translation by dreessen et al .1998 ) was used to assess psychiatric comorbid disorders of which one is adhd . for 36 out of the 40 children ( 90 % ) classified as having adhd , it was decided not to exclude these children because after disclosure of the kid - scid results these children still received a dsm - iv based diagnosis of adhd as established by the multi - disciplinary team based on other diagnostic criteria ( e.g. the cognitive profile on the wechsler intelligence scale for children - revised , wisc - r ( wechsler 1974 ; van haasen et al .1986 ) , the ratings on the child behavior check list , cbcl ( achenbach 1991 ) , and / or the impairment of attention problems for those children in daily functioning ) . of the children with asd , 28 ( 70.0 % ) were diagnosed with pdd - nos and 12 children were diagnosed with aspergers syndrome ( 30.0 % ) . of the adhd sample ,23 children were classified as having adhd - combined type ( 57.5 % ) , nine as having adhd - inattentive type ( 22.5 % ) and five as having adhd - hyperactivity type ( 12.5 % ) . for three children ( 7.5 % ) , dsm - iv - tr classification of adhdwas postponed ( i.e. a formal diagnosis of adhd was not received because families dropped out ) . however , we decided not to exclude those three children from the study because they all met dsm - iv criteria of adhd based on the kid - scid . the asd sample consisted of 36 boys and four girls with a mean age of 11.10 years ( range = 818 years ; sd = 2.82 ) . the adhd sample consisted of 37 boys and three girls and had a mean age of 11.13 years ( range = 717 years ; sd = 2.85 ) . no group differences were found for gender , x ( 1 ) = 0.157 ; p = .692 , or age , f ( 1 , 78 ) = 0.002 ; p = .969 . for a summary of the education level and cognitive functioning of both groups , no differences between groups were found for primary education level , x ( 1 ) = 0.005 ; p = 1.00 , secondary education level , mann - whitney u = 43.50 ; p = .260 , or level of cognitive functioning , mann whitney u = 487.50 ; p = .371 . table 2education level and cognitive functioning of the asd and adhd sampleasd ( n = 40 ) adhd ( n = 40 ) n % n % schoolprimary ( elementary ) special25 .025.0 regular2870 .02665.0 secondary special12 .5410.0 low level12 .512.5 moderate level37 .537.5 high level37 .537.5 vocational low level12 .512.5 moderate level00 .000.0 high level12 .500.0 cognitive functioning ( iq ) 506925.000.07079410.037.5808900.0512.5901101640.01127.5111120922.51127.512113037.500.013037.500.0 iq data not available37 .51025.0 schools in the netherlands are divided in primary , secondary and vocational schools . secondary and vocational schools are split into three education levels : low , moderate and high . special education is viewed as a separate category ; however , all levels ( low - moderate - high ) may be present . after graduation , transfers are possible ( 1 ) from a lower to a higher level within secondary or vocational schools and ( 2 ) from a secondary to a vocational school with the same level education level and cognitive functioning of the asd and adhd sample schools in the netherlands are divided in primary , secondary and vocational schools . secondary and vocational schools are split into three education levels : low , moderate and high . special education is viewed as a separate category ; however , all levels ( low - moderate - high ) may be present . after graduation , transfers are possible ( 1 ) from a lower to a higher level within secondary or vocational schools and ( 2 ) from a secondary to a vocational school with the same levelthe kid - scid ( hien et al . 1994 ; dutch translation by dreessen et al . 1998 ) was used to assess ( comorbid ) psychiatric dsm - iv disorders . the kid - scid is based on the widely used adult scid with the questions adapted for applicability to children ( and with additional childhood disorders ) . the adult scid has demonstrated acceptable reliability and validity levels ( e.g. basco et al . 2000 ; lobbestael et al . 2011 ; spitzer et al . 1992 ; williams et al . 1992 ) . in addition , several studies support the validity and reliability of the kid - scid ( matzner 1994 ; matzner et al . kappa values for the test retest reliability of the kid - scid were found to range from .63 to .84 for the disruptive behavior disorders ( kappa was .84 , .63 , and .84 for adhd , odd , and cd respectively ) and from .44 to 1.0 for the anxiety disorders ( kappa was 1.0 , .66 , and .44 for social anxiety disorder , separation anxiety disorder , and post - traumatic stress disorder , respectively ) ( matzner et al . in addition , kappa values for the inter - rater reliability were 1.0 for disruptive behavior disorders , .63 for anxiety disorders , and .76 for the diagnosis of a current major depressive disorder ( trimbremont et al . the symptom is rated as : ( 1 ) absent , ( 2 ) possibly present , or ( 3 ) present . both child and parent ( s ) provide answers and the interviewer combines the information of all respondents to rate aif the required number of symptoms is met ( i.e. the dsm - iv symptom - criterion is met ) , the interviewer asks about other dsm - criteria ( such as at what age symptoms emerged or whether symptoms cause interference with daily activities ) . finally , a kid - scid diagnosis is obtained when all dsm - iv criteria are met . in the present study , information was obtained from parent ( s ) and child and the following sections of the kid - scid were administered : disruptive behavior disorders ( adhd , odd and cd ) , mood disorders ( major depressive disorder and dysthymic disorder ) and anxiety disorders ( separation anxiety disorder , social anxiety disorder , specific phobia , generalized anxiety disorder , obsessive compulsive disorder , panic disorder , agoraphobia , post - traumatic stress disorder , and anxiety disorder not otherwise specified ) . dsm - iv classification of asd or adhd was established by a multi - disciplinary team of psychologists , therapists , social workers and child psychiatrists , and was based on clinical evaluations . clinical evaluations included for example interviews with parent ( s ) and child , observations of child - parent interaction , school observations , diagnostic assessments ( e.g. wisc - r , wechsler 1974 ; van haasen et al . approval was given by the medical - ethical committee , and participants signed informed consent . the kid - scid was part of the intake procedure in the outpatient mental health center and was administered by psychologists who had multiple years of experience with the assessment and treatment of children with psychiatric disorders . in addition , the interviewers were trained by the translators of the kid - scid who themselves were extensively trained in the use of the adult scid . first , the overall comorbidity rate as well as the rates for internalizing and externalizing comorbid disorders in children with asd and adhd were compared using chi - square analyses . if this test reached significance , then additional chi - square analyses were conducted to explore group differences within the internalizing ( mood / anxiety disorders ) or externalizing ( odd / cd ) disorders . in addition , the relation between comorbidity and age and between comorbidity and iq was explored with spearman s rho . considering the explorative nature of the research questions , alpha levels were set at .05 for all analyses . children with asd were classified as having a comorbid disorder if they met kid - scid criteria for at least one comorbid disorder . in line with the cbcl manual ( achenbach 1991 ) we defined participants as having a comorbid externalizing disorder if they met kid - scid criteria for odd and / or cd . participants were classified to have an internalizing disorder if they met kid - scid criteria for at least one mood disorder ( major depressive disorder or dysthymic disorder ) and / or one anxiety disorder ( separation anxiety disorder , social anxiety disorder , specific phobia , generalized anxiety disorder , obsessive compulsive disorder , panic disorder , agoraphobia , post - traumatic stress disorder , or anxiety disorder not otherwise specified ) . in table3 the frequencies of the comorbid disorders for both samples are displayed . in the asd sample , twenty - three children ( 57.5 % ) were classified as having a comorbid disorder ; internalizing disorders ( 35.0 % ) were somewhat more common than externalizing disorders ( 22.5 % ) . sixteen children of the adhd - sample ( 40.0 % ) met criteria for a comorbid disorder ( note that for children with adhd a kid - scid diagnosis of adhd was excluded from this comorbidity rate ) ; externalizing disorders ( 27.5 % ) being somewhat more common than internalizing disorders ( 12.5 % ) . table 3frequency of comorbid psychiatric disorders in children with asd and children with adhdasd ( n = 40 ) adhd ( n = 40 ) n % n % comorbid disorder2357 .51640.0 internalizing disorders1435 .0512.5 anxiety disorders1127 .5410.0 separation anxiety disorder12 .525.0 social anxiety disorder410 .012.5 specific phobia512 .512.5 generalized anxiety disorder25 .000.0 obsessive compulsive disorder37 .500.0 panic disorder12 .500.0 agoraphobia00 .000.0 post - traumatic stress disorder00 .000.0 anxiety disordernot otherwise specified00 .000.0 mood disorders512 .525.0 major depressive disorder12 .525.0 dysthymic disorder410 .000.0 externalizing disorders922 .51127.5 oppositional defiant disorder922 .5820.0 conduct disorder12 .5512.5 attention deficit hyperactivity disorder922 .53690.0 participants met kid - scid criteria for at least one comorbid disorder ( for the adhd sample a kid - scid diagnosis of adhd was excluded ) participants met kid - scid criteria for at least one anxiety disorder and / or mood disorderparticipants met kid - scid criteria for odd and / or cdgroup assignment was based on clinical diagnosis and therefore it was possible that not all participants with adhd were having an adhd diagnosis according to the kid - scid frequency of comorbid psychiatric disorders in children with asd and children with adhd participants met kid - scid criteria for at least one comorbid disorder ( for the adhd sample a kid - scid diagnosis of adhd was excluded ) participants met kid - scid criteria for at least one anxiety disorder and / or mood disorder participants met kid - scid criteria for odd and / or cd group assignment was based on clinical diagnosis and therefore it was possible that not all participants with adhd were having an adhd diagnosis according to the kid - scid the two groups did not differ with respect to their overall rate of comorbid disorders , x ( 1 ) = 2.45 ; p = .117 . group differences were found to be significant for internalizing disorders , x ( 1 ) = 5.59 ; p = .018 , but not for externalizing disorders , x ( 1 ) = 0.27 ; p = .606 . of the internalizing disorders , children with asd were found to have significantly more anxiety disorders , x ( 1 ) = 4.02 ; p = .045 , but not mood disorders , x ( 1 ) = 1.41 ; p = .432 , compared to children with adhd . correlations between comorbidity and age , and between comorbidity and iq , are displayed in table 4 . correlations were only small and none were found to be significant ( all p s .10 ) indicating no relation between the presence of comorbidity and age , or between the presence of comorbid disorders and iq.table 4correlations between comorbidity and age , and between comorbidity and iqtotal ( n = 80 ) asd ( n = 40 ) adhd ( n = 40 ) comorbidintextcomorbidintextcomorbidintextage .07.03.10.17.23.06.00.21.15 iq .01.15.11.07.19.05.19.05.18 comorbid having at least one comorbid disorder ( for the adhd sample a diagnosis of adhd was excluded ) , ext having at least one externalizing disorder ( odd / cd ) , int having at least one internalizing disorder ( anxiety / mood disorder ) iq - data was not available for three children with asd and for ten children with adhd correlations between comorbidity and age , and between comorbidity and iq comorbid having at least one comorbid disorder ( for the adhd sample a diagnosis of adhd was excluded ) , ext having at least one externalizing disorder ( odd / cd ) , int having at least one internalizing disorder ( anxiety / mood disorder ) iq - data was not available for three children with asd and for ten children with adhdthe present study examined psychiatric comorbidity in children with asd and compared this to a group of children with adhd . this was the first study to compare these two groups with respect to the frequencies of comorbid disorders ( instead of symptoms ) with a structured diagnostic interview . children with asd did not differ from children with adhd with respect to their overall comorbidity rate . however , anxiety disorders were more often present in children with asd compared to children with adhd . the finding that children with asd and adhd do not differ with respect to their overall comorbidity rate is not very surprising , since a review of comorbidity in children with adhd ( gillberg et al .2004 ) reported similar comorbidity rates ( 60100 % ) to those found by studies focusing on children with asd ( 63.396.4 % , see table 1 ) . first , comorbidity rates of children with asd have not been compared directly to children with adhd before . in addition , comparing the comorbidity rates between studies that have included children with asd versus children with adhd is difficult because of the wide variability in study designs , measurements to assess psychiatric comorbidity and study samples ( i.e. community - based versus clinic - based samples ) . secondly , the present findings suggest that children with asd and children with adhd are equally likely to develop comorbid psychiatric disorders , although specific comorbid disorders may be more present in one group than the other . in the present studyit was found that children with asd exhibit more anxiety disorders compared to children with adhd . this may partly be due to overlap between the core symptoms of asd and symptoms of anxiety , particular in the case of obsessive compulsive disorder and social anxiety disorder [ see for example wood and gadow ( 2010 ) and van steensel et al . nevertheless , our finding that children with asd would have more anxiety disorders is in agreement with the study of gadow et al . ( 2009 ) which found children with asd to have more anxiety symptoms compared to children with adhd . in addition , anxiety symptoms are usually not the core deficits in children with asd , however , they respond favorably to treatment and extensive protocols for pharmacotherapy , and behavioral therapy for these additional anxiety symptoms in asd is available ( e.g. posey and mcdougle 2000 ; santosh and baird 2001 ) . it is thus important to be aware of these comorbid symptoms , because not only are they treatable ( whereas the core asd symptoms are not ) , not treating them may lead to extra impairments in daily life skills such as completing school work or engaging in social situations . in addition , it is commonly found that children with asd have higher levels of anxiety compared to typically developing children ( e.g. kim et al .2000 ) , however , for children with adhd , as compared to typically developing children , these findings are more mixed ( e.g. biederman et al . 1991 ; gau et al . 2010 ; van den heuvel et al . ( 2009 ) , we found that children with asd and adhd do not differ with respect to comorbid externalizing disorders ( odd / cd ) . in addition , in general , comorbidity between adhd and odd / cd is higher than between adhd and internalizing disorders ( e.g. gillberg et al . 2004 ) . of note , in post hoc analyses we also found that children with asd and a comorbid diagnosis of adhd ( n = 9 ) were significantly more likely to have odd / cd ( but not internalizing disorders ) compared to those children with asd without a comorbid adhd - diagnosis ( n = 31 ) . in contrast , we did not find higher levels of mood disorders in children with asd . ( 2009 ) symptoms instead of disorders were assessed , which may explain the disagreement . important to add here is that our study sample consisted of school - aged children only . from studies of ghaziuddin2002 ) it is known that the rate of depression in asd may rise with age . from the adolescent phase , andeven more so for ( young ) adults , depression ( i.e. a mood disorder ) is the most common comorbid disorder in people with asd ( ghaziuddin et al . it is therefore likely that our findings regarding comorbidity are not representative for the different stages of a life with asd . possibly , differences between adhd and asd become more prominent later in life ( roeyers et al . this percentage is somewhat lower compared to the rates found in comparable studies ( 63.396.4 % , see table 1 ) . a first explanation for the relatively low rate we found is that we included only internalizing and externalizing disorders , excluding disorders such as enuresis , encopresis , chronic tic disorder , tourette s syndrome , and schizophrenia , which were included in several previous studies . a second explanation for the relatively low percentage of comorbidity might be related to the center to which the children of our sample were referred to . as such , children with a large heterogeneity in psychiatric problems were referred , and possibly the more severe or complex cases ( with higher comorbidity ) were referred to more specialized centers . a third explanation for the relatively low comorbidity rate is that in most other studies different standardized interviews were used ( e.g. the diagnostic interview schedule for children [ disc - iv ; ferdinand and van der ende 1998 ; shaffer et al . the kid - scid , similar to the dsm - iv , includes a criterion that the symptoms of adhd , separation anxiety disorder , social anxiety disorder and generalized anxiety disorder may not be explained by the presence of an asd . this criterion may have lowered the comorbidity rates of those disorders in the current study . nonetheless , the percentage of comorbidity in children with asd found in the current study ( 57.5 % ) is still much higher compared to the rates ( 9.514.5 % ) commonly found in typically developing children ( e.g. meltzer 2007 ; ravens - sieberer et al . 2008 ; scholte et al . first , a larger sample size would have more power to detect possible influences of age and iq . for example , the sample size of the current study was too small to examine possible influences of age or iq for each specific disorder individually ( e.g. social anxiety disorder , dysthymic disorder , etc . ) . in addition , while we did not find a significant relation between age ( or iq ) and comorbidity in the present study , other studies did find differences across specific disorders for the influence of age in children with asd ( e.g. matilla et al .2010 found that behavioral disorders in children with asd decreased with age , and gjevik et al .2011 found children with asd and comorbid obsessive compulsive disorder to be significantly older compared to those without obsessive compulsive disorder ) . further , the influence of other factors such as gender or asd / adhd subtype would be interesting to examine , however , this was not possible in the present study because of power issues . that is , a number of children with asd ( n = 9 , 22.5 % ) also had adhd ( according to kid - scid criteria ) and were found to differ from children with asd without adhd with respect to the rates of comorbid externalizing disorders . none of the children with adhd were suspected to have asd , however , although we have not assessed asd symptoms in children with adhd in the present study , it is likely that some of these children had ( sub - ) clinical levels of asd symptoms .2011 ) have found higher levels of asd traits in children with adhd compared to typically developing children , and a substantial proportion of those children with adhd reached screening thresholds predictive for an asd diagnosis . third , with respect to the diagnostic instrument ( kid - scid ) it needs to be noted that psychometric studies are still ongoing . results of studies examining the kid - scid so far yielded fair to excellent test retest reliability and inter - rater reliability ( matzner 1994 ; matzner et al .2004 ) , however , studies examining the validity of the kid - scid are rare . a last limitation of the study is that we did not confirm asd classification by standardized assessments such as the adi - r ( lord et al .1994 ) or the autism diagnostic observation schedule generic ( ados - g ; lord et al .1999 ) . to the authors knowledge , this was the first study to examine the rate of psychiatric disorders in children with asd and compared this to a group of children with adhd , by using a structured and standardized diagnostic interview . it was found that children with asd were equally likely to suffer from mood disorders and externalizing disorders ( odd / cd ) as children with adhd ; however , they showed significantly more anxiety disorders compared to children with adhd . considering the large comorbidity found in children with asd ( and adhd ) , clinicians should be alert of , and ideally , should always screen for comorbid disorders . not onlymay these disorders interfere with daily functioning over and above the core symptoms of asd , they may also exacerbate asd - symptoms ( wood and gadow 2010 ) . however , reliable and valid screening instruments for assessing comorbidity as well as effective treatment programs for treating comorbidity in the asd population are yet to be established . note that there is a small but growing body of evidence to suggest that cognitive - behavioral therapies are effective for the treatment of anxiety disorders in youth with high - functioning asd ( e.g. chalfant et al .2009 ) , however , additional research is needed to examine the long - term follow up and factors that might influence treatment outcome . furthermore , research concerning prevention programs as well as treatment options for the more challenging cases ( e.g. children with intellectual disabilities or multiple comorbid disorders ) is specifically needed .\noutput:\n" }, { "from": "agent", "value": "the present study was conducted with the aim to identify comorbid psychiatric disorders in children with autism spectrum disorders ( asd ) ( n = 40 ) and to compare those comorbidity rates to those in children with attention deficit hyperactivity disorder ( adhd ) ( n = 40 ) . participants were clinically referred children aged 718 years . dsm - iv classifications were used for the primary diagnosis ( asd / adhd ) , while comorbid psychiatric disorders were assessed using a structured diagnostic interview , the structured clinical interview for dsm - iv , childhood diagnoses ( kid - scid ) . twenty - three children with asd ( 57.5 % ) had at least one comorbid disorder , whereas 16 children with adhd ( 40.0 % ) were classified as having at least one comorbid disorder . no group differences were found with respect to this comorbidity rate or for the rate of comorbid externalizing disorders ( odd and / or cd ) . however , children with asd had more comorbid internalizing disorders compared to children with adhd . more specifically , children with asd had higher rates of anxiety disorders , but not mood disorders . no associations between comorbidity and age or between comorbidity and the intelligence quotient was found . it is important for clinicians to always be aware of , and screen for , comorbidity , and to consider treatment for these comorbid disorders . in addition , research should focus on establishing valid and reliable screening tools as well as effective treatment options for these comorbid disorders ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: chironomus riparius ( chironomidae , diptera ) , is widely used in aquatic exotoxicological studies for assessing acute and sub - lethal toxicities of contaminated sediments and for water monitoring due to their widespread occurrence , short life - cycle , easy to be reared in the laboratory , physiological tolerance to various environmental conditions . to date , the endpoints used for monitoring such effects in c. riparius are based on a small number of specific biomarkers and measurements of organism level effects , such as survival and reproduction . genomic - based techniques based on expression analysis of genes are important tools for investigating molecular level effects caused by exposure to environmental pollutants , which will provide the ability to detect mechanisms of action and subsequent adverse cellular level effects and associated with different types of toxicity . as a pre - requisite for genomic based eco - toxicological studies knowledge of the c. riparius transcriptome is important but despite its eco - toxicological importance , no large scale transcriptome analysis of c. riparius has been done so far . in a previous report arvestad et al . reported the transcriptome analysis of c. tentans midgut and an epithelial cell line using cdna sequencing using conventional cdna synthesis and sequencing method . however , with the advent of new high throughput pyrosequencing technologies using several genome sequencers , such as gs - flx , gs - flx - titanium and solexa , extensive cdna sequence information can be obtained in a short period of time . the gs - flx pyrosequencer , from 454 life science / roche , is well - suited for de novo transcriptome sequencing for the rapid production of sequence data with reduced time , labor and cost , and generates the longest reads . moreover , well characterized reference genomes of insects [ 8 - 10 ] could provide platforms for comparative genome analyses of non model organisms like c. riparius . in this study , we present the first comprehensive characterization of the transcriptome of c. riparius 4 instar larvae using 454 pyrosequencing . based on data corresponding to one single run on the flx gene sequencer from 454 life science , almost 49,774,676 bases were assembled into transcripts and the majority of these have been annotated and functionally classified . in light of limited genomic and transcriptomic information , these data would significantly enrich the molecular aspects of c. riparius and its role in genomics based ecotoxicological studies . c. riparius strains were obtained from korea institute of chemical technology ( daejon , korea ) . the larvae were reared on an artificial diet of fish flake food ( tetramin , tetrawerke , melle , germany ) in glass chambers containing dechlorinated tap water and acid washed sand , with aeration under a 16 - 8 h light - dark photoperiod at room temperature ( 201 ) . the larvae were collected and total rna samples were isolated using trizol reagent ( invitrogen life technology , usa ) . the rna samples ( a260 / a2801 .8 ) were collected and mrna was purified from the pooled total rna ( 500 g ) by binding to oligo ( dt ) cellulose twice ( poly ( a ) purist , ambion ) . for first strand synthesis , 10 l of the purified mrna ( 5 g ) , denatured at 65 for 10 minutes in a rnase free tube , rapidly chilled on ice , mixed with 5 l of 10x first - strand buffer , 5 lof 100 mm dtt , 5 lof dntps ( 2.5 mm each ) , 5 lof oligo dt20 ( 50 m ) , 2.5 lof strata script reverse transcriptase ( 200 u / l ) in a 50 lreaction volume . first strand cdna was synthesized at 42 for 60 minutes and cdna synthesis and heat inactivated at 70 for 15 minutes and the tubes were placed on ice . for second strand cdna synthesis , h2o ( 61 l ) ,100 m tris - hcl , 20 l of second - strand buffer , dntps ( 6 l , 10 mm each ) , dna polymerase i ( 4 l , 10 u / l ) , and rnase h ( 2 l , 1.5 u / l ) were mixed with the first strand synthesis reaction and incubated at 16 for 150 minutes . for end blunting , 23 l of blunting dntp mix , 2 l of cloned pfu dna polymerase ( 2.5 u / l ) was incubated with the second strand synthesis reaction at 16 for 5 minutes . the cdna was purified using qiaquick pcr purification kit ( qiagen , ca , usa ) in a final elution volume of 50 l . approximately , 1 g of the final pcr product dna was used to generate dna library for genome sequencer flx titanium ( roche , mannheim , ge ) . the fragments ends were polished ( blunted ) , and short two adapters were ligated onto both ends . the adapters provide priming sequences for both amplification and sequencing of the sample library fragments , as well as the \" sequencing key \" , a short sequence of 4 nucleotides used by the system software for base calling and , following repair of any nicks in the double - stranded library , release of the unbound strand of each fragment ( with 5, - adaptor a ) . finally the quality of the library of single - stranded template dna fragments ( ssdna library ) was assessed using 2100 bioanalyzer ( agilent , waldbronn , ge ) , and the library was quantitated , including a functional quantitation to determine the optimal amount of the library to use as input for emulsion - based clonal amplification . single \" effective \" copies of template species from the dna library to be sequenced were hybridized to dna capture beads . the immobilized library was then resuspended in the amplification solution , and the mixture is emulsified , followed by pcr amplification . after amplification , the dna - carrying beads were recovered from the emulsion and enriched . the second strands of the amplification products were melted away as part of the enrichment process , leaving the amplified single - stranded dna library bound to the beads . after amplification , the dna - carrying beads were set into the wells of a picotiterplate device ( ptp ) such that wells contain single dna beads . the loaded ptp was then inserted into the genome sequencer flx instrument , and sequencing reagents were sequentially flowed over the plate . information from all the wells of the ptp is captured simultaneously by the camera , and can be processed in real time by the onboard computer . after assembly , the resulting contigs and singlets were blastx searched against the protein databases \" nr \" and \" uniprot \" ( the uniprot consortium , 2008 ) . the sequences were annotated using the gene ontology ( go ) terms where possible according to molecular function , biological process and cellular component using database ( http://www.geneontology.org/ ) . pathway assignments according to kyoto encyclopedia of genes and genomes ( kegg ) mapping was carried out using unique sequences that had blastx scores with a cut off value of e = 10 the sequences were mapped to different kegg biochemical pathways according to the ec distribution in the pathway database ( http://www.genome.ad.jp/kegg/ ) . c. riparius strains were obtained from korea institute of chemical technology ( daejon , korea ) . the larvae were reared on an artificial diet of fish flake food ( tetramin , tetrawerke , melle , germany ) in glass chambers containing dechlorinated tap water and acid washed sand , with aeration under a 16 - 8 h light - dark photoperiod at room temperature ( 201 ) . the larvae were collected and total rna samples were isolated using trizol reagent ( invitrogen life technology , usa ) . the rna samples ( a260 / a2801 .8 ) were collected and mrna was purified from the pooled total rna ( 500 g ) by binding to oligo ( dt ) cellulose twice ( poly ( a ) purist , ambion ) . for first strand synthesis , 10 l of the purified mrna ( 5 g ) , denatured at 65 for 10 minutes in a rnase free tube , rapidly chilled on ice , mixed with 5 l of 10x first - strand buffer , 5 lof 100 mm dtt , 5 lof dntps ( 2.5 mm each ) , 5 lof oligo dt20 ( 50 m ) , 2.5 lof strata script reverse transcriptase ( 200 u / l ) in a 50 lreaction volume . first strand cdna was synthesized at 42 for 60 minutes and cdna synthesis and heat inactivated at 70 for 15 minutes and the tubes were placed on ice . for second strand cdna synthesis , h2o ( 61 l ) ,100 m tris - hcl , 20 l of second - strand buffer , dntps ( 6 l , 10 mm each ) , dna polymerase i ( 4 l , 10 u / l ) , and rnase h ( 2 l , 1.5 u / l ) were mixed with the first strand synthesis reaction and incubated at 16 for 150 minutes . for end blunting , 23 l of blunting dntp mix , 2 l of cloned pfu dna polymerase ( 2.5 u / l ) was incubated with the second strand synthesis reaction at 16 for 5 minutes . the cdna was purified using qiaquick pcr purification kit ( qiagen , ca , usa ) in a final elution volume of 50 l . approximately , 1 g of the final pcr product dna was used to generate dna library for genome sequencer flx titanium ( roche , mannheim , ge ) . the fragments ends were polished ( blunted ) , and short two adapters were ligated onto both ends . the adapters provide priming sequences for both amplification and sequencing of the sample library fragments , as well as the \" sequencing key \" , a short sequence of 4 nucleotides used by the system software for base calling and , following repair of any nicks in the double - stranded library , release of the unbound strand of each fragment ( with 5, - adaptor a ) . finally the quality of the library of single - stranded template dna fragments ( ssdna library ) was assessed using 2100 bioanalyzer ( agilent , waldbronn , ge ) , and the library was quantitated , including a functional quantitation to determine the optimal amount of the library to use as input for emulsion - based clonal amplification . single \" effective \" copies of template species from the dna library to be sequenced were hybridized to dna capture beads . the immobilized library was then resuspended in the amplification solution , and the mixture is emulsified , followed by pcr amplification . after amplification , the dna - carrying beads were recovered from the emulsion and enriched . the second strands of the amplification products were melted away as part of the enrichment process , leaving the amplified single - stranded dna library bound to the beads . the sequencing primer is then annealed to the immobilized amplified dna templates . after amplification , the dna - carrying beads were set into the wells of a picotiterplate device ( ptp ) such that wells contain single dna beads . the loaded ptp was then inserted into the genome sequencer flx instrument , and sequencing reagents were sequentially flowed over the plate . information from all the wells of the ptp is captured simultaneously by the camera , and can be processed in real time by the onboard computer . after assembly , the resulting contigs and singlets were blastx searched against the protein databases \" nr \" and \" uniprot \" ( the uniprot consortium , 2008 ) . the sequences were annotated using the gene ontology ( go ) terms where possible according to molecular function , biological process and cellular component using database ( http://www.geneontology.org/ ) . pathway assignments according to kyoto encyclopedia of genes and genomes ( kegg ) mapping was carried out using unique sequences that had blastx scores with a cut off value of e = 10 the sequences were mapped to different kegg biochemical pathways according to the ec distribution in the pathway database ( http://www.genome.ad.jp/kegg/ ) . to get an overview of c. riparius transcriptome , total rna was isolated from fourth instar larvae , and mrna purification , cdna synthesis , and sequence determination was done . these were then pyrosequenced , and in total , 138,091 reads were obtained , constituting a total of 49,774,676 bases of cdna . following the assembly of the sequences , a total of 8,565 contigs and 11,455 singletons were obtained ( table 1 ) . among the 8,565 contigs , 3,131 and 5,434 had lengths more than 500 and 100 base pairs , respectively ( table 2 ) . after assembly , the contigs and singletons were blastx searched against the protein databases \" nr \" and \" uniprot \" ( the uniprot consortium , 2008 ) . of the 8,565 c. riparius contigs , 5,102 matched proteins in \" uniprot \" and 5,114 matched proteins in \" nr \" , while the numbers for the 11,455 singlets where 4,697 and 4,710 , respectively ( table 3 ) . after removing all redundant sequences , 9,512 sequences were obtained , representing a significant part of the c. riparius transcriptome . gene ontology ( go ) has been widely used to characterize gene function , annotation and classification . as a whole , 24 % of the sequences matched with known function genes to existing gene models in blastx searches ( e - value 1 ) , 24 % showed no significant match and 52 % of the pyrosequencing assemblies ( e - value 1 ) did not match with any known sequences in the existing genbank database and ; thus , are likely to represent novel transcripts identified in this study ( figure 1 ) . similarities based on the results of blastx searches showed the highest percentage of sequences match with aedes aegypti ( 26 % ) , followed by culex quinquefasciatus ( 21 % ) , drosophila spp . ( 18 % ) , anopheles gambiae ( 15 % ) , tribolium castaneum ( 4 % ) , apis mellifera ( 2 % ) and nasonia vitripennis ( 2 % ) . a small number of sequences ( 1 % ) showed similarities with previously characterized genes of different chironomus species and 6 % of sequences matched with other insects and rest of the 5 % matched with other ( human , chicken , mouse , zebrafish , c. elegans or other organisms ) species ( figure 2 ) . kegg pathway analyses are widely used as a reference for the systematic interpretation of sequence data by linking individual genes to components of the kegg biochemical pathways . the pyrosequenced transcriptome of c. riparius was searched for the number of annotated gene sequences involved in shared specific kegg pathways among animal phyla , using the unique sequences that had blastx scores with a cut off value of e = 10 . it was found that 2908 ( 34.73 % ) genes were involved in proteins with a binding function or cofactor requirement , 1,165 ( 13.91 % ) genes were involved in subcellular localizations , 915 ( 11 % ) in metabolism , 917 ( 10.95 % ) in regulation of metabolism and protein function and 700 ( 8.36 % ) in cellular transport , transport facilities and transport routes representing the largest groups with putative function , indicating the important metabolic activities in c. riparius ( table 4 ) . these results showed the effectiveness of our transcriptome analysis of c. riparius , and indicated many of the candidate genes involved in many pathways and cellular processes . a closer examination of the annotations revealed several genes that are of particular interest for environmental monitoring and ecological research . several proteins catalyzing biotransformation of many xenobiotic and a number of important biomarkers for a large number of different compounds were present . among the sequenced c.riparius transcripts , 117 different cytochrome p450 variants from 13 different families could be identified . other interesting classes of proteins such as heat shock protein ( 24.1 , 27 , 67b2 , 70 , 90 ) , genes coding for oxidative stress such as catalase , glutathione peroxidase , glutathione s - transferase , superoxide dismutase , thioredoxin reductase and several other biomarker genes such as metallothionein , vitellogenin were also present ( table 5 ) . to get an overview of c. riparius transcriptome , total rna was isolated from fourth instar larvae , and mrna purification , cdna synthesis , and sequence determination was done . these were then pyrosequenced , and in total , 138,091 reads were obtained , constituting a total of 49,774,676 bases of cdna . following the assembly of the sequences , a total of 8,565 contigs and 11,455 singletons were obtained ( table 1 ) . among the 8,565 contigs , 3,131 and 5,434 had lengths more than 500 and 100 base pairs , respectively ( table 2 ) . after assembly , the contigs and singletons were blastx searched against the protein databases \" nr \" and \" uniprot \" ( the uniprot consortium , 2008 ) . of the 8,565 c. riparius contigs , 5,102 matched proteins in \" uniprot \" and 5,114 matched proteins in \" nr \" , while the numbers for the 11,455 singlets where 4,697 and 4,710 , respectively ( table 3 ) . after removing all redundant sequences , 9,512 sequences were obtained , representing a significant part of the c. riparius transcriptome . gene ontology ( go ) has been widely used to characterize gene function , annotation and classification . as a whole , 24 % of the sequences matched with known function genes to existing gene models in blastx searches ( e - value 1 ) , 24 % showed no significant match and 52 % of the pyrosequencing assemblies ( e - value 1 ) did not match with any known sequences in the existing genbank database and ; thus , are likely to represent novel transcripts identified in this study ( figure 1 ) . similarities based on the results of blastx searches showed the highest percentage of sequences match with aedes aegypti ( 26 % ) , followed by culex quinquefasciatus ( 21 % ) , drosophila spp . ( 18 % ) , anopheles gambiae ( 15 % ) , tribolium castaneum ( 4 % ) , apis mellifera ( 2 % ) and nasonia vitripennis ( 2 % ) . a small number of sequences ( 1 % ) showed similarities with previously characterized genes of different chironomus species and 6 % of sequences matched with other insects and rest of the 5 % matched with other ( human , chicken , mouse , zebrafish , c. elegans or other organisms ) species ( figure 2 ) . kegg pathway analyses are widely used as a reference for the systematic interpretation of sequence data by linking individual genes to components of the kegg biochemical pathways . the pyrosequenced transcriptome of c. riparius was searched for the number of annotated gene sequences involved in shared specific kegg pathways among animal phyla , using the unique sequences that had blastx scores with a cut off value of e = 10 . it was found that 2908 ( 34.73 % ) genes were involved in proteins with a binding function or cofactor requirement , 1,165 ( 13.91 % ) genes were involved in subcellular localizations , 915 ( 11 % ) in metabolism , 917 ( 10.95 % ) in regulation of metabolism and protein function and 700 ( 8.36 % ) in cellular transport , transport facilities and transport routes representing the largest groups with putative function , indicating the important metabolic activities in c. riparius ( table 4 ) . these results showed the effectiveness of our transcriptome analysis of c. riparius , and indicated many of the candidate genes involved in many pathways and cellular processes . a closer examination of the annotations revealed several genes that are of particular interest for environmental monitoring and ecological research . several proteins catalyzing biotransformation of many xenobiotic and a number of important biomarkers for a large number of different compounds were present . among the sequenced c.riparius transcripts , 117 different cytochrome p450 variants from 13 different families could be identified . other interesting classes of proteins such as heat shock protein ( 24.1 , 27 , 67b2 , 70 , 90 ) , genes coding for oxidative stress such as catalase , glutathione peroxidase , glutathione s - transferase , superoxide dismutase , thioredoxin reductase and several other biomarker genes such as metallothionein , vitellogenin were also present ( table 5 ) . c. riparius has been studied extensively because of their importance as an ecologically important biomonitoring species . however , due to limited knowledge of genomic resources necessary for mechanistic study , the effect of toxicants at the genomic level was rarely studied . this work describes the first assessment of the use of pyrosequencing in c. riparius and we have obtained a significant portion of the c. riparius transcriptome using this approach . to facilitate identifying sets of genes involved in a broad range of processes we developed our ests set from a normalized whole - body library . as compared to sanger - based approaches , which require cdna cloning and bacterial transformation , transcriptome sequencing using massively parallel pyrosequencing exhibits high sensitivity and detection of low - abundant transcripts . transcripts that previously have been hard to sequence can therefore be detected as in the case of arabidopsis transcriptome profiling using pyrosequecing as reported by weber et al . . even though , the length of the sequence is shorter than as compared to sanger sequencing , the flx gene sequencer used in this study generated 3,131 contigs with an average of 924 bp length which is longer compared to previous studies . in our study , sequence names to the assembled sequences were given based on the best blast match for that sequence available in the public sequence data base and almost 50 % of the genes were assigned gene names . however , another 50 % of the sequences not matching to known genes in public sequence databases . in our studies we obtained 9,512 , non - redundant genes and thus , a major part of the transcriptome of c. riparius has been obtained . one of the limitations in non - model organisms lacking fully sequenced genome where the transcriptome pyrosequencing is based on the number of genes expressed and without a fully - sequenced genome no clear data is available . genome sequences for the insects d. melanogaster , a. gambiae and a. aegypti have been reported and many other species are nearing completion . in our studies 81 % of the c. riparius transcriptome closely related to insects a. aegypti , d. melanogaster , c. quinquefasciatus , and a. gambiae and therefore will provide a rich source of information for further investigation using comparative genome analyses . the expression levels of unknown transcripts were also as high as those aligning in annotated regions and these transcripts are likely to represent novel transcripts , which offer possibility to study new genes which may be specific to c. riparius . in earlier reports , many unique genes are observed in transcriptome studies of m. sexta . in data analysis , many genes involved in different pathways , cellular processes and genes involved in metabolism of toxic substances or well - known biomarker genes ( table 4 ) are identified . since c. riparius is extensively used in ecotoxicological studies , gene expression analysis are needed for mechanistic studies to understand changes in aquatic environment and the large collection of annotated sequences produced in this study represents a reasonably complete description of the c. riparius larval transcriptome . by correlating morphological as well as physiological charecters with molecular - level responses , caused by exposure to various toxicants , the subtle effect of various toxicantspyrosequencing offers rapid characterization of a large portion of the transcriptome and therefore provides a comprehensive tool for gene discovery . pyrosequencing the ests of 4 instar c. riparius larvae resulted in the identification of many sequences of ecotoxicological relevance . analysis of the c. riparius transcriptome has revealed several gene candidates of ecotoxicological interest and further functional characterization will identify genes with relevance to ecotoxicology . the obtained transcriptome offers the additional option to design microarrays to study transcript regulation to understand the effect of environmental stressors . transcriptome comparison with well - studied organisms will facilitate further the understanding of how environmental stressors effect at higher organisms levels using c. riparius as a model system . the platform will allow correlation of molecular - level responses , caused by exposure to various toxicants , to the unique morphological and physiological characters of c. riparius .\noutput:\n" }, { "from": "agent", "value": "objectiveschironomus riparius , a non - biting midge ( chironomidae , diptera ) , is extensively used as a model organism in aquatic ecotoxicological studies , and considering the potential of c. riparius larvae as a bio - monitoring species , little is known about its genome sequences . this study reports the results of an expressed sequence tags ( ests ) sequencing project conducted on c. riparius larvae using 454 pyrosequencing.methodsto gain a better understanding of c. riparius transcriptome , we generated ests database of c. ripairus using pyrosequencing method.resultssequencing runs , using normalized cdna collections from fourth instar larvae , yielded 20,020 expressed sequence tags , which were assembled into 8,565 contigs and 11,455 singletons . sequence analysis was performed by blastx search against the national center for biotechnology information ( ncbi ) nucleotide ( nr ) and uniprot protein database . based on the gene ontology classifications , 24 % ( e - value 1 - 5 ) of the sequences had known gene functions , 24 % had unknown functions and 52 % of sequences did not match any known sequences in the existing database . sequence comparison revealed 81 % of the genes have homologous genes among other insects belonging to the order diptera providing tools for comparative genome analyses . targeted searches using these annotations identified genes associated with essential metabolic pathways , signaling pathways , detoxification of toxic metabolites and stress response genes of ecotoxicological interest.conclusionsthe results obtained from this study would eventually make ecotoxicogenomics possible in a truly environmentally relevant species , such as , c. riparius ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: endogenous hypercortisolism usually presents in association with neoplastic or hyperplastic disorders , such as pituitary adenomas , ectopic adrenocorticotropic hormone ( acth ) - producing neoplasm , and adrenal tumors or hyperplasia . its principal symptoms and signs are central obesity , hyperglycemia , hypertension , electrolyte imbalance , and so on , and are known as cushing 's disease or cushing 's syndrome . excess endogenous steroids , as well as exogenous / iatrogenic ones , potentially induce opportunistic infections . its secretion is increased via activation of hypothalamus pituitary adrenal axis by diverse stresses . in critically ill patientsthis pathophysiological phenomenon is known as functional hypercortisolism or pseudo - cushing 's syndrome , which can be differentiated from truealthough it is considered a kind of adaptive reaction against severe stresses , it may introduce unfavorable effects to patients in the same manner as true cushing 's syndrome . recently , we experienced a case of severe opportunistic infections associated with functional hypercortisolism . the patient died of candidiasis that superinfected on gastroduodenal ulcers ( gdu ) associated with cytomegalovirus ( cmv ) infection . to our knowledge , this is the first case report of its kind . in the light of its clinical importancea 77 - year - old woman with alzheimer 's disease was admitted to our hospital because of vomiting and anorexia persisting for over a month . she had been managed as an outpatient of our hospital from january 2013 due to hiatal hernia and iron - deficiency anemia . gdu was suspected , but endoscopic examination revealed no lesions in her stomach and duodenum . despite detailed examinations , an etiology of her iron - deficiency anemia was not determined . simultaneously , her alzheimer 's disease worsened , and oral intake of donepezil was initiated from november 2013 . subsequently , she complained of nausea , which was supposed to be attributed to donepezil , and rivastigmine patches were begun instead of donepezil . however , her sickness had become severe , and she developed uncontrollable anorexia and vomiting . the radiological examination revealed moderate amounts of ascites and pleural effusion besides already - known scoliosis and hiatal hernia . laboratory test results demonstrated hypernatremia ( 156 meq / l ) , hypokalemia ( 3.4 meq / l ) , hypoalbuminemia ( 2.8 g / dl ) , and mild leukocytosis ( 9400 / mm ) . the physicians were aware that there had been electrolyte imbalance since 1 week ago and hyperglycemia appeared 2 weeks ago ( fig . hormonal tests were performed and revealed the elevated plasma cortisol level ( 78.2 g / dl [ normal range , 3.918.1 g / dl ] ) accompanied by the low plasma acth level ( 7.5 pg / ml [ normal range , 7.763.1 pg / ml ] ) . , the physicians decided to correct her dehydration and electrolyte imbalance first , and planned to perform a dexamethasone suppression test and detailed gastrointestinal examinations later . although strict intravenous infusion therapy was continued , the patient 's general condition and laboratory data did not improve . oral intake was initiated on the 8th hospital day , but no nutritional efficacy was obtained . the amounts of ascites and pleural effusion progressively increased , and her respiratory condition worsened . on the 11th hospital day , she complained of severe abdominal pain , and suddenly fell into shock status . a markedly elevated serum level of c - reactive protein ( 11.73 mg / dl ) suggested that she was suffering from a critical infectious / inflammatory disorder . at that time , both the plasma cortisol ( 228.0 g / dl ) and acth ( 339.3 pg / ml ) levels were remarkably elevated ( fig . an autopsy was performed to clarify what had happened in her body during these couple of months . written informed consent was obtained from the patient 's family , and this case study was approved by the hospital ethical committee . then , every thoraco - abdominal organ was removed , examined macroscopically , and fixed in buffered formalin . paraffin - embedded tissue specimens were sectioned in 3 m thick and stained with hematoxylin - eosin , periodic acid - schiff , and immunoperoxidase for cytomegalovirus ( dakopatts , glostrup , denmark ) . the autopsy findings , including results of the blood culture , indicated that the cause of her death was candidemia . candida albicans had invaded into the bloodstream via exposed vessels in the lesions of gdu , which was associated with cmv infection ( fig . cmv - infected cells were also seen in the lungs , colon , uterus , and lymph nodes . no neoplastic / hyperplastic changes were found in any examined organs including adrenal glands ( fig . ( a ) a deep gastric ulcer ( asterisk ) associated with fungal colonization ( hematoxylin - eosin ; loupe magnification ) . ( b ) fungi invading the vascular lumen ( arrowheads ) in the ulcer bed ( periodic acid - schiff stain ; low magnification ) . ( c ) many cmv - infected cells ( arrows ) in mucosa adjacent to the ulcer ( hematoxylin - eosin ; high magnification ) . final pathologic diagnoses were : ( 1 ) functional hypercortisolism ( pseudo - cushing 's syndrome ) , ( 2 ) cmv - associated gdu , and ( 3 ) candida superinfection in gdu and candidemia ( cause of death ) . unfortunately , we could not rescue the patient . to convert this negative experience to future success , we thoroughly reviewed the clinical and pathological findings , guessed the pathophysiology , and pondered how we should have managed the patient . detailed endocrinological examinations were planned but could not be performed because her general condition rapidly worsened . no diagnostic procedures and radical therapies could be done , and all our treatment approaches to her were conservative and symptomatic . she suddenly fell into shock and died , and during this short period we could nt understand what had happened . the post - mortem examination revealed that the patient had died of candidemia that had occurred as an unimaginable incidental complication of cmv - associated gdu ( fig . in general , it is recognized that cmv - associated gdu is caused mostly in immunocompromised patients , especially patients receiving immunosuppressive therapies . . however , since their precise immune conditions were not fully examined , they might have been in immunocompromised settings . in our patient , hypercortisolism possibly affected her immune condition and contributed to development of the life - threatening opportunistic infections . in fact , endogenous hypercortisolism is considered an important etiologic factor in immunosuppression . as described above , endogenous hypercortisolismour patient 's hypercortisolism was considered a purely functional disorder , namely pseudo - cushing syndrome . anorexia , probably adverse effects of donepezil and the use of rivastigmine patches , is thought to have been strongly stressful for her both physically and psychologically . this highly stressful condition continued for a couple of months and was thought to have led to increased cortisol secretion via activation of hypothalamus pituitary adrenal axis . functional hypercortisolism has been considered a secondary disorder that is induced in association with anorexia , diabetes , alcoholism , and critically ill conditions , and so on . however , accumulating evidence has revealed its harmful effects comparable with those of true cushing syndrome and benefits of correction of the patients plasma cortisol levels . we should have considered an active hormonal intervention when we noticed her hypercortisolism . a more critical issue during the hospitalization was the insufficient gastrointestinal examination . if gastroduodenal endoscopy had been repeatedly carried out , we would have found the gdu and made a correct diagnosis in time . in actual fact , her severe general condition did not allow us to perform detailed gastrointestinal examinations . moreover , treatment of cmv - associated gdu requires antiviral drugs , which can not be used without pathologic evidence of cmv infection shown in gastroduodenal biopsy specimens . a chance of making a correct diagnosis and choosing curable treatments is thought to have been extremely low . premortem diagnosis of cmv - associated gdu in a patient in a severe condition is quite difficult even by modern medical technologies . in conclusionthis case suggested that functional hypercortisolism , even though transient , can cause a patient to become immunocompromised .\noutput:\n" }, { "from": "agent", "value": "abstractcytomegalovirus ( cmv ) - associated gastroduodenal ulcers ( gdu ) are a rare digestive disease , which principally affect immunocompromised patients . we recently experienced cmv - associated gdu occurring in a seemingly immunocompetent patient . the rarity of such a condition was inimical to a correct clinical diagnosis.a 77 - year - old woman with alzheimer 's disease was admitted to our hospital because of vomiting and anorexia . her general condition was extremely poor due to severe dehydration . any invasive procedures including gastroduodenal endoscopy could not be performed . laboratory test results showed electrolyte imbalance , hyperglycemia , and hypercortisolemia . the plasma adrenocorticotropic hormone level was rather low . on her 11th day in hospital , she suddenly fell into shock status . despite intensive care , the patient could not be rescued . an autopsy was performed and revealed that she had suffered from cmv - associated gdu and died of candidemia that invaded through the ulcer . her adrenal glands showed neither neoplasm nor hyperplasia , suggesting that her hypercortisolism was a purely functional disorder . we concluded that the severe opportunistic infections were developed in association with functional hypercortisolism.this case suggests that functional hypercortisolism , even though transient , can cause a patient to be immunocompromised ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in april 1997 , an 11 - year - old girl visited a pediatric clinic for evaluation of repeated febrile episodes and was found to have a low white blood cell count of 2800 / l . her bone marrow biopsy showed that blasts accounted for 94.1 % of white blood cells , peroxidase staining was negative , and the cells were positive for cd10 , cd19 , and hla - dr . she was subsequently diagnosed with acute lymphocytic leukemia ( all ; french - american - british class l1 , common all ) . on the basis of the high - risk protocol of the children s cancer & leukemia study group ( cclsg ; all 941 protocol study ; ages 10 to 19 y ) ,1 she was administered tetrahydropyranyl adriamycin , vincristine , prednisone , and 6 - mercaptopurine and achieved complete remission . systemic chemotherapy is usually ineffective as a central nervous system treatment because of the inability to cross the blood - brain barrier . to prevent central nerve recurrence , thus , in october of the same year , the patient received pci of 18 gy in 12 fractions . from march to september 1998 , she remained in remission and was administered maintenance therapy consisting of cyclophosphamide ( cy ) , cytarabine , and 6 - mercaptopurine . in october , the patient was admitted to receive bone marrow transplant from her brother who was a complete hla match . as preconditioning chemotherapy , she received etoposide ( 60 mg / kg ) for 24 hours , followed by the administration of cy ( 60 mg / kg ) for 2 days . thereafter , at 13 years of age , she received tbi with uterine and ovarian shielding ; a total dose of 12 gy with a fraction dose of 3 gy , once a day , for 4 days . the following day ( day 0 ) , she received 6.3710 / kg of bone marrow from her hla - matched brother . on day 30 , graft survival was confirmed by bone marrow biopsy . methotrexate ( short - mtx ) and cyclosporine a were administered for gvhd prevention . as the patient had neither gvhd nor other complications , she was discharged on day 41 . the patient was treated with radiotherapy using 2 anteroposterior opposed fields with 10 mv x - rays from a linear accelerator ( primus ; toshiba medical systems corp . , a dose of 3 gy per fraction was delivered once daily 4 times during the 4 - day period ( total : 12 gy ) , and the dose rate was 10 cgy / min . for ovarian shielding , pelvic computed tomography was performed before tbi to identify the locations of the uterus and ovaries . next , pelvic radiographs were obtained and using pelvic computed tomography images for reference , the locations of the uterus and ovaries were identified and shielding was performed with an 80 mm thick lead block ( fig . the attenuation rate of the lead block was measured using a water - equivalent phantom corresponding to the size measured in the patient ; it was one eighth . accordingly , the ovarian dose was reduced to approximately 1.5 gy . a , radiograph for confirmation of the uterine and ovarian shielding location . b , a portal image obtained at the location of the uterine and ovarian shielding in tbi . ovarian function before and after bone marrow transplantation was evaluated using the luteinizing hormone - releasing hormone ( lh - rh ) loading test . follicle - stimulating hormone ( fsh ) and luteinizing hormone ( lh ) levels at baseline before transplantation were 8.6 and 6.2 miu / ml , respectively , both of which were normal premenarche levels . levels 30 minutes after lh - rh administration were 12.2 and 20.6 miu / ml for fsh and lh , respectively , which represent normal responses . fsh and lh levels at baseline 2 months after transplantation were 114.8 and 25.2 miu / ml , respectively . as only the fsh level was abnormally high , secondary ovarian dysfunction was suspected ( fig . thirty minutes after lh - rh administration , fsh and lh levels were 143.7 and 25.2 miu / ml , respectively , which represent normal responses . the patient remained in remission and experienced no chronic gvhd or other complications . in march 2000 , menarche began at 14 years of age . thereafter , she had a slightly irregular menstrual cycle . however , in january 2003 her fsh was 6.3 miu / ml , lh 7.7 miu / ml , and estradiol ( e2 ) 73.4 pg / ml , which were all normal . in july 2009 , she was confirmed pregnant at 23 years of age and had a favorable course thereafter . in april 2010 , at 24 years of age , she naturally delivered a baby girl weighing 3182 g at 40 weeks and 3 days gestation . the mother and baby have been well ever since , with no apparent abnormalities nor complications . ovarian function evaluated using luteinizing hormone - releasing hormone ( lh - rh ) before and after tbi . fsh indicates follicle - stimulating hormone ; lh , luteinizing hormone ; tbi , total body irradiation . tbi and cy are often administered as preconditioning regimens for bone marrow transplantation to achieve effective immunosuppression and to eradicate tumor cells . in girls , however , such preconditioning regimens are highly likely to result in ovarian dysfunction and infertility . when cy alone is used for preconditioning , ovarian function recovers at a high rate even if the cy concentration was high .2 meanwhile , ovarian function recovery is only observed in 6.25 % of patients treated with cy plus tbi .3 an irradiation dose of 3 gy reportedly causes ovarian complications in 5 % of patients ,4 and the recovery rate in patients who receive tbi without ovarian shielding is no more than 15 % .5 moreover , tbi can cause uterine hypoplasia and disturb blood flow .6 thus , even if patients become pregnant , they may experience miscarriages or preterm delivery . however , fertility may be preserved if the uterus and ovaries are shielded during tbi . from previous reports , ovarian function recovery was reported in 6 of 8 patients undergoing tbi with ovarian shielding , and 2 of the 6 ultimately gave birth to a baby .7,8 table 1 shows a summary of the reports in which pregnancies were obtained after tbi with ovarian shielding . among the patients who underwent tbi with ovarian shielding , ours was the youngest at only 13 years old and in premenarche . the most important factor is reportedly age , with better results obtained in younger patients .9 as our patient showed transiently elevated fsh levels 2 months after bone marrow transplantation , ovarian dysfunction was suspected ( fig . this was attributed to preconditioning , because ovarian function immediately before transplantation had been normal . as the cy dose for preconditioning regimen was a total of 120 mg , and therefore not especially high , the fsh elevation might have been due to tbi as a preconditioning agent . a past report on tbi with ovarian shielding described a patient with high fsh level and transient amenorrhea .7 the irradiation dose to the ovary in our patient was approximately 1.5 gy with 8 fractioning times for 4 days due to performing tbi with ovarian shielding , but transient ovarian dysfunction still occurred . this is the first report of a patient giving birth to a baby after receiving pci plus tbi , as she underwent an 18 gy dose of pci before tbi . when cranial plus spinal radiotherapy is performed to treat leukemia , the risk of miscarriage is approximately doubled owing to the effect of direct spinal cord irradiation or scattered rays , though the risk reportedly increases by 1.4-fold with cranial radiotherapy alone .10 our patient had normal menarche at 14 years of age , normal menstruation . there is a model predicting the age of ovarian failure after radiotherapy .11 in this model , at the age of 13 years our patient received tbi , when ovarian dose is 12 gy , the predicted age at ovarian failure is 13.6 to 21.4 . therefore , we consider uterine and ovarian shielding with tbi to be effective for preserving fertility . recently , technologies in delivery of external beam of radiotherapy advance and intensity - modulated radiotherapy is used to concentrate dose into target tumors with sparing normal tissue . total marrow irradiation using intensity - modulated radiotherapy to reduce doses to normal organs is reported12 and this technique may be used to tbi instead of ovarian shielding . although advances in the field of reproductive endocrinology have made it possible to perform in vitro fertilization and to store frozen embryos , the clinical application of these procedures to children is difficult . in addition , it may delay treatment owing to ovarian stimulation and there is a high risk that collected cells may contain tumor cells .13 uterine and ovarian shielding in tbi is a useful technique and can be performed relatively easily . however , as uterine and ovarian shielding may result in shielding tumor cells present in the pelvic bone , it should only be performed when patients and their family request fertility preservation and provide sufficient informed consent .\noutput:\n" }, { "from": "agent", "value": "total body irradiation is performed as a preconditioning regimen to inhibit graft - versus - host disease after bone marrow transplantation and to eradicate remaining tumor cells . however , these regimens result in delayed secondary sex characteristics and failure of ovarian function recovery , leading to amenorrhea and infertility . herein , we report a case of an 11 - year - old girl diagnosed with acute lymphocytic leukemia who received induction chemotherapy and prophylactic cranial irradiation . for bone marrow transplantation , she received total body irradiation of 12 gy with uterine and ovarian shielding at 13 years of age . the patient remained in remission and menarche began at 14 years of age . at 23 , she became pregnant and delivered a baby naturally with no abnormalities ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the polymodal sensory neuron must transform disparate stimuli such as heat and touch into informative neural activity that relays the physical description of the stimulus to the nervous system . like mammalian sensory neurons , polymodal md sensory neurons from drosophila express multiple channel types including members of the deg / enac , trp and piezo channel families , that are required for md neurons to respond to a broad range of noxious stimuli including chemical , mechanical , or thermal . whether the biophysical properties of the individual channels are sufficient to inform the nervous system about the nature of stimuli remains unclear . considering the data demonstrating the genetic separation of sensory modalities in invertebrates , a simple model is that the channels sensing these modalities function in parallel and that perception is the result of a unique current signature produced from the specific combination of channels responding to a distinct stimuli ( fig . trp channels play an important role in modifying and filtering the current generated by the upstream incidence receptors . ( c ) the adsr waveform as a result of the combination of ra and sa currents . interestingly , some trp channels , such as the painless or trpa1 channels , are required in the md neuron for the appropriate response to more than one sensory modality . in addition , genetic epistasis analysis of channel protein mutants in flies finds that these channels are arranged in genetic pathways . for example , in drosophila md sensory neurons the mechanosensitive piezo channel , the trp family member painless and the deg / enac family member ppk1 are all required for mechanical nociception . genetic epistasis finds that piezo and ppk1 function independently during mechanical nociception but that piezo and painless function in the same genetic pathway ( fig . combined with the observation that painless is required for multiple modalities in md neurons , these data suggest an organization where trp channels function downstream of deg and pzo channels in a sensory network ( fig . this organization could allow for the encoding of a broader range of stimuli and places trp channels as critical modifiers of incidence detection . the collection of ion channel currents found in sensory neurons can be characterized by their nonstationary response to continued stimulation : currents that rapidly adapt ( ra ) resulting in transient responses , slowly adapting ( sa ) currents resulting in a persistent response and currents that are intermediate to ra and sa in adaptation ( ia ) to stimuli . furthermore , sensory neurons can contain multiple adapting currents for the same modality . during stimulationit is predicted that a large number of channels , conducting both ra and sa currents , are recruited contributing to a cell - wide current signature that is representative of the stimuli . currently there is little evidence that the current signatures generated in md neurons during stimulation encode sensory information . we find that drosophila md neurons harbor molecularly distinct ra and sa acid - sensitive currents . specific activation of the ra current generated by the ppk1 channel is sufficient to generate a burst of action potentials that precisely reflects the kinetics of the adaptation of this ppk1 - dependent current . furthermore , a gain of function mutation in ppk1 that alterschannel gating generates a sustained burst of action potentials reflective of the more sustained adaptation of the mutant channel . importantly , larvae harboring this mutant ppk1 channel have impaired nociception , providing evidence that the adaptation kinetics of the ppk1 channel is important for encoding information about the nature of the stimuli . also consider drosophila larvae that have the same behavioral response to harsh touch and high heat , even though these modalities utilize distinct collections of channel proteins . if the current signature of the md neuron encodes information about the nature of the stimuli , than we predict that the current signatures generated by harsh touch and high heat should be very similar . although data from heterologous cells support that the channels supporting this behavior have similar adaptation kinetics , it will be important to extend these analyses into sensory neurons to evaluate the bursting patterns generated during nociceptive stimuli . because our stimulation of ppk1 is heterotypic , it remains to be seen what the in vivo bursting pattern of md neurons during stimulation is . one possibility is that these currents combine to create a distinct current waveform with a shape that describes the stimulus . this waveform could resemble the attack - decay - sustain - release ( adsr ) waveform used by moog synthesizers to generate sounds as diverse as a cymbal crash to a low hum ( fig . the utility of the adsr waveform for information encoding is demonstrated by the broad range of unique waveforms that can be generated as well as the ability of this waveform to report changes in the quality of stimuli over time . thus , perception by md sensory neurons could consist of the activation of unique sets of currents ( ra and sa ) that generate a cellular current signature resulting in a unique bursting event that sufficiently describes the stimuli . further comparisons of sensory neuron bursting , channel currents and the resulting behavior will be required to determine how the biophysical properties of channels can guide behavior .\noutput:\n" }, { "from": "agent", "value": "polymodal sensory neurons inform organisms about the nature of the physical world around them . the activity of these cells guide behaviors including the withdrawal from nocifensive stimuli such as intense heat or harsh force to feeling the comforting weight of a warm blanket . molecular and genetic analysis of the channel proteins required for these divers behavioral responses have revealed an elaborate and disparate collection of channel proteins within the polymodal sensory neuron . recent data supports that the biophysical traits of the channel proteins combined with the collection of channels activated during stimulation is sufficient to describe the nature of the stimulus . it is currently unclear what the functional arrangement of channel proteins are during perception . specifically , are channel proteins arranged in parallel and function independently during perception , or are these channel proteins arranged in functional sensory networks . we propose a hierarchal functional arrangement of channels within polymodal sensory neurons that incorporates aspects of both parallel and serial arrangements of channel proteins ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in croatia , lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death in men . in women , it is the third most frequently diagnosed cancer and the second cause of cancer death , with poor overall survival . adenocarcinoma is the most common type of lung carcinoma , usually presenting in the advanced stage as an inoperable disease . therefore , minimally invasive procedures have to be employed in order to obtain tumor tissue for histological and molecular analysis . the combination of ttf - 1 and napsin a immunohistochemistry shows highly improved sensitivity and specificity for lung adenocarcinoma diagnosis . ttf - 1 is a nuclear tissue - specific dna - binding protein mainly expressed in thyroid follicular cells , type ii pneumocytes , and nonciliated bronchiolar epithelial cells . platinum - based chemotherapy is still the first - line therapy for advanced non - small cell lung cancer ( nsclc ) , but in some patients chemotherapy does not have any clinical benefit . ercc1 is a nuclear protein involved in the nucleotide excision repair pathway essential for the repair of platinum - dna adducts . ercc1 is associated with resistance to platinum - based chemotherapy , so could be a prognostic and predictive biomarker . egfr and alk molecular testing is recommended to select patients with lung adenocarcinoma for targeted therapy with thyrosine kinase inhibitors ( tkis ) . egfr mutation has been associated with lung adenocarcinoma , female sex , non - smokers , and asian ethnicity , ranging from 24 % to 66 % . studies from the usa and europe reported lower mutation rates , ranging from 13 % to 17 % . alk rearrangement is another important finding in lung adenocarcinoma , ranging from 3 % to 13 % across different ethnicities , in young adult patients who never smoked . unfortunately , according to guidelines of croatian health insurance , tkis are not yet the first line of treatment for the patients with egfr or alk mutation , whose treatment still rests on platinum - based therapy . the present study was carried out in order to evaluate our institutional experience in daily practice and to provide an evidence - based approach for the utilization of immunohistochemical biomarkers and molecular testing in lung adenocarcinoma on small specimens , according to the recommendations for tissue management and guidelines for molecular testing . from january 2013 till december 2014 , 196 cases of new primary lung adenocarcinomas , 133 ( 68 % ) in males and 63 ( 32 % ) in females , were diagnosed at the institute of pathology , forensic medicine and cytology , clinical hospital center split , croatia . among them , 142 ( 72 % ) were diagnosed on small biopsy , 36 ( 18 % ) on the surgical resection , 10 ( 5 % ) on transthoracic needle biopsies , and 8 ( 4 % ) on cytology samples . a total of 142 patients diagnosed only on small biopsy who did not undergo previous therapy were investigated in this study . original slides and paraffin blocks were collected from the archive , clinical data were collected from the hospital records of the department of pulmonology , and the time of death from the mortality registry . overall survival was evaluated from the date of diagnosis until the end of march 2015 or the time of death , and patients treated with symptomatic therapy were excluded . diagnosis of lung adenocarcinoma was performed based on morphology and immunohistochemical markers if necessary : cytokeratin ( ck ) 7 , ttf - 1 , and napsin a. ck7 was obligatorily positive . adenocarcinomas were subclassified into histological subtypes according to the latest world health organization ( who ) classification of lung carcinoma from 2015 . approval for the study was obtained from the hospital ethics committee ( code 500 - 03/15/01 / 42 ) . the slides of tumor tissue were stained with monoclonal mouse antibodies napsin a ( 1:200 ) , ttf - 1 ( 1:100 ) , and ercc1 ( 4f9 , ready to use ) ( all reagents dako , glostrup , denmark ) , and rabbit monoclonal antibody alk ( d5f3 , ventana , tucson , arizona ) . ttf - 1 , napsin a , and ercc1 were visualized with the iview dab detection kit ( ventana , tucson , arizona ) and alk with the optiview dab ich detection kit and the optiview amplification kit ( ventana , tucson , arizona ) on the automatic stainer benchmark gx ( ventana , tucson , arizona ) . a total of 89 patients had a sufficient sample for immunohistochemical analysis for napsin a , 118 for ttf - 1 , 102 for alk , and 73 for ercc1 . the results were analyzed by two pathologists on a light microscope olympus 51 bx ( olympus , tokyo , japan ) . a positive expression of napsin a and alk was shown as brown granular cytoplasmic staining and positive expression of ttf - 1 as homogenous nuclear staining in any cell . ercc1 staining was estimated on 100 tumor cells under light microscope at magnification of 400 . percentages of positive tumor nuclei were determined , and staining intensity was graded on the scale 0 to 3 . respiratory epithelium with staining intensity of 2was used as an internal positive control . by multiplying the staining intensity by the percentage of positive nuclei , the ercc1 h scoremedian value of all h scores was used in order to classify tumors as ercc1 positive or negative . another way of discrimination was to use 0 to indicate ercc1 - negative tumors ( no immunohistochemical reaction in any cell ) and ercc10 to indicate ercc1 - positive tumors ( positive immunohistochemical reaction in any cell ) . a total of 113 patients had a sufficient sample for reflex molecular analysis of the egfr mutation . molecular analysis of the egfr mutation was done at the time of diagnosis with a cobas egfr mutation test ( roche , basel , switzerland ) real - time polymerase chain reaction ( rtpcr ) . a cobas sample preparation kit ( roche , basel , switzerland ) automatic amplification and detection were done on a cobas z 480 analyzer ( roche , basel , switzerland ) . statistical significance was set at p 0.05 , and all confidence intervals ( cis ) were at the 95 % level . statistical significance of the difference in categorical characteristics was calculated by using the test . analysis of statistical significance of differences in numerical groups was performed with the kruskal - wallis test and of differences between two groups with the mann - whitney test . the cox proportional model and logistic regression model were used to identify factors that might significantly influence survival . survival curves were calculated according to the kaplan - meier method , and differences between curves were evaluated with the log - rank test . statistical analysis was performed using the statistical package for the social sciences ( spss ) software ( version 19 for windows ; spss inc . , from january 2013 till december 2014 , 196 cases of new primary lung adenocarcinomas , 133 ( 68 % ) in males and 63 ( 32 % ) in females , were diagnosed at the institute of pathology , forensic medicine and cytology , clinical hospital center split , croatia . among them , 142 ( 72 % ) were diagnosed on small biopsy , 36 ( 18 % ) on the surgical resection , 10 ( 5 % ) on transthoracic needle biopsies , and 8 ( 4 % ) on cytology samples . a total of 142 patients diagnosed only on small biopsy who did not undergo previous therapy were investigated in this study . original slides and paraffin blocks were collected from the archive , clinical data were collected from the hospital records of the department of pulmonology , and the time of death from the mortality registry . overall survival was evaluated from the date of diagnosis until the end of march 2015 or the time of death , and patients treated with symptomatic therapy were excluded . diagnosis of lung adenocarcinoma was performed based on morphology and immunohistochemical markers if necessary : cytokeratin ( ck ) 7 , ttf - 1 , and napsin a. ck7 was obligatorily positive . adenocarcinomas were subclassified into histological subtypes according to the latest world health organization ( who ) classification of lung carcinoma from 2015 . approval for the study was obtained from the hospital ethics committee ( code 500 - 03/15/01 / 42 ) . the slides of tumor tissue were stained with monoclonal mouse antibodies napsin a ( 1:200 ) , ttf - 1 ( 1:100 ) , and ercc1 ( 4f9 , ready to use ) ( all reagents dako , glostrup , denmark ) , and rabbit monoclonal antibody alk ( d5f3 , ventana , tucson , arizona ) . ttf - 1 , napsin a , and ercc1 were visualized with the iview dab detection kit ( ventana , tucson , arizona ) and alk with the optiview dab ich detection kit and the optiview amplification kit ( ventana , tucson , arizona ) on the automatic stainer benchmark gx ( ventana , tucson , arizona ) . a total of 89 patients had a sufficient sample for immunohistochemical analysis for napsin a , 118 for ttf - 1 , 102 for alk , and 73 for ercc1 . the results were analyzed by two pathologists on a light microscope olympus 51 bx ( olympus , tokyo , japan ) . a positive expression of napsin a and alk was shown as brown granular cytoplasmic staining and positive expression of ttf - 1 as homogenous nuclear staining in any cell . ercc1 staining was estimated on 100 tumor cells under light microscope at magnification of 400 . percentages of positive tumor nuclei were determined , and staining intensity was graded on the scale 0 to 3 . respiratory epithelium with staining intensity of 2 was used as an internal positive control . by multiplying the staining intensity by the percentage of positive nuclei , the ercc1 h score was determined , according to besse et al . . median value of all h scores was used in order to classify tumors as ercc1 positive or negative . another way of discrimination was to use 0 to indicate ercc1 - negative tumors ( no immunohistochemical reaction in any cell ) and ercc10 to indicate ercc1 - positive tumors ( positive immunohistochemical reaction in any cell ) . a total of 113 patients had a sufficient sample for reflex molecular analysis of the egfr mutation . molecular analysis of the egfr mutation was done at the time of diagnosis with a cobas egfr mutation test ( roche , basel , switzerland ) real - time polymerase chain reaction ( rtpcr ) . a cobas sample preparation kit ( roche , basel , switzerland ) automatic amplification and detection were done on a cobas z 480 analyzer ( roche , basel , switzerland ) . statistical significance was set at p 0.05 , and all confidence intervals ( cis ) were at the 95 % level . statistical significance of the difference in categorical characteristics was calculated by using the test . analysis of statistical significance of differences in numerical groups was performed with the kruskal - wallis test and of differences between two groups with the mann - whitney test . the cox proportional model and logistic regression model were used to identify factors that might significantly influence survival . survival curves were calculated according to the kaplan - meier method , and differences between curves were evaluated with the log - rank test . statistical analysis was performed using the statistical package for the social sciences ( spss ) software ( version 19 for windows ; spss inc . , in 24 months , among 196 newly diagnosed patients with lung adenocarcinoma ( ages 4489 years ) , 133 ( 68 % ) were males and 63 ( 32 % ) were females . the cumulative incidence per 10,000 inhabitants was 9.5 ( 95 % ci : 8.110.8 ) ; in females it was 5.6 ( 95 % ci : 4.27 ) and in males it was 13.9 ( 95 % ci : 11.516.2 ) , which was 2.9 times more in males than in females . in our study ,142 patients with lung adenocarcinoma diagnosed only on small biopsy were analyzed : 95 ( 67 % ) males and 47 ( 33 % ) females . the median age was 64 years ( minimum - maximum : 4489 years ) . within 27 months of follow - up , 76 ( 53.5 % ) patients died . median survival was 8 months ( se : 0.87 ; 95 % ci : 6.39.7 ) . solid subtype was found in 80 patients , acinar in 42 , papillary in 15 , and lepidic subtype in 5 patients . patients were analyzed according to histologic subtype in relation to clinicopathologic characteristics ( table 1 ) . no statistically significant difference was observed between solid and other subtypes in sex ( = 0.061 ; p = 0.805 ) and age ( = 0.030 ; p = 0.843 ) . no statistically significant difference was observed between solid and other subtypes in tnm stage ( = 5 ; p = 0.171 ) , tumor size ( = 5.96 ; p = 0.133 ) , and lymph nodes ( = 0.761 ; p = 0.383 ) . nevertheless , when the stage i disease was excluded , the solid subtype was 2.4 times more common in the stage iii disease with a level of significance of 92 % ( = 4.99 ; p = 0.082 ) . metastases were observed 1.8 times more often in the acinar subtype compared with the solid subtype , with a level of significance of 94 % ( = 3.46 ; p = 0.063 ) . napsin a expression correlated with ttf - 1 positivity ( = 28.25 ; p 0.001 ) . among 18 napsin a - negative cases , 10 ( 55 % ) were ttf - 1 negative , which was 13.7 times more than in napsin a - positive cases . among 85 napsina - positive cases , 64 ( 95 % ) were ttf - 1 positive , which was 2 times more than in napsin a - negative cases . among 68 ttf -1-positive cases ,41 ( 60 % ) had distant metastases , and among 16 ttf -1-negative cases , 14 had distant metastases ( 87 % ) , which was 1.5 times more , with a level of significance of 92 % ( = 3.1 ; p = 0.077 ) . no statistically significant difference was found in ercc1 expression between solid and other subtypes ( z = 0.148 ; p = 0.882 ) , as well as egfr statusnine patients had exon 19 deletion ( 19 del ) , one had exon 21 l858r point mutation ( l858r mutation ) , and one had a mutation on exon 18 g719x . they all had positive expression of ttf - 1 and napsin a in tumor cells . the positive alk expression and egfroverall survival ( table 2 ) was twice longer in ttf - 1 and napsin a positive cases ( p = 0.007 and p = 0.026 , respectively ) . overall survival was significantly associated with a lower tnm stage ( p = 0.001 ) , negative lymph nodes ( p = 0.04 ) , and negative distant metastasis ( p 0.001 ) . the patients with stage ii disease lived 1.6 times longer than the patients with stage iii disease , and 2.8 times longer than the patients with stage iv disease . the patients treated with chemotherapy after surgical resection had an average survival 1.9 times longer than patients treated with chemotherapy alone , and 3.7 times longer than patients treated with the combination of chemotherapy and radiotherapy ( p = 0.001 ) . no statistically significant difference in overall survival according to age ( lr 0.13 ; p = 0.722 ) , sex ( lr 1.5 ; p = 0.218 ) , smoking status ( lr 0.59 ; p = 0.439 ) , tumor subtype ( lr 0.483 ; p = 0.487 ) , tumor size ( lr 3.8 ; p = 0.285 ) , and ercc1 expression ( lr 1.6 ; p = 0.210 ) was found . average survival of patients with egfr mutation was 11 ( 913 ) months , and average survival of patients with wild type was 14 ( 712 ) months ( lr 0.56 ; p = 0.456 ) . the patients without expression of ttf - 1 and napsin a had higher relative risk of death than those with a positive expression ( p = 0.011 and p = 0.036 , respectively ) ( figure 2a , 2b ) . the best discrimination between ercc1 - positive and ercc1 - negative tumors was obtained when any positive cell was used as the definition of an ercc1 - positive tumor ( ercc10 ) and when no immunohistochemical reaction in any cell was used as the definition of an ercc1 - negative tumor ( ercc1 = 0 ) . using this definition , patients with ercc1 - positive tumors had 1.9 times higher relative risk for death ( p = 0.041 ) than patients with ercc1 - negative tumors ( figure 3a , 3b ) . relative risk of death rose by 1.2 times whenever ercc1 expression rose ( p = 0.12 ) , with a level of significance of 90 % . relative risk of death was strongly associated with distant metastasis ( p = 0.001 ) and lymph nodes ( p = 0.059 ) , with a level of significance of 94 % . all patients were treated with the chemotherapy based on platinum , alone or in combination with surgical resection or radiotherapy . the patients who were treated with chemotherapy and radiotherapy had a 2.4 times higher relative risk of death than the patients treated only by chemotherapy ( p = 0.009 ) . the patients who received only chemotherapy had a 5.7 times higher risk of death than patients who underwent surgical resection and chemotherapy ( p = 0.087 ) , with a level of significance of 91 % . in 24 months , among 196 newly diagnosed patients with lung adenocarcinoma ( ages 4489 years ) , 133 ( 68 % ) were males and 63 ( 32 % ) were females . the cumulative incidence per 10,000 inhabitants was 9.5 ( 95 % ci : 8.110.8 ) ; in females it was 5.6 ( 95 % ci : 4.27 ) and in males it was 13.9 ( 95 % ci : 11.516.2 ) , which was 2.9 times more in males than in females . in our study ,142 patients with lung adenocarcinoma diagnosed only on small biopsy were analyzed : 95 ( 67 % ) males and 47 ( 33 % ) females . the median age was 64 years ( minimum - maximum : 4489 years ) . within 27 months of follow - up , 76 ( 53.5 % ) patients died . median survival was 8 months ( se : 0.87 ; 95 % ci : 6.39.7 ) . solid subtype was found in 80 patients , acinar in 42 , papillary in 15 , and lepidic subtype in 5 patients . patients were analyzed according to histologic subtype in relation to clinicopathologic characteristics ( table 1 ) . no statistically significant difference was observed between solid and other subtypes in sex ( = 0.061 ; p = 0.805 ) and age ( = 0.030 ; p = 0.843 ) . no statistically significant difference was observed between solid and other subtypes in tnm stage ( = 5 ; p = 0.171 ) , tumor size ( = 5.96 ; p = 0.133 ) , and lymph nodes ( = 0.761 ; p = 0.383 ) . nevertheless , when the stage i disease was excluded , the solid subtype was 2.4 times more common in the stage iii disease with a level of significance of 92 % ( = 4.99 ; p = 0.082 ) . metastases were observed 1.8 times more often in the acinar subtype compared with the solid subtype , with a level of significance of 94 % ( = 3.46 ; p = 0.063 ) . napsin a expression correlated with ttf - 1 positivity ( = 28.25 ; p 0.001 ) . among 18 napsin a - negative cases , 10 ( 55 % ) were ttf - 1 negative , which was 13.7 times more than in napsin a - positive cases . among 85 napsina - positive cases , 64 ( 95 % ) were ttf - 1 positive , which was 2 times more than in napsin a - negative cases . among 68 ttf -1-positive cases ,41 ( 60 % ) had distant metastases , and among 16 ttf -1-negative cases , 14 had distant metastases ( 87 % ) , which was 1.5 times more , with a level of significance of 92 % ( = 3.1 ; p = 0.077 ) . no statistically significant difference was found in ercc1 expression between solid and other subtypes ( z = 0.148 ; p = 0.882 ) , as well as egfr statusnine patients had exon 19 deletion ( 19 del ) , one had exon 21 l858r point mutation ( l858r mutation ) , and one had a mutation on exon 18 g719x . they all had positive expression of ttf - 1 and napsin a in tumor cells . the positive alk expression and egfr mutation were exclusive . overall survival ( table 2 ) was twice longer in ttf - 1 and napsin a positive cases ( p = 0.007 and p = 0.026 , respectively ) . overall survival was significantly associated with a lower tnm stage ( p = 0.001 ) , negative lymph nodes ( p = 0.04 ) , and negative distant metastasis ( p 0.001 ) . the patients with stage ii disease lived 1.6 times longer than the patients with stage iii disease , and 2.8 times longer than the patients with stage iv disease . the patients treated with chemotherapy after surgical resection had an average survival 1.9 times longer than patients treated with chemotherapy alone , and 3.7 times longer than patients treated with the combination of chemotherapy and radiotherapy ( p = 0.001 ) . no statistically significant difference in overall survival according to age ( lr 0.13 ; p = 0.722 ) , sex ( lr 1.5 ; p = 0.218 ) , smoking status ( lr 0.59 ; p = 0.439 ) , tumor subtype ( lr 0.483 ; p = 0.487 ) , tumor size ( lr 3.8 ; p = 0.285 ) , and ercc1 expression ( lr 1.6 ; p = 0.210 ) was found . average survival of patients with egfr mutation was 11 ( 913 ) months , and average survival of patients with wild type was 14 ( 712 ) months ( lr 0.56 ; p = 0.456 ) . the patients without expression of ttf - 1 and napsin a had higher relative risk of death than those with a positive expression ( p = 0.011 and p = 0.036 , respectively ) ( figure 2a , 2b ) . the best discrimination between ercc1 - positive and ercc1 - negative tumors was obtained when any positive cell was used as the definition of an ercc1 - positive tumor ( ercc10 ) and when no immunohistochemical reaction in any cell was used as the definition of an ercc1 - negative tumor ( ercc1 = 0 ) . using this definition , patients with ercc1 - positive tumors had 1.9 times higher relative risk for death ( p = 0.041 ) than patients with ercc1 - negative tumors ( figure 3a , 3b ) . relative risk of death rose by 1.2 times whenever ercc1 expression rose ( p = 0.12 ) , with a level of significance of 90 % . relative risk of death was strongly associated with distant metastasis ( p = 0.001 ) and lymph nodes ( p = 0.059 ) , with a level of significance of 94 % . all patients were treated with the chemotherapy based on platinum , alone or in combination with surgical resection or radiotherapy . the patients who were treated with chemotherapy and radiotherapy had a 2.4 times higher relative risk of death than the patients treated only by chemotherapy ( p = 0.009 ) . the patients who received only chemotherapy had a 5.7 times higher risk of death than patients who underwent surgical resection and chemotherapy ( p = 0.087 ) , with a level of significance of 91 % . small biopsies are the most common tissue samples for the diagnosis of lung cancer , because 70 % of patients present in advanced stages . these data are largely in accordance with our observations : 72 % adenocarcinomas were diagnosed on a small biopsy and 87.9 % of patients presented in advanced stages . found that solid subtype is a marker of unfavorable prognosis associated with advanced stages of disease compared with the acinar and lepidic subtypes . in our study , the solid and acinar subtypes were more common in advanced stage of disease . more common distant metastases in the acinar subtype could be explained by lung adenocarcinoma histologic heterogeneity , resulting in a discrepancy with the final histologic diagnosis in resection specimen . the ttf - 1 and napsin a expressions were positive in 81 % and 78 % cases , respectively , and were not associated with the tumor subtype . zhang et al . showed the similar results for both markers , with positivity in 85 % cases . the lower number of napsin a - positive cases in our study could be related to technical problems in sampling . to the best of our knowledge , we have not found available data on the prognostic significance of ttf - 1 and napsin a expression analyzed exclusively on small biopsy specimens , but only on resected specimens . thus , the results reported herein extend the favorable prognosis related to a positive ttf - 1 staining to the patients diagnosed only on a small biopsy specimen . . showed that the expression levels of napsin a and ttf - 1 are independent prognostic factors for survival . . concluded in meta - analysis that the overexpression of ttf - 1 is associated with a favorable prognosis . the reasons why ttf - 1 is related to prognosis of patients with primary lung adenocarcinoma are unclear . myong revealed that a positive ttf - 1 staining has been inversely related to the proliferative activity evaluated through ki - 67 expression . these observations suggest that ttf - 1 and napsin a are not only useful diagnostic markers but also valuable prognostic markers in patients with lung adenocarcinoma and may play a role in molecular cancerogenesis . overall survival was longer in patients without lymph node and distant metastasis and with a lower stage of disease , which is consistent with published data . patients who underwent surgical resection and chemotherapy had a lower relative risk of death . a possible explanation for this could be that surgical therapy was performed in patients with lower stages of disease . all of our patients were treated with platinum - based chemotherapy , which targets dna and induces damage that cancer cells struggle to overcome . ercc1 expression levels have been explored as a marker of dna repair capacity in tumor cells . in our study , high ercc1 expression was associated with increased relative risk for death and decreased overall survival . this effect may be attributed to increased dna repair of platinum - induced dna adducts in ercc1 - positive patients . although low ercc1 expression is generally associated with sensitivity to platinum , the published results are not always consistent . several studies demonstrate that nsclc patients treated with platinum - based therapy and having ercc1 - negative tumors had an increased survival , but booton et al . previous studies observed that egfr mutation was associated with lower level of ercc1 expression , which was not confirmed in our study , probably because the number of patients with egfr mutation was too low . it can be postulated that decreased ability to repair dna damage may be correlated with increased genome instability and tumor mutations . chen et al . showed an association between lepidic , papillary , and acinar subtypes and higher egfr mutation rate , while the solid and mucinous components were associated with lower egfr mutation rate . prognostic value of egfr mutation in patients who did not receive tkis was rarely reported . in our studyfollowing guidelines for good practice of small biopsy samples in patients with lung adenocarcinoma , we established a tissue management strategy to ensure the optimal treatment of patients who can benefit from new targeted therapies . our data confirmed that ttf - 1 and napsin a are not only useful diagnostic markers but also valuable prognostic markers in patients with lung adenocarcinoma . positive ercc1 expression was identified as a negative prognostic marker in patients treated with platinum - based therapy . the percentages of egfr and alk mutations corresponded to those in previously published reports for caucasian patients .\noutput:\n" }, { "from": "agent", "value": "backgroundthe present study was carried out in order to evaluate our institutional experience with small biopsy in diagnosis and molecular testing of lung adenocarcinoma . few specific and predictive markers have been evaluated and correlated with clinicopathologic characteristics and survival in patients with lung adenocarcinoma who received platinum - based chemotherapy . there have not been such reports from croatia.material / methodsa total of 142 cases of lung adenocarcinoma were retrospectively investigated in small biopsies for the immunohistochemical expression of ttf - 1 , napsin a , ercc1 , alk , and the egfr mutation by real - time polymerase chain reaction ( rtpcr ) . resultsttf - 1 , napsin a , and ercc1 expression was found in 81 % , 78 % , and 69 % of patients , respectively , and the expressions were not significantly associated with subtype . expression of alk was found in 4 % and egfr mutation in 10 % of patients . exon 19 deletions were the most common . longer survival was significantly associated with ttf - 1 positivity ( p = 0.007 ) and napsin a positivity ( p = 0.026 ) . higher relative risk of death significantly correlated with positive expression of ercc1 ( p = 0.041 ) . conclusionspositive ttf - 1 and napsin a expressions in lung adenocarcinoma tissues were useful diagnostic and favorable prognostic parameters . positive ercc1 expression was identified as a negative prognostic marker in patients treated with platinum - based chemotherapy . the percentages of egfr and alk mutations corresponded to those in previously published reports for caucasians ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: , films have portrayed a multitude of issues about society , science , mythology , and mankind . over the decades , films have depicted various psychiatric conditions ranging from suicide and substance use disorders to multiple personality disorders and schizophrenia . although such portrayals may not always be perfect , they may nevertheless be good enough for us to understand and analyze some aspect of the disorder . it is inevitable that films are made for entertainment , unlike documentaries which are meant for education . times have changed from the films being criticized for the negative portrayal of psychiatrists and psychiatric conditions to the current times when they can be used to teach in classrooms . this paper describes how films can be successfully used as a tool for training the psychiatry residents along with potential pitfalls in using these methods . story - telling has been a favorite mode of teaching right from childhood and kindergarten to high - school . in childhood , stories and telling of storiesone can draw parallels to short stories and view them being similar to case presentations in medical schools which ultimately lead one to the diagnosis and management of a patient 's disorder . case presentation has been a classical mode of teaching in medicine and in psychiatry too . when one looks at films , one can see stories being told in a more presentable and audio - visually appealing form . films make the audience laugh , cry , sing to their tunes , and question some of the very vital decisions of life . films are often viewed as an art form , a source of entertainment , an industry , and an instrument of social change , powerful enough to shape the attitudes of audience . a number of academicians and researchers have examined and studied the portrayal of various psychiatric and related issues and therapies like electroconvulsive therapy in films and the impact that they have on the viewers . it is only recently that their use in teaching psychiatry has been realized . a few related articles have appeared every now and then in renowned journals like academic psychiatry , while a whole issue of international review of psychiatry ( 2009 , volume 21 , number 3 ) has been dedicated solely to the portrayal of psychiatric conditions in films across the world . not relying solely on their entertainment value , one can combine entertainment and education and get a better understanding of the issues portrayed in the film . films can be successfully used to point out various aspects of psychiatric conditions and patients . through films , students can learn some delicate intricacies of the personal and social aspects of psychiatric patients , and understand patient perspectives in a better way . the advantage of using films to teach as opposed to that of case conference is that one gets to see rather than simply hear about psychopathology and that important information is presented in condensed form in films . although in india most patients will come to the clinic accompanied by their relatives and families , the notion of confidentiality is strikingly different ; it is possible to see the reactions of others generated by the patient in films . another benefit of using films is that all trainees have the same data about the character ( patient in the film ) , rather than just one trainee having full information as in case presentation ; everyone sees the same character and same story from their own perspective and hence can contribute differently to the discussion of the topic . misch ( 2000 ) pointed out how stories in films reflect the situations in a psychiatrist 's office : certain aspects of the story in a film are highlighted by the director , while others are not told at all , similar to case histories in psychiatry which may be based on incomplete data . interest in this area started with film reviews by gabbard and gabbard and hyler et al . among others . thus , when this idea was suggested to the head of department of psychiatry at l.t.m . medical college , he was very interested and enthusiastically supported this initiative . when the same idea was suggested to the trainees , they were equally thrilled about it . at the psychiatry department of l.t.m . medical college , a psychiatry movie club was thus started that consisted of screening a film based on a psychiatric condition regularly . since different residents may be on calls on different daysthe trainees were thus free to attend the training sessions at their own will with no intended or unintended pressure . a list of possible films that could be used to teach various aspects of psychiatry to the trainees was prepared after reading relevant articles from different journals . it usually started with a short introduction to the film and how it is important to understand the condition that is portrayed in it . the trainees are instructed to watch the film closely , and if required , ask for certain scenes to be replayed for a better understanding . this is then followed by screening of the film and then , an in depth discussion on the positive points and criticisms on the negative points in relation to the psychiatric illness , the patient and the mental health professional in the film . usually , one to two issues that have been portrayed in the film and have already been preselected and prepared by the author are then subsequently taught to the students . if needed , the films are also paused at appropriate scenes that depict different aspects of the psychiatric condition or the patient , or the patient - therapist relationship for discussion of those scenes . the trainees are expected to comment on whatever aspect of the film they feel like . some of the films that can be used to teach various psychiatric conditions in movie clubs are enumerated in table 1 . these films are personal choices of the author and one may use them as a guide and come up with one 's own library of films . those who may wish to start similar ventures or use films for teaching will have their own ideas and selected films . films that can be used in teaching usually , the film names are not revealed until the final time of screening so as to maintain a level of curiosity in trainees . however , this is not mandatory and the film names can be revealed beforehand ; trainees may then choose to watch these films themselves before the club and re - watch it during the club screening in a group , and actively partake in the discussions giving insights into different aspects of the film . other method of using films to teach residents is by using clips instead of whole films . the use of clips is time efficient and provides emotionally engaging experiences for both the faculty and residents . one can incorporate a collection of such suitable clips into 1 - hour long teaching conferences along with discussions . by using films for teaching , one can get an interesting combination of entertainment and education . however , this method is not without its drawbacks . one has to be aware that commercial films are primarily made for entertainment and not education . they may not be made based on sufficient research and hence may reflect how an individual understands a mental illness rather than presenting a scientific understanding of the same . there may be distortion of data in order to make the stories more compelling and get better reviews and public attention . similarly , diagnoses may not be always clear , in which case one has to always consider differential diagnosis and not icd - 10 or dsm iv categories . there is also a disadvantage of distortion and increased stigmatization of mental illness and the mentally ill in their portrayals in films that may lead to stronger stereotypes in the viewer 's minds . from an initial experience with this entertainment - filled educational initiative , it was learnt that films do teach us . we , as viewers , may go to watch films for different reasons , because the film is a box - office hit , or because it is our favorite starrer , or just to kill time , but little do we realize that in the process , we may get newer insights and perspectives on our own life issues and learn newer ways to deal with problems . this departmental film training venture has been welcomed by the trainees as a teaching tool and still takes place regularly , with the head of the psychiatry department fully endorsing the concept of using films to teach . learning from this venture , one can use films in various vernacular languages and some from bollywood too in teaching psychiatry to residents . films are a social phenomenon that have always had a keen interest in portraying different aspects of the mind , be it emotions or the emotional upheavals resulting from various reasons in the lead characters . the general public and psychiatry residents as well are likely to build opinions on some psychiatry topics after having watched them being portrayed in films . these opinions are likely to become stereotypically strong with every new film that portrays the same condition similarly . thus , in case one thinks of using films to teach any aspect of psychiatry , one has to do so sensibly . in educating psychiatry trainees , all the available methods should be used to ensure that they gain sufficient knowledge and skills in order to achieve competence in their fields . andin doing so , the tools of entertainment , films can be successfully used thus educating through entertainment .\noutput:\n" }, { "from": "agent", "value": "for decades , films across the world have entertained people and affected their attitudes regarding certain issues and conditions . documentary films have been used by governments in different parts of the world to educate the general public and promote health and prevent the spread of disease as part of public health programs . psychiatry as a branch of medicine like the rest of medicine continues to develop . with an increasing awareness among the general population and popularity of films showing various aspects of mental illnesses on the rise , educators and teachers are turning their attention to using films for education of medical students and psychiatric trainees . although films may be stereotypical and prejudiced , they can be used successfully in teaching psychiatry trainees . in this paper , development of a movie club and its use are described and suggestions made to improve the use of films in this process ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: clinical data including age , sex , presenting symptoms and clinical course , duration of hospitalization , medication , and neurologic status at discharge were collected in all patients . routine csf analyses included leukocyte count , csf protein concentration , qalb , csf / serum igg ratio ( qigg ) , csf culture , csf serology ( herpes simplex virus [ hsv ] igg / igm , varicella - zoster virus [ vzv ] igg / igm , measles igg / igm , mumps igg / igm , borrelia burgdorferi igg / igm , syphilis , hiv ) , and pcr analysis for neurotropic viruses ( hsv 1/2 , vzv , cmv , epstein - barr virus , enterovirus , human herpesvirus 6 ) . brain barrier dysfunction and intrathecal synthesis of igg were determined based on the method of reiber . the resulting data are presented in reibergrams ( figure 1 ) , discriminating the qigg from the igg / serum albumin ratio with hyperbolic reference range . the upper limit of the reference range for an intact brain barrier function is age - dependent and was calculated for each patient according to the formula qalb ( 4 + age / 15 ) 10 . brain barrier dysfunction was classified as mild ( qalb 1010 ) , moderate ( qalb 102010 ) , or severe ( qalb 2010 ) . increasing albumin quotients reflect increasing blood - brain barrier dysfunction ( x - axis ) . the cutoff value for brain barrier dysfunction depends on the patient 's age and is therefore not marked . on the y - axis , the blue line separates blood - borne igg ( below the line ) and intrathecal igg synthesis ( above the line ) . in our patient cohort , the csf / serum albumin ratio ( qalb ) was significantly higher in patients with leptomeningeal enhancement on postcontrast fluid - attenuated inversion recovery ( flair ) imaging ( red ) than in those without leptomeningeal enhancement ( green ) . clinical data and csf analyses of the included patients mri studies were performed on a 3 t mri system ( magnetom skyra ; siemens healthcare , erlangen , germany ) using a standardized protocol including t2 - weighted flair echo planar diffusion - weighted imaging including apparent diffusion coefficient calculations and subsequent contrast - enhanced t1 - weighted and flair sequences . the mri data were analyzed with a structured reporting scheme independently by 2 reviewers unaware of clinical detail and experienced with diagnostic and research studies using postcontrast flair mri . statistical analysis was performed using spss version 22.0.0.0 ( ibm , armonk , ny ) . group comparisons between patients with and without leptomeningeal postcontrast flair hyperintensity regarding the severity of brain barrier dysfunction and csf protein concentration , qalb , and qigg were calculated by mann - whitney u test and 2 - tailed student t test , as appropriate . a p value 0.05 was considered to be statistically significant . this study was approved by the local institutional review board ( medizinische ethikkommission ii der medizinischen fakultt mannheim , university of heidelberg ) and performed in accordance with the ethical standards of the 1964 declaration of helsinki and its later amendments . patient consent was not required by our institutional review board due to the retrospective nature of the study and the lack of patient interaction . this study was approved by the local institutional review board ( medizinische ethikkommission ii der medizinischen fakultt mannheim , university of heidelberg ) and performed in accordance with the ethical standards of the 1964 declaration of helsinki and its later amendments . patient consent was not required by our institutional review board due to the retrospective nature of the study and the lack of patient interaction . during the analyzed period , 15 patients with a diagnosis of aseptic meningitis were examined with a standardized 3 t mri protocol including postcontrast flair sequences and were potentially eligible for the study . one patient had to be excluded due to incomplete csf workup ( qalb missing ) . fourteen patients ( 8 men , age range 1858 years , all immunocompetent ) were included in our study . all patients presented with moderate to severe new - onset headache ; 8/14 had fever at presentation . in the clinical course , 2 patients developed cranial nerve palsy ( abducens nerve in 1 , facial and vestibulocochlear nerve in 1 ) . on the initial mri , no parenchymal signal alterations were detected in precontrast sequences including native flair imaging in any of the patients . on postcontrast flair images , 7/14 patients showed leptomeningeal and / or sulcal contrast enhancement . in 4/7 , a distinct leptomeningeal enhancement was present along each cerebral lobe of both hemispheres and the cerebellum ; in 3/7 , contrast enhancement was more subtle and confined to the supratentorial leptomeninges . an example of ubiquitous contrast enhancement of the meninges in a patient with meningitis caused by vzv is given in figure 2 . on contrast - enhanced t1 - weighted images , no parenchymal or meningeal signal abnormalities were noted . mri of a 54 - year - old patient with viral meningitis caused by varicella - zoster virus . ( a ) unenhanced precontrast fluid - attenuated inversion recovery ( flair ) images . on postcontrast flair images ( b ) , sulcal contrast enhancement and a fine hyperintense lining can be seen , probably involving the leptomeninges in the absence of obvious white or gray matter lesions on both flair and postcontrast t1 - weighted mri ( c ) . csf analyses were performed a mean of 2.6 days ( 2.1 days , range 08 days ) prior to mri and showed lymphocytic pleocytosis ( mean 206 cells / l , range 21491 ) indicating aseptic meningitis in all patients . there was no evidence of noninfectious aseptic meningitis ( postvaccinal , drugs , systemic inflammatory disease , neoplastic disorder ) in any of the patients . of these , the 3 patients with leptomeningeal enhancement were infected by herpesviridae ( vzv , hsv2 , cmv ) , whereas the 4 patients without leptomeningeal enhancement were positive for enterovirus rna . in relation to qigg , qalb accounted for a dysfunction of the brain barriers that was classified as severe in 3/13 , moderate in 5/13 , and mild in 5/13 . patients with leptomeningeal enhancement on postcontrast flair imaging showed significantly higher values of brain barrier dysfunction ( p = 0.001 ) . leptomeningeal enhancement on postcontrast flair imaging was present in all but 1 patient with moderate or severe brain barrier dysfunction , whereas none of the patients with mild or no disturbance of the brain barriers showed contrast enhancement of the leptomeninges . the presence of postcontrast leptomeningeal enhancement was associated with higher qalb ( p = 0.003 ) and qigg ( p = 0.002 ) as well as a higher csf protein concentration ( p = 0.016 ) . leukocyte count did not differ between patients with or without postcontrast leptomeningeal enhancement ( p = 0.449 ) . clinical outcome was favorable , with resolution of symptoms within 2 weeks in all but 1 patient . this patient showed marked leptomeningeal enhancement and moderate brain barrier disturbance on csf analysis and had several complications , including sixth cranial nerve palsy , undulating leukocyte count 100 / l over 4 weeks , and increase of intracranial pressure requiring continuous lumbar csf drainage for 7 days . in patients without leptomeningeal contrast enhancement , symptoms regressed more quickly than in those showing postcontrast flair signal enhancement . as a result , the average length of hospital stay was longer in patients with leptomeningeal contrast enhancement ( mean 19 days vs 7 days in those without enhancing leptomeninges ) . postcontrast flair mri sequences have been shown to be valuable in the detection and evaluation of different leptomeningeal diseases , including subarachnoid hemorrhage , meningeosis , and infectious meningitis . the nulling of the csf signal due to the inversion time facilitates an optimized delineation of hyperintense pathology adjacent to the csf in the sulcal and leptomeningeal space while the t1 shortening in flair sequences is responsible for the highly sensitive delineation of pathologic contrast enhancement following application of gadolinium . in a large cohort of infants with bacterial meningitis , contrast enhancement of the leptomeninges was the most common pathologic finding on mri . from a pathophysiologic point of view , leakage from damaged pial vessels leading to focal extravasation of contrast agent into the csf adjacent to the brain is the likely cause for leptomeningeal enhancement on flair images . contrast enhancement of the leptomeninges on postcontrast flair sequences may thus be a surrogate for dysfunction of the bcsfb and , more indirectly , a marker of bbb dysfunction . in contrast to patients with ischemic stroke or cerebral amyloid angiopathy , in whom localized brain barrier breakdown can be observed , in patients with meningitis a more generalized pattern of contrast enhancement was seen , involving both hemispheres and also the infratentorial space in some patients . we substantiate this hypothesis by correlating the csf findings with the presence of leptomeningeal enhancement in patients with aseptic meningitis . contrast enhancement of the meninges occurred only in patients with moderate to severe dysfunction of the brain barriers and not in those with mild or no brain barrier disturbance . moreover , we demonstrate a positive correlation between the qalb as a quantitative marker for brain barrier dysfunction and the occurrence of leptomeningeal enhancement . partly in line with these findings , an association of log10 - transformed csf protein and a leptomeningeal enhancement score has been reported in patients with infectious meningitis . however , log10 - transformed csf protein is only an approximate value for brain barrier disturbance , as it is not corrected for serum protein content . the positive correlation may thus be primarily based on the inclusion of patients with bacterial meningitis and marked csf protein elevation . severe damage to the brain barriers , particularly as seen in bacterial meningitis , may predispose to complications and poor prognosis . accordingly , a positive correlation between the extent of leptomeningeal enhancement on postcontrast flair images and the occurrence of complications has been demonstrated in a study of 43 patients with meningitis of various etiologies . however , complications affected only 3 patients with bacterial meningitis and 1 patient with fungal meningitis , while the clinical course of patients with viral meningitis was benign overall . our study focused on patients with aseptic meningitis , characterized by mostly mild to moderate brain barrier dysfunction . of interest , although only 1 patient in our cohort had a complicated clinical course , the presence of leptomeningeal enhancement still accounted for a delayed resolution of clinical symptoms and a longer hospital stay . on the other hand , a mild increase in brain barrier permeability in patients with viral meningitis may be a precondition for lymphocyte infiltration and subsequent effective viral clearance . furthermore , the extent of brain barrier dysfunction may vary depending on the specific viral agent . viral infections are characterized by individual patterns of chemokine secretion that promote vascular permeability . in our cohort ,3 patients with leptomeningeal enhancement were infected by herpesviridae ( vzv , hsv2 , cmv ) , coated double - stranded dna viruses , whereas 4 patients without leptomeningeal enhancement were positive for enteroviruses , uncoated double - stranded rna viruses . although data on hsv2 are lacking , hsv1 has been shown to affect the bbb mainly via increased mmp2 and mmp9 activity , leading to collagen type iv degradation . instead , in vitro studieshave shown that infection of choroid plexus cells with echovirus 30 , a member of the enterovirus family , leads to enhanced secretion of cxcl1 - 3 , chemoattractants for t lymphocytes . this is motivation to study the potential association between viral agents and the occurrence of leptomeningeal enhancement in future cohorts with more patients . because contrast - enhanced mri was performed after csf analysis , it is theoretically possible that leptomeningeal enhancement was caused or enhanced by the lumbar puncture . however , meningeal enhancement seems to occur only in the case of post lumbar puncture headache or intracranial hypotension , which did not occur in any of our patients . in patients with aseptic meningitis , leptomeningeal enhancement on postcontrast flair imagesis closely related to the extent of leakage of blood - borne proteins into the csf . both leptomeningeal enhancement and qalbangelika alonso : conceptualization of the study , data acquisition , analysis and interpretation of the data , drafting and revising the manuscript . philipp eisele : data acquisition , analysis and interpretation of the data , revising the manuscript . anne d. ebert : analysis and interpretation of the data , revising the manuscript , statistical analysis . martin griebe : acquisition , analysis , and interpretation of the data , revising the manuscript . kristina szabo : acquisition , analysis , and interpretation of the data , revising the manuscript . achim gass : conceptualization of the study , data acquisition , analysis and interpretation of the data , drafting and revising the manuscript . b. engelhardt is on the scientific advisory board for swiss multiple sclerosis society , arsep , cluster of excellence for systems neurology synergy , and zentrum fr molekulare neurobiologie ; is on the editorial board for european journal of immunology , fluids and barriers of the cns , and acta neuropathologica ; and received research support from swiss national science foundation , swiss multiple sclerosis society , arsep , bangerther rhyner foundation , and schweizerische herzstiftung . k. szabo is on the editorial board for cerebrovascular diseases and case reports in neurology and received research support from german research foundation . hennerici is an editor for cerebrovascular diseases and interventional neurology , is a consulting editor for international journal of stroke , receives publishing royalties from thieme publishers , and received research support from tiaregistry . gass received travel funding and / or speaker honoraria from bayer schering , biogen idec , merck serono , novartis , and teva neurosciences and is on the editorial board for cerebrovascular diseases and journal of neuroimaging .\noutput:\n" }, { "from": "agent", "value": "objective : to investigate the blood - csf barrier ( bcsfb ) dysfunction in aseptic meningitis.methods : in our case series of 14 patients with acute aseptic meningitis , we compared mri characteristics with csf findings.results : contrast enhancement in the sulcal space in a leptomeningeal pattern was visualized in 7 patients with bcsfb dysfunction categorized as moderate to severe as evidenced by the csf / serum albumin ratio ( qalb ) but was not present in those with mild or no barrier disturbance ( p = 0.001 ) . the qalb as a marker for the leakiness of the bcsfb and , more indirectly , of the blood - brain barrier ( bbb ) was positively correlated with the incidence of leptomeningeal contrast enhancement seen on postcontrast fluid - attenuated inversion recovery ( flair ) mri ( p = 0.003 ) . patients with a more pronounced brain barrier dysfunction recovered more slowly and stayed longer in the hospital.conclusions : the severity of meningeal bbb disturbance can be estimated on postcontrast flair mri , which may be of diagnostic value in patients with aseptic meningitis ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: human schistosomiasis is a disease caused by any of 5 species of trematodes , the blood flukes , in the genus schistosoma , and infections are acquired by contact with freshwater containing parasite larvae . world health organization ( who ) estimates that over 237 million people required treatment for schistosomiasis in 2010 with estimates of up to an additional 779 million at risk globally . about 85 % of the people at risk of schistosomiasis are from africa with more than 90 % of the cases occurring in sub - saharan africa . king estimated that schistosome infections accounted for 24 - 56 million disability - adjusted life years ( dalys ) lost in 2010 . two major schistosome species are prevalent in sub - saharan region , schistosoma mansoni and schistosoma haematobium causing intestinal and urogenital schistosomiasis , respectively . both types of schistosomiasis are hyper - endemic in the great lake regions of east africa , owing to the favorable habitat for snails of biomphalaria and bulinus genera , which are the intermediate host for s. mansoni and s. haematobium , respectively . surveys have revealed the presence of the disease in other parts of the country , including lake victoria . lakeshore communities are typically dependent on water from these lakes , rivers , and ponds for various daily activities , including cooking , bathing , and washing clothes . fishing is usually a major occupation of men of these communities , further bringing them into contact with water . historical studies have revealed that both schistosomiasis mansoni and schistosomiasis haematobium have been endemic for a long time in tanzania . through a full consideration of the amount of end - organ pathologies to the liver ( in the case of s. mansoni and s. japonicum infections ) and bladder and kidneys ( in the case of s. haematobium infection ) , together with chronic morbidities associated with impaired child growth and development , chronic inflammation , anemia , and other nutritional deficiencies , some new disease burden assessments estimate that schistosmiasis accounts for up to 70 million dalys lost annually . who estimates that more than 1 billion people are chronically infected with soil - transmitted helminths ( sths ) . sths persist exclusively in the poorest populations often living in remote , rural areas , urban slums , or in conflict zones . ascaris lumbricoides , hookworms ( ancylostoma duodenale and necator americanus ) , and trichuris trichiura are the most common sth species with global prevalence of about 1,000 , 900 - 1,300 , and 500 million cases , respectively [ 16 - 18 ] . of the sth species , hookworms are the most widely distributed species occurring throughout much of east africa . both schistosomiasis and sths have long been known to be co - endemic in the lake victoria basin in tanzania . a comaparable situation has been reported in the kenya and uganda sides of the basin . a. lumbricoides and t. trichuria have the highest prevalences in areas close to lake victoria of tanzania , western kenya , and southeastern uganda . the morbidity caused by sthsseveral studies have revealed the impact of sth infections as significant predictors of protein - energy malnutrition , iron - deficiency anemia ( ida ) , vitamin a deficiency ( vad ) , and poor academic performance among schoolchildren in different countries [ 26 - 29 ] . moreover , these consequences may continue into adulthood with effects on the economic productivity which trap the communities at risk of infections in a cycle of poverty , underdevelopment , and disease . hence , benefits of successful sth control programmes extend well beyond eliminating sth as they improve the nutritional and health status of children as well as contribute to higher educational attainment , labor force participation , productivity , and income among the most vulnerable populations [ 31 - 33 ] . schistosomes and sth - immunosuppressive featureshave possible impact on promoting susceptibility to hiv / aids , tuberculosis , and malaria , and there is evidence that female genital schistosomiasis caused by s. haematobium may significantly increase the likelihood of contracting hiv / aids . moreover , there are adverse effects on pregnancy outcome and agricultural worker productivity [ 2,6,36 - 39 ] ; helminths are strongly associated with poverty in sub - saharan africa . therefore , new and ongoing efforts to control and eliminate helminths and neglected tropical diseases ( ntds ) generally represent key elements for achieving africa 's millennium development goals ( mdgs ) . as such , the successful sth control programmes have enormous benefits of improved nutritional and health status of children for higher educational attainment , labor force participation , productivity , and income among the most vulnerable populations . mass drug administration ( mda ) has been a major approach to control human helminthiases in developing countries . in order to control schistosomiasis and sths , who recommends mda if the prevalence exceeds 10 % and has the target of deworming at least 75 % of school - aged children and other high - risk groups by administration with praziquantel for schistosomes and albendazole or mebendazole for sths . conversely , control of helminth infections has been suggested as the means to facilitate control of the big 3 species , especially by reducing the frequency of malaria fevers , the frequency of severe and cerebral malaria , and the prevalence of anemia [ 45 - 47 ] . furthermore , new evidence points to substantial geographic overlap between ntds and the big 3 helminthic diseases , with emerging data suggesting that control of ntds could actually become a powerful tool for combating hiv / aids , tuberculosis , and malaria . the main objective of this study was to carry out a survey on schistosomiasis and sths in order to suggest feasible and effective intervention strategies in the lake victoria basin , tanzania . the study area is the basin of lake victoria located on the northwest of tanzania ( fig . the area stretches from the west through south to the eastern side of the lake . it is comprised with kagera , mwanza , and mara on the lake shore and shinyanga about 60 km away from the lake . the study area is bordered by uganda on the north , and rwanda and burundi on the west . the main ethnic groups include wahaya , wasukuma , wazinza , wakerewe , wajita , wakurya , and waluo . much of the activities have a bearing to schistosomiasis and sth infections as they are performed without protective gear . the level of sanitation and hygiene in the area is as low as in any poor resource settings . collection of stool and urine specimens was done at the selected schools where inhabitants visited . each village person was given 1 stool container and 1 urine container on the first day and asked to bring the urine and stool specimens . the stool samples collected were processed to make duplicate kato - katz thick smears covered with cellophane soaked in glycerine and malachite green . the smears were examined for hookworms and other helminth eggs or larvae within 1 hr after preparation . the egg counts on each of the 2 slides were added together and divided by 2 to get the mean number of egg counts . urine samples were collected after 10.00 a.m. to diagnose s. haematobium based on detection of eggs in urine using the filtration technique with nuclepore membranes according to who . urine samples were mixed thoroughly and 10 ml were drawn using a syringe and passed through the membrane where eggs were logged . examination was done on site where detected eggs were counted and expressed as the number of eggs per 10 ml of urine . data entry was done using dbase iv ( borland international , scotts valley , california , usa ) and a double entry system was used for quality control . data was transferred to stata version 8 software ( statacorp 2000 , college station , texas , usa ) for analysis . analysis was done by generation of some frequency tables , cross tabulations , and calculation of prevalence . the ethical and scientific clearance was obtained from the medical research coordinating committee of the national institute for medical research before the implementation of the study . the study team visited villages where community leaders were met and the objectives , procedure , potential harm , and benefits of the study were explained to them . the leaders in turn convened meetings of the community members and the same was explained to them before the consent to participate in the study was sought . any participant would be free to withdraw from the study at any time of the study period when he or she felt to do so . the decision to refuse or withdraw from the study would have no negative effect on benefits provided during and after the study . all subjects who would be found infected with schistosomiasis or intestinal helminths would be treated following standard treatment guidelines . participants were informed that information will be confidentially kept only using code numbers instead of names of participants . the study area is the basin of lake victoria located on the northwest of tanzania ( fig . the area stretches from the west through south to the eastern side of the lake . it is comprised with kagera , mwanza , and mara on the lake shore and shinyanga about 60 km away from the lake . the study area is bordered by uganda on the north , and rwanda and burundi on the west . the main ethnic groups include wahaya , wasukuma , wazinza , wakerewe , wajita , wakurya , and waluo . much of the activities have a bearing to schistosomiasis and sth infections as they are performed without protective gear . the level of sanitation and hygiene in the area is as low as in any poor resource settings . collection of stool and urine specimens was done at the selected schools where inhabitants visited . each village person was given 1 stool container and 1 urine container on the first day and asked to bring the urine and stool specimens . the stool samples collected were processed to make duplicate kato - katz thick smears covered with cellophane soaked in glycerine and malachite green . the smears were examined for hookworms and other helminth eggs or larvae within 1 hr after preparation . examination for s. mansoni eggsthe egg counts on each of the 2 slides were added together and divided by 2 to get the mean number of egg counts . urine samples were collected after 10.00 a.m. to diagnose s. haematobium based on detection of eggs in urine using the filtration technique with nuclepore membranes according to who . urine samples were mixed thoroughly and 10 ml were drawn using a syringe and passed through the membrane where eggs were logged . examination was done on site where detected eggs were counted and expressed as the number of eggs per 10 ml of urine . data entry was done using dbase iv ( borland international , scotts valley , california , usa ) and a double entry system was used for quality control . data was transferred to stata version 8 software ( statacorp 2000 , college station , texas , usa ) for analysis . analysis was done by generation of some frequency tables , cross tabulations , and calculation of prevalence . the ethical and scientific clearance was obtained from the medical research coordinating committee of the national institute for medical research before the implementation of the study . the study team visited villages where community leaders were met and the objectives , procedure , potential harm , and benefits of the study were explained to them . the leaders in turn convened meetings of the community members and the same was explained to them before the consent to participate in the study was sought . any participant would be free to withdraw from the study at any time of the study period when he or she felt to do so . the decision to refuse or withdraw from the study would have no negative effect on benefits provided during and after the study . all subjects who would be found infected with schistosomiasis or intestinal helminths would be treated following standard treatment guidelines . participants were informed that information will be confidentially kept only using code numbers instead of names of participants . a total of 1,606 from 36 selected communities , mostly from the shoreline of the lake victoria basin in tanzania , were recruited for the study ( table 1 ) . out of 1,606 adults who provided stool specimens , 199 ( 12.4 % ) were positive for s. mansoni , 349 ( 21.7 ) for hookworms , 133 ( 8.3 % ) for a. lumbricoides , and 33 ( 2.0 % ) for t. trichiura . a total of 1,400 adults provided urine for s. haematobium diagnosis out of whom 25 ( 1.8 % ) from mwanza and mara were positive for eggs ( table 1 ) . the highest prevalence ( 18.9 % ) of intestinal schistosomiasis were recorded in mwanza region followed by kagera with 17.8 % . it was only in kagera region that all the 3 common sths at various prevalence rates were found . interestingly , no schistosomiasis haematobium patient was recorded in shinyanga region despite its being located in the hinterland . shinyanga is naturally the driest of the 4 regions , and the study was done in mid - july during draught when s. haematobium transmission is low . the few adult members with urogenital infections observed in mwanza and mara were from wet areas with paddy fields . such areas are good habitats for snail hosts of the genus bulinus . by that time bulamba locality was dry besides being close to the lake . the study team visited a total of 9 localities in 5 out of 8 districts in kagera region . in this region , ( 17.8 % ) were positive for intestinal schistosomiasis , 182 ( 37.3 % ) for hookworms , 113 ( 23.2 % ) for ascariasis , and 33 ( 6.8 % ) for trichuriasis ( table 2 ) . the highest prevalence ( 77.1 % ) of intestinal schistosomiasis was recorded at bwina locality in chato district followed by bwanga ( 30.3 % ) and kiziramuyaga ( 18.5 % ) in chato and muleba districts , respectively . hookworm infections were the highest at runazi ( 69.6 % ) , bwina ( 68.8 % ) , and kiziramuyaga ( 66.2 % ) in biharamulo , chato , and muleba districts , respectively . the prevalence of ascariasis was the highest at kyenshama ( 66.0 % ) in muleba district , followed by an urban community of bunena ( 42.9 % ) , then bwina ( 31.3 % ) and bwanga ( 24.2 % ) , both in chato district . trichuriasis was highly prevalent at bunena ( 33.3 % ) in bukoba urban district ( table 2 ) . the study team visited a total of 12 communities from 7 of the 8 districts of mwanza region . out of 471 adult participants who provided stool specimens , 89 ( 18.9 % ) had intestinal schistosomiasis and 42 ( 8.9 % ) had hookworms . no one was found to be infected with ascaris , trichuris , or other intestinal helminths ( table 3 ) . out of 265 adults who hadtheir urine specimen examined , only 3 ( 1.1 % ) from 2 communities of geita had urogenital schistosomiasis . about a half ( 51.1 % ) of those who presented stools at bungonya in sengerema had intestinal schistosomiasis . six of 14 individuals ( 42.9 % ) at tumaini in ilemala and 21 out of 50 examinees ( 42.0 % ) at nyamikoma in magu district were found infected with intestinal schistosomiasis . mwaginghi in kwimba district recorded the highest prevalence of hookworms ( 50.0 % ) followed by tumaini ( 35.7 % ) and lumeji ( 21.6 % ) in ilemela and magu districts , respectively ( table 3 ) . we recruited 344 adult members from mara region who provided both stool and urine specimens . the region had relatively low prevalence ( 6.7 % ) of s. mansoni and even lower prevalence ( 0.9 % ) of hookworms . the highest recorded prevalence of intestinal schistosomiasis in the region was from nyamitwebili where out of 44 members who provided stool specimens , 8 ( 18.2 % ) were positive for the disease . mwisenge locality was the second by having 7 ( 13.7 % ) positive cases for the disease . only hookworms were recorded at minigo in rorya district and mwisenge in musoma urban districts . with the exception of bulamba in bunda district , all communities in mara region had cases infected with s. haematobium . shinyanga region had totally different findings from the other 3 regions . in this region , out of 303 members who provided both stool and urine specimens , only 33 ( 10.9 % ) were positive for hookworm eggs ( table 5 ) . the highest prevalence for hookworms was found in kahama district at bukomela and mseki localities with 40.4 % and 33.3 % prevalence , respectively ( table 5 ) . the study results showed that generally the prevalence of s. mansoni , s. haematobium , and sths is widespread in the study area . however , the prevalence of s. mansoni in kagera region was very low with the exception of a few pockets in chato district . this could be attributed to the fact that lake shores in kagera region are open ones instead of bays such that when the wind blows makes the waves splash the shores making the place an unconduncive habitat for snail intermediate hosts for schistosomes . moreover , some of the shores in kagera region are formed by escarpments thus deep and less habitable by the snails . the situation is quite different from shores in chato district in the southwest of lake victoria which are mainly shallow and in bays thus not susceptible to strong winds and can habor the snails . the relatively higher prevalence of ascariasis and trichuriasis in kagera region than in other regions could be attributed to the difference in soil temperature , altitude , soil type , and rainfall [ 51 - 53 ] . kagera region is wet almost throughout the year as compared to the rest of the regions in the area . the highest prevalence of s. mansoni in kagera region that was recorded at bwina community could be attributed to the location of the study site . bwina ward is a thin peninsular with an average width of less than 2 km . as such , most of the area is surrounded by lake victoria water that is inhabited by the snail intermediate host biomphararia species for s. mansoni . bwanga and kiziramuyaga localities are close to the lake area that has small bays that are conduncive areas for the snail hosts . this has an implication of the region having the best breeding ground of the sths as well as more people consuming more vegetables that may be carrying the helminth eggs than those from other areas . the absence of urogenital schistosomiasis in kagera could be due to an absence of ponds and streams during the time of the study , and the fact that no paddy cultivation is practiced in the area . the high prevalence of intestinal and urogenital schistosomisiasis in the study area was a function of the distance from lake victoria ; the former being more prevalent at localities close to the lake , whilist the latter is more so away from it . the high prevalence of intestinal schistosomiasis at nyamitwebili and mwisenge localities could be associated with their being at the lake shore . minigo had a lot of paddy fields that are good habitats for snail intermediate hosts for s. haematobium . the distribution of s. haematobium and s. mansoni along lake victoria is largely related to the distribution of the intermediate hosts . along the shore of the lake , members of the genus biomphalaria are common with populations living along the lake shores and islands being highly affected by s. mansoni , as the risk of infection increases . in mara region , the distribution of s. mansoni was similar to that of mwanza with more s. mansoni close to the lake and s. haematobium on the hinterland . moreover , in areas where s. haematobium was high , there was a significant prevalence of hookworms . the findings are in line with the ones from a previous study in magu district in mwanza region . the spatial distribution of s. haematobium and hookworm is in accordance with the presence of ponds and streams as well as wetness and warmth of the soil in the reference area that are prerequisite for proliferation of the 2 helminths . we could not easily establish why there were no infections due to a. lumbricoides and t. trichiura in mwanza region or intestinal schistosomiasis in shinyanga region . a major reason could be geographical as stated above or there were treatment programmes prior to this study . the study results showed that schistosomiasis and 3 sths infections ( hookworms , ascaris , and trichuris ) were co - endemic in lake victoria basin in tanzania with a high probability of polyparasitism in the study participants . the prevalence of s. mansoni , s. haematobium , and sths ranged from low to moderate in most parts of the study area . intestinal schistosomiasis was prevalent along the lake victoria shores and decreased with distance from it . the distributions of both schistosome and geohelminth infections have important implications for integrated intervention including periodic community deworming programmes , provision of safe water supply , and proper health education relevant to good personal hygiene and good sanitary practices . these activities will facilitate the reduction of both prevalence and intensity of infections of schistosomiasis and sths in such endemic communities . pre - and post - intervention studies to assess knowledge , attitude , and practices of the concerned population can not be overemphasized .\noutput:\n" }, { "from": "agent", "value": "the objective of this study was to carry out a community survey on schistosomiais and soil - transmitted helminth ( sth ) infections in order to suggest feasible and effective intervention strategies in lake victoria basin , tanzania . a total of 37 communities selected from 23 districts of the 4 regions in the lake victoria basin of tanzania were involved in the study . from each of the selected locality , 50 adult community members , 25 males and 25 females , were recruited for the study . each study participant was requested to submit stool and urine specimens . from each stool specimen , duplicate kato - katz thick smears were prepared and microscopically examined for schistosoma mansoni and sth eggs . urine specimens were processed by the filtration technique and microscopically examined for schistosoma haematobium eggs . ultrasound examination for morbidity due to schistosomiasis was performed . mass treatment was done using praziquantel and albendazole for schistosome and sths infections , respectively . out of 1,606 adults who provided stool specimens , 199 ( 12.4 % ) were positive for s. mansoni , 349 ( 21.7 % ) for hookworms , 133 ( 8.3 % ) for ascaris lumbricoides , and 33 ( 2.0 % ) for trichuris trichiura . out of 1,400 participants who provided urine specimens , 25 ( 1.8 % ) were positive for s. haematobium eggs . because of the co - endemicity of these afflictions and their impact on vulnerable population groups , the helminthiasis could be simultaneously treated with 2 drugs , praziquantel for schistosomiasis and albendazole for sths ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in the previous issue of critical care , muller and colleagues present risk factors for renal dysfunction and renal replacement therapy in a cohort of 388 patients with severe sepsis or septic shock using multivariate analyses . of their results , the authors emphasise that there was no association between treatment with hydroxyethyl starch ( he s ) 130/0 .4 in the first 24 hours of the study period and renal impairment . whether or not he s 130/0 .4 causes acute kidney failure in septic patients is heavily debated . on one hand , the former starch solutions with higher molecular weight and substitution ratio caused acute kidney failure in septic patients when assessed in randomised clinical trials ( rcts ) . also , the use of colloids has never been proven to decrease mortality in critically ill patients when compared with crystalloids . on the other hand , the newer he s 130/0 .4 the volume - sparing effect of he s 130/0 .4 seems much smaller than expected , however , and the safety and efficacy of this solution have not been adequately evaluated , as demonstrated in a recent systematic review . the observational nature of the present study allows many explanations for the lack of association between he s treatment and poor renal outcome ; for example , the authors probably underestimate the true incidence of renal dysfunction when using baseline creatinine from the current hospital admission , clinicians may have avoided he s treatment in patients at risk of developing renal failure , and the study power is too low . it is important to bear in mind that observational data should be used to identify potential adverse reactions of medical products , but should not be used to assess safety . issues of safety must be assessed in well - powered rcts with patient - important endpoints such as persistent organ failure , mortality and quality of life . he s 130/0 .4 therefore can not be considered safe even after the publication of the data by muller and colleagues . better evidence will soon help clinicians decide on the use of he s 130/0 .4 in sepsis . one larger trial has recently been published , and three large trials have finished the inclusion and their results will soon be reported [ 7 - 9 ] . together , the results of these rcts will elucidate the safety profile of he s 130/0 .4 and inform us whether this starch should be used for septic patients . until then , we believe that he s 130/0 .4 should be given to septic patients only in the settings of rcts as stated in the recently published european society of intensive care medicine guidelines for colloid therapy in intensive care . the use of vasopressor was independently associated with a need for renal replacement therapy in their cohort of septic patients . does this mean we should not use vasopressors for septic shock ? hopefully , in general , low validity of multivariate adjusting in icu datasets with complex interventions contributes to this association . on the other hand , when choosing interventions in septic shock , the option often is either / or . if you give less fluid , you have to give more vasopressor . fluid volume was not included in the analysis by muller and colleagues , but again multivariate adjusting is unlikely to contribute to the answer to the question of the balance between fluid and vasopressor therapy . herercts are urgently needed , in particular , as practice may be changing with more restrictive fluid therapy also in patients with sepsis . ap is the sponsor and nh is the coordinating investigator of the scandinavian starch for severe sepsis / septic shock trial - a public - funded rct investigating the effect of he s 130/0 .4 versus crystalloid in patients with severe sepsis .\noutput:\n" }, { "from": "agent", "value": "it is heavily debated whether or not treatment with hydroxyethyl starch 130/0 .4 contributes to the development of acute kidney failure in patients with severe sepsis . in the previous issue of critical care , muller and colleagues report no association between initial resuscitation with hydroxyethyl starch 130/0 .4 and renal impairment in a cohort of septic patients . can we then consider hydroxyethyl starch 130/0 .4 a safe intervention ? the answer is no - observational data should be interpreted with caution and should mainly be used to identify risks , while safety must be assessed in randomised clinical trials . with these factors in mind , muller 's data associate the use of vasopressors with poor outcome , underlining the need for further randomised clinical trials to assess the potential harmful effects of common interventions in the critically ill ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: churg - strauss syndrome ( css ) so called allergic granulomatosis is a rare primary , non - inheritable , non - transmissible systemic disease , which typically occurs in patients with a history of bronchial asthma . peripheral eosinophilia and medium and small vessel autoimmune necrotizing vasculitis , involving multiple organs are the main features of the disease . css can be diagnosed by the presence of any four or more of the six criteria , including asthma , eosinophilia greater than 10 % , paranasal sinusitis , pulmonary infiltration , histologically confirmed vasculitis and neuropathy . a fifty - year - old female presented with a one month history of progressive dyspnea , productive cough , pain of elbows and knees , and 40c fever despite antibiotic treatment . she had been diagnosed with bronchial asthma over 25 years before admission and oral and depot glucocorticosteroids as a long - term therapy was applied . physical examination revealed tachypnea , wheezes , rhonchi and wet cracles on auscultation , tachycardia , skin nodules , urticarial rash and necrotic bullae all over the body ( table 1 , figure 1 ) . chest x - ray showed transient , patchy , nonsegmental areas of consolidation , with predilection for lower zones with the area of consolidation in lower left zone ( table 1 , figure 2a ) . transbronchial lung biopsy revealed granulomas , formed by eosynophils with central necrosis , macrophages and giant cells ( table 1 , figure 2b ) . a - x - ray of the chest : transient , patchy , nonsegmental areas of consolidation with predilection for lower zones with the area of consolidation in lower left zone ; b - transbronchial lung biopsy : granulomas , formed by eosynophils with central necrosis , macro phages and giant cells . patient was diagnosed with churg strauss syndrome and initial treatment with prednisone was introduced at a dose of 60 mg per day , i.e. 1 mg / kg / day . after four days of treatment , after 18 months of treatment , the patient reported no signs or symptoms of the disease . patient continues oral corticosteroid therapy at a dose of 10 mg of prednisone per day . idiopathic primary systemic vasculitides are defined , according to the chapel hill consensus conference , on the basis of the size of vessels involved , clinical symptoms , and histopathological features . according to the american college of rheumatology ( acr ) , classification criteria of the css are : small vessel vasculitis along with wegener 's granulomatosis ( wg ) , microscopic polyangiitis ( mpa ) , and idiopathic necrotizing crescentic glomerulonephritis ncgn . although , css can affect any organ system in the body , lung blood vessels involvement is one of the main features of the disease . asthma , peripheral eosinophilia , peripheral neuropathy , pulmonary infiltrates , and paranasal sinus abnormalities remain the major classification criteria of the disease . our patient had been diagnosed with bronchial asthma over 25 years before admission . skin lesions are the most common extra - pulmonary findings in the course of the disease . the main types of skin lesions reported include erythematous maculopapules resembling erythema multiform , hemorrhagic lesions ranging from petechiae to extensive ecchymosis , often associated with wheals , necrosis and ulceration , and cutaneous and subcutaneous nodules that are usually deep - seated and tender with a predilection for the scalp and temple region . others report livedo reticularis , papulovesicles , non - pitting periorbital edema , and nail - fold infarcts [ 4 - 8 ] . skin nodules urticarial rash and necrotic bullae all over the body were found in our patient . regarding clinical features , our patient complained of progressive dyspnea , productive cough , pain of elbows and knees , and 40c fever , despite the antibiotic and steroid treatment . we also found radio - logic changes , such as pulmonary infiltrates detected by x - ray and computed tomography , and other manifestations including , mononeuritis multiplex , eosino philic endomyocarditis , with no renal involvement documented . these are consistent with main clinical findings describing the disease [ 1,3 - 5 ] . we did not find positive antineutrophil cytoplasmic antibodies ( anca ) in our patient . according to reidet al and della rosa et al positive anca may be found in 39 to 59 % of patients with css . sable - fourtassou et al found the predominance of glomerulonephritis and peripheral neuropathy among positive anca patients , and more frequent cardiac involvement , and fever , among anca negative patients . based on that , these authors hypothesized that anca positivity may reect an active vasculitic process , while anca negativity may be more frequently linked to another clinical phenotype that could correspond to different pathogenic mechanisms which are less often associated with anca . consistently with their hypothesis , cardiac involvement and no gromerulonphritis characterized our case , with the exception for peripheral neuropathy presented . according to sable - fourtassou et al a higher frequency of vasculitis in biopsy specimens from the anca - positive group and a close association of renal involvement with anca positivity support a pathogenic role for anca . kallenberg et al focusing on anca directed to proteinase - 3 ( pr3 - anca ) or myeloperoxidase ( mpo - anca ) summarized that anca alone are not sufficient , as based on clinical and experimental data , and other , probably exogenous factors , seem necessary for disease induction and ( re ) activation . in particular , silica , the carriage of staphylococcus aureus , and various genetic factors may underline susceptibility to the disease . we did not find any bacterial source of infection or any genetic factors in our patient . concerning treatment , our patient received a conventional prednisone therapy , resulting in early regression of clinical features . further dose of the drug was titrated according to the level of blood eosinophils , with no signs or symptoms of the disease during a follow - up of 18 months of therapy . despite novel therapies being introduced , swietlik and doboszynska suggest the use of inhaled corticosteroids as a recurrence preventing approach and this may be a further step to be taken in our patient . lamprecht et al in their most recent publication summarize that anti - cd20 therapy and tnf - alpha - antagonists may represent strategies for refractory disease , but evidence from controlled trials is still lacking .\noutput:\n" }, { "from": "agent", "value": "a fifty - year - old female presented with a one month history of progressive dyspnea , productive cough , pain of elbows and knees , and 40c fever despite antibiotic treatment . she has been diagnosed of bronchial asthma over 25 years before admission and oral and depot glucocorticosteroids as a long - term therapy was applied . recently , an attempt of inhaled corticosteroids and laba treatment was introduced with no success . four years before admission she also developed peripheral neuropathy . physical examination revealed tachypnea , wheezes , rhonchi and wet cracles on auscultation , tachycardia , skin nodules , urticarial rash and necrotic bullae all over the body . chest x - ray showed transient , patchy , nonsegmental areas of consolidation with predilection for lower zones with the area of consolidation in lower left zone . obstruction was found on spirometry . tachycardia on ecg and myocardial fluid on echo were also detected . lab exams revealed elevated crp , wbc , eosinophils , and ige levels . ana and anca antibodies were not found . patient was diagnosed of churg strauss syndrome and initial treatment of prednisone was introduced . after four days of treatment , temperature normalized , and dyspnea diminished . after one month of therapy skin lesions regressed . after 18 months of the treatment patient reports no signs , nor symptoms of the disease . patient continues oral corticosteroid therapy ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: nanostructured materials are of great interest due to their tunable microstructure , phase transformations and quantum confinements , required for potential usage [ 1 - 3 ] . among these nano particles , wires , rings , combs , tetrapods of materials such as zno [ 4 - 8 ] , wo3 [ 9 - 12 ] , and tio2 [ 13 - 21 ] are most desired for various semiconducting , electrochromic , and mechanical applications . tio2 has been reported a versatile material , required for sensors , optical devices , photocatalysis , photoelectrochemical [ 26 - 28 ] , tribological , and bio - compatible surgical instruments . recently thermally evaporated tio2 nanowires have been examined and an efficient photoluminescence was registered in the blue region . in our preliminary observations a correlation between microstructural features of sol gel derived tio2 and photoluminescence has been attempted . the applications of tio2pertaining to engineering , semiconducting , and medicinal industries are enormous and expected to enhance by manifold times if the material is nanostructured to design fundamental nanodevices . however , detailed experimental studies on crystalline phases and the stability of microstructures of tio2that normally are temperature dependent are imperative to enable their use for any practical device . in this context , the present report provides a systematic evaluation of phase transformations and morphological features of tio2films by use of electron beam imaging and corresponding reciprocal space interpretations . these nano - scaled modifications upon annealing complement raman and photoluminescence spectroscopic results . the powder was sonicated in polyethylene glycol 400 and the resulting white , homogeneous dispersion was spin coated at 3,500 rpm for 30 s on sno2 : f coated glass - substrates . subsequently these films were subjected for annealing at different temperatures , viz . , 450 , 500 , 600 , and 700 c for 2 h. this dispersion was heat treated in an alumina crucible at 1,100 and 1,200 c for the same duration . the powder was then grounded for 1 h and then re - dispersed in ethanol . the resulting suspension was spin coated and the films were heat treated at 150 c . a transmission electron microscope ( tem , model fei cm12 ) was employed for microstructural imaging and phase analysis . several samples of tio2for tem characterization were prepared by a careful removal of these films from the substrate using a sharp - edged surgical blade . in this processthe films with 12 mm in dimension were possible to load on commercially available copper grids ( diameter : 3.05 mm ) of 200 mesh - pore size . surface morphology was characterized with an environmental scanning electron microscope ( sem , model hitachi tm1000 ) . photoluminescence investigations were performed on a perkin elmer ls - 55 luminescence spectrometer and raman spectra were recorded on a perkin - elmer gx 2000 optica spectrophotometer .1 a ) shows the film to be constituted by randomly distributed particles , 210 nm in size . at higher magnifications , polyhedral morphologies of nanoparticles with well - defined facetsa corresponding selected area electron diffraction pattern ( sadp ) shows the debye rings in reciprocal space ( fig .2 a ) which arise from the anatase crystal structure ( body centered tetragonal and space group i41 / amd ) of tio2with lattice constantsa = 0.38 nm andc = 0.95 nm . the planes of anatase ( 101 , 004 , 200 , 105 , 211 ) structure are marked on the different rings in sadp ( fig . tem bright field micrographs of nanoparticles in as - deposited condition showingahomogeneous distribution andbdifferent shape and size selected area electron diffraction patterns recorded from samples ofaas deposited and different annealing conditions ; b450c andc700 c annealing the as - deposited tio2film at 450 c is accompanied by grain growth as uniformly distributed particles of 1025 nm dimensions were observed ( fig . the corresponding sadp comprises additional rings ( as compared to the sadp of as - deposited film in fig .2 a ) and these new rings belong to the rutile crystal structure ( primitive tetragonal ; space group p42 / mnm ) of tio2with lattice constantsa = 0.45 nm andc = 0.29 nm . the existence of two - phase mixture in the film annealed at 450 c is indicative of initiation of solid - state phase transformation and this phase transformation does not get completed even at 600 c , as even at this temperature both rutile and anatase phases were found to be co - existent in the film ( sadps not shown here ) . the nanoparticulate morphology does not register much change as annealing temperature was raised from 450 to 500 c and this can be easily perceived from fig . but particle size grows visibly when the film was annealed at 600 c ( fig .3 c ) . on increasing the annealing temperature to 700 c , a substantial transformation of crystal structure and microstructure of tio2was registered . the film now has a smooth faceted surface and particles size lies in the range of 3060 nm and the grain shapes are largely cubical and euhedral ( fig . c ) . the corresponding sadp shows a complete phase transformation from anatase to rutile crystal structure with lattice constantsa = 0.45 nm andc = 0.29 nm . the corresponding planes ( 110 , 101 , 111 , 211 , 002 ) are marked on the debye rings in sadp ( fig .2 c ) and no planes related to the anatase phase were seen . at this temperature , elongated wire type structures were also formed . one such nanowire of about 40 nm diameter with a length of about 100 nm is shown in fig . formation of nanowires indicates a preferred growth of certain high - density crystallographic planes of rutile phase at the lattice scale . this variation in particle shapes as a function of annealing temperature is also illustrated schematically in fig . attempts were made to correlate the grain coarsening and annealing temperature to fit with an exponential function , to obtain a general trend of heating on such oxides . ( x / t ) , whereyandxare coordinate axes representing particle size and annealing temperature , respectively . tem bright field micrographs of nanoparticles in different annealing conditions ; a450 c , b500 c andc600 c tem bright field micrographs ( a c ) of nanoparticles annealed at 700 c graphical presentation of size of nanoparticles with annealing temperature . a corresponding data fitted polynomialy = cexp . ( x / t ) showing a good agreement between theory and experiment the mechanism for the solid state phase transformation from anatase to rutile at high temperatures is not clear , especially when the particle size is of the order of tens of nanometers . we conjecture that on annealing as - deposited tio2 , the rearrangement of ti and o atoms is such that the unit cell of tio2 tries to be more uniform in all three axes ( a , b , c ) to attain a more stable and defect - free configuration . this phenomenon reduces the value of c / a from 2.51 ( anatase ) to 0.65 ( rutile ) significantly and hence the volumes of basic unit cell as well . the unit cell of rutile is more dense ( = 4.25 g cm ) compared to anatase ( = 3.894 g cm ) . although both anatase and rutile phases are tetragonal , but the rutile structure is close to cubic . the cubic structure is known to be the most symmetrical lattice ( c / a = 1 ) and thermodynamically most stable . during the crystallographic transition , the movement of atoms is such that the highest atomically dense plane ( 101 ) of the anatase phase becomes the second most intense plane of the rutile structure . moreover the ( 110 ) plane evolves as the highest atomically dense plane in the rutile structure , which is not a preferred plane for atomic sites in the anatase form . recently the transformation from anatase to rutile on annealing at the temperature about 800 c has been investigated by wu et al . . figure 6 represents a schematic , delineating these two planes : 110 and 101 in anatase and rutile unit cells , respectively , of tio2 . this is remarkable as the 110 plane of rutile has also been found to be responsible for the growth of tio2 nanowires with a single crystalline structure . schematics of anatase - and rutile - unit cells marked with 101 and 110 planes and lattice points in a similar fashion , here annealing at 700 c steers the preferred growth under specific crystallographic directions , which in turn initiates the formation of nanowires . for the film grown from the sampleannealed at 1,100 c , nanoparticles and nanowires / fibers ensconcing a granular morphology were seen . the sem micrograph of this film reveals this unique fibrous and particulate morphology for tio2 ( fig .7 b shows a few aggregated nanowires ( region marked as a ) that appear to originate from a porous nano - grained structure ( region marked as b ) . a set of intermingled nanowires , abutting each other , are further elucidated as inset in fig .8 a ) shows short length porous nanowires as the principal component in the sample annealed at 1,100 c .8 a shows two parallel single crystalline nanowires of same diameter ( ~ 10 nm ) and length ( ~ 500 nm ) . however , further annealing at 1,200 c causes the collapse of the nanowires to yield a dendrite like shape of a main stem consisted with fine branches of nanoparticles ( fig . at this stage , it was observed that the main stem ( primary branch ) of the dendrite continues to have a rutile structure , whereas the grains associated with secondary branches have an anatase structure .8 b shows the sadp recorded from one of these secondary branches , along the zone axis of anatase crystal structure with 110 and 10 planes marked therein . sem micrographs ( a , b ) of samples annealed at 1,100 c showing coexistent morphologies of fibrous ( wires ) and fine grains .7 b shows intermingled wires tem bright field micrographs of different annealing conditions ; a1 ,100 c nanowires and fibrous grains and ( b ) 1200 c dendritic growth . insets are sadps fromarutile along andbanatase along [ 001 zone axes the overall microstructural transformation can be summarized as follows : from faceted granular ( up to 700 c , figs .14 ) structure to fibrous grains / wires ( at 1100 c , fig . 8a ) and finally to dendritesthe schematic in fig . 9shows the transformation from nano - grained microstructure below 700 c ( fig .9 c ) , and collapse of nanowires to ensue in dendrite like shapes at 1,200 c ( fig . it appears that the fibrous features ( at 700 c ) evolve due to solid - state phase transition , which is accompanied by lessening of strain and reduction of defects prevalent at the lattice scale in the material . the mottled contrast in the micrograph of the film annealed at 700 c arises due to the strain present at lattice scale . annealing allows the formation of a more thermodynamically stable microstructure and therefore wire like shapes with effective surface are higher than that of regular particles are formed at 1,100 c . it is evident that the rutile phase triggers the growth of nanowire as at 1,200 c when the anatase phase re - appears , the wire morphology gives way to a fibrous structure encompassing a regular granular phase . mechanism showing different microstructural transformations on annealing at temperatures : aas deposited , b700 c , c1 ,100 c , andd1 ,200 c xrd patterns of tio2films annealed at different temperatures are shown in fig .10 . for the as - deposited film , the intense peaks due to the planes ( hkl ) : 101 , 103 , 004 , 200 , 105 , 211 , 204 , 116 , 220 , 215 , 303 , 312 of the anatase phase of tio2 in accordance with pdf number 21 - 1272 corresponding to the interplanar spacings ( d ) : 0.35 , 0.242 , 0.237 , 0.187 , 0.169 , 0.166 , 0.148 , 0.136 , 0.134 , 0.126 , 0.12 , 0.117 nm , respectively , are marked on the diffractogram ( fig . the phase transformation from anatase to rutile structure is complete as peaks corresponding to single phase rutile crystal structure with the planes ( hkl ) : 110 , 101 , 200 , 111 , 210 , 211 , 220 , 310 , 221 , 301 , 112 , 321 , corresponding to interplanar spacings ( d ) : 0.323 , 0.247 , 0.229 , 0.218 , 0.205 , 0.166 , 0.162 , 0.148 , 0.145 , 0.136 , 0.134 , 0.117 nm , are seen in the diffractogram ( fig .10 b ) as per pdf number 21 - 1276 from the jcpds library of spectra . the partial transformation of rutile phase into anatase ( as seen from tem in fig .8 b ) on annealing the sample at 1,200 c is also supplemented by the xrd data , as an extra peak at interplanar spacing of 0.35 nm corresponding tohkl : 101 of anatase phase is seen in the diffractogram of this sample ( fig . all other peaks in the xrd pattern at this temperature ( 1,200 c ) still belong to the rutile phase . xrd patterns from tio2 in different conditions ; aas deposited , bandcannealed at 1,100 and 1,200 c , respectively . an : anatase , ru : rutile photoluminescence ( pl ) spectra recorded at room temperature from the different annealed samples ( at 700 , 1,100 and 1,200 c ) are depicted in fig . the emission of the samples was recorded at excitation wavelength of 200 nm , under similar excitation conditions . in all three samples , three peaks corresponding to uv , blue , and greeneuveb , and eg are energies corresponding to the emission bands maxima for the uv ( 414422 nm ) , blue ( 470483 nm ) , and green ( 518526 nm ) , respectively . the uv emission originates from interband transition of electrons and the visible emission is due to transition of electrons from shallow donor level of the oxygen vacancies in the valence band . the oxygen vacancies evolved during growth of the material , trap electrons and thus become paramagnetic and give the characteristic electron spin resonance signal . when the material gets exposed to ultraviolet , these vacancies then become susceptible to trap holes generated by the uv exposure . the recombination of hole with the electron already trapped at the oxygen vacancies emits light , which is generally in the visible region . a net energy - peak shifts in all these samples , showed that the blue shift is significant ( e = 0.072 ev , table 1 ) with the annealing temperature . however , we did not observe considerable change in intensity of various bands with annealing at these temperatures ( 700 , 1100 , and 1,200 c ) . in our previous study , the emission bands recorded up to maximum annealing temperature of 700 c showed a trend of decreasing pl intensity with increasing temperature and the observations were understood on the basis of the various processes such as self - trapped excitons recombination which is a combined effect of defect centres generated from oxygen vacancies and particle size variation . in the present case , a dominant blue shift with increasing annealing temperature with considerable variation in pl intensity may be attributed to structural transformation from anatase to rutile and then partial transformation of rutile to anatase on increasing annealing temperature . photoluminescence spectra of tio2 in different annealed conditions : 700 , 1100 , and 1,200 c . symbols : excitation at 205 nm ( - - - ) ; 700 c ( ) ; 1100 c ( ) ; 1200 c ( ) schematic showing a general energy band diagram describing the photoluminescence of nanostructured tio2 effect of annealing conditions on different photoluminescent emission peaks of tio2 raman spectra of tio2 films are shown in fig . 13 . raman bands in anatase phase ( in as - deposited condition ) exist at raman shifts corresponding to 398 ( b1 g ) , 515 ( a1 g ) and 640 ( eg ) cm of vibrational modes . in contrast , the raman bands in rutile phase ( annealing at 1,100 c ) reveals frequencies at 448 ( eg ) and 612 ( a1 g ) cm of corresponding vibrational modes . however , the prior studies have further been confirmed by studying the samples annealed at 1,200 c . a weak raman shift ( 515 cm , a1 g of anatase phase ) in addition to strong peaks ( 448 , 612 cm : eg and a1 g of rutile phase ) shows that there is a partial phase transition of rutile to anatase at 1,200 c . the peak shifts arise due to different influences on change in the polarizability of electronic structures of rutile and anatase ( although both are tetragonal with the same group : d4h ) .14 ) in the present work shows the peak due to anatase at high temperatures ( 1,200 c ) although this phase is not a thermodynamically stable phase and is not revealed between 700 and 1,100 c . the optical phonon energies corresponding to different vibrational modes in anatase and rutile phases are very small , but the fine structural changes at lattice scale are significantly visible in the energy band diagram . the fine energy shifts in uv , blue , and green emissions in photoluminescence are also dependent on these vibrational states upon photoexcitation . for example the energy - shifts in photoluminescence at different annealing conditions in uv , blue , and green as plotted in fig .4 , 0.048 , 0.072 , and 0.038 ev , respectively , ( table 1 ) are of the order of raman active vibrations ( fig . this implies that the raman active optical phonons are excited due to external energy and subsequently assist the band - to - band recombination ( uv region ) and transitions due to different surface states and defects ( blue and green region ) . it has been stated that the band - to - band recombination ( anatase phase ) can be considered as a two phonons ( eg ( 5 ) : 0.017 ev + eg ( 6 ) : 0.024 ev = 0.041 ev ) one photon ( 0.04 ev ) coupling course . the kinetics of the conversion of anatase to rutile has been studied in the past by raman spectroscopy . authors in observed a sequential change in intensity of the anatase form were observed with laser irradiation time and it was noticed that there is a rise of 236 cm ( rutile ) and fall of 515 cm ( anatase ) . but in the present work at high temperature ( 1,200 c ) the initiation of 515 cm ( anatase ) and a sharp decrease in intensity of 44 and 612 cm ( rutile ) bands has been observed for the first time . this is possible only if the tio6 octahedra ( rutile at 1,100 c ) is distorted at 1,200 c in such a way that it tends to achieve anatase - crystallographic symmetry and in this process a vibrational mode of anatase at 515 cm is seen in the raman spectrum . since the transformation of rutile to anatase is not complete at this temperature ( 1,200 c ) , bands at 448 and 612 cm of rutile phase continue to exist in the spectrum . raman spectra of tio2 in different conditions ; aas deposited , bandcannealed at 1,100 and 1,200 c , respectively vibrational energy level diagrams for raman scattering from tio2 in different conditions ; aas deposited , bandcannealed at 1,100 and 1,200 c , respectively1a ) shows the film to be constituted by randomly distributed particles , 210 nm in size . at higher magnifications , polyhedral morphologies of nanoparticles with well - defined facetsa corresponding selected area electron diffraction pattern ( sadp ) shows the debye rings in reciprocal space ( fig .2 a ) which arise from the anatase crystal structure ( body centered tetragonal and space group i41 / amd ) of tio2with lattice constantsa = 0.38 nm andc = 0.95 nm . the planes of anatase ( 101 , 004 , 200 , 105 , 211 ) structure are marked on the different rings in sadp ( fig . tem bright field micrographs of nanoparticles in as - deposited condition showingahomogeneous distribution andbdifferent shape and size selected area electron diffraction patterns recorded from samples ofaas deposited and different annealing conditions ; b450c andc700 c annealing the as - deposited tio2film at 450 c is accompanied by grain growth as uniformly distributed particles of 1025 nm dimensions were observed ( fig . the corresponding sadp comprises additional rings ( as compared to the sadp of as - deposited film in fig .2 a ) and these new rings belong to the rutile crystal structure ( primitive tetragonal ; space group p42 / mnm ) of tio2with lattice constantsa = 0.45 nm andc = 0.29 nm . the existence of two - phase mixture in the film annealed at 450 c is indicative of initiation of solid - state phase transformation and this phase transformation does not get completed even at 600 c , as even at this temperature both rutile and anatase phases were found to be co - existent in the film ( sadps not shown here ) . the nanoparticulate morphology does not register much change as annealing temperature was raised from 450 to 500 c and this can be easily perceived from fig . but particle size grows visibly when the film was annealed at 600 c ( fig .3 c ) . on increasing the annealing temperature to 700 c , a substantial transformation of crystal structure and microstructure of tio2was registered . the film now has a smooth faceted surface and particles size lies in the range of 3060 nm and the grain shapes are largely cubical and euhedral ( fig . c ) . the corresponding sadp shows a complete phase transformation from anatase to rutile crystal structure with lattice constantsa = 0.45 nm andc = 0.29 nm . the corresponding planes ( 110 , 101 , 111 , 211 , 002 ) are marked on the debye rings in sadp ( fig .2 c ) and no planes related to the anatase phase were seen . at this temperature , elongated wire type structures were also formed . one such nanowire of about 40 nm diameter with a length of about 100 nm is shown in fig . formation of nanowires indicates a preferred growth of certain high - density crystallographic planes of rutile phase at the lattice scale . this variation in particle shapes as a function of annealing temperature is also illustrated schematically in fig . attempts were made to correlate the grain coarsening and annealing temperature to fit with an exponential function , to obtain a general trend of heating on such oxides . ( x / t ) , whereyandxare coordinate axes representing particle size and annealing temperature , respectively . tem bright field micrographs of nanoparticles in different annealing conditions ; a450 c , b500 c andc600 c tem bright field micrographs ( a c ) of nanoparticles annealed at 700 c graphical presentation of size of nanoparticles with annealing temperature . a corresponding data fitted polynomialy = cexp . ( x / t ) showing a good agreement between theory and experiment the mechanism for the solid state phase transformation from anatase to rutile at high temperatures is not clear , especially when the particle size is of the order of tens of nanometers . we conjecture that on annealing as - deposited tio2 , the rearrangement of ti and o atoms is such that the unit cell of tio2 tries to be more uniform in all three axes ( a , b , c ) to attain a more stable and defect - free configuration . this phenomenon reduces the value of c / a from 2.51 ( anatase ) to 0.65 ( rutile ) significantly and hence the volumes of basic unit cell as well . the unit cell of rutile is more dense ( = 4.25 g cm ) compared to anatase ( = 3.894 g cm ) . although both anatase and rutile phases are tetragonal , but the rutile structure is close to cubic . the cubic structure is known to be the most symmetrical lattice ( c / a = 1 ) and thermodynamically most stable . during the crystallographic transition , the movement of atoms is such that the highest atomically dense plane ( 101 ) of the anatase phase becomes the second most intense plane of the rutile structure . moreover the ( 110 ) plane evolves as the highest atomically dense plane in the rutile structure , which is not a preferred plane for atomic sites in the anatase form . recently the transformation from anatase to rutile on annealing at the temperature about 800 c has been investigated by wu et al . . figure 6 represents a schematic , delineating these two planes : 110 and 101 in anatase and rutile unit cells , respectively , of tio2 . this is remarkable as the 110 plane of rutile has also been found to be responsible for the growth of tio2 nanowires with a single crystalline structure . schematics of anatase - and rutile - unit cells marked with 101 and 110 planes and lattice points in a similar fashion , here annealing at 700 c steers the preferred growth under specific crystallographic directions , which in turn initiates the formation of nanowires . for the film grown from the sampleannealed at 1,100 c , nanoparticles and nanowires / fibers ensconcing a granular morphology were seen . the sem micrograph of this film reveals this unique fibrous and particulate morphology for tio2 ( fig .7 b shows a few aggregated nanowires ( region marked as a ) that appear to originate from a porous nano - grained structure ( region marked as b ) . a set of intermingled nanowires , abutting each other , are further elucidated as inset in fig .8 a ) shows short length porous nanowires as the principal component in the sample annealed at 1,100 c .8 a shows two parallel single crystalline nanowires of same diameter ( ~ 10 nm ) and length ( ~ 500 nm ) . however , further annealing at 1,200 c causes the collapse of the nanowires to yield a dendrite like shape of a main stem consisted with fine branches of nanoparticles ( fig . at this stage , it was observed that the main stem ( primary branch ) of the dendrite continues to have a rutile structure , whereas the grains associated with secondary branches have an anatase structure .8 b shows the sadp recorded from one of these secondary branches , along the zone axis of anatase crystal structure with 110 and 10 planes marked therein . sem micrographs ( a , b ) of samples annealed at 1,100 c showing coexistent morphologies of fibrous ( wires ) and fine grains .7 b shows intermingled wires tem bright field micrographs of different annealing conditions ; a1 ,100 c nanowires and fibrous grains and ( b ) 1200 c dendritic growth . insets are sadps fromarutile along andbanatase along [ 001 zone axes the overall microstructural transformation can be summarized as follows : from faceted granular ( up to 700 c , figs .14 ) structure to fibrous grains / wires ( at 1100 c , fig . 8a ) and finally to dendritesthe schematic in fig . 9shows the transformation from nano - grained microstructure below 700 c ( fig .9 c ) , and collapse of nanowires to ensue in dendrite like shapes at 1,200 c ( fig . it appears that the fibrous features ( at 700 c ) evolve due to solid - state phase transition , which is accompanied by lessening of strain and reduction of defects prevalent at the lattice scale in the material . the mottled contrast in the micrograph of the film annealed at 700 c arises due to the strain present at lattice scale . annealing allows the formation of a more thermodynamically stable microstructure and therefore wire like shapes with effective surface are higher than that of regular particles are formed at 1,100 c . it is evident that the rutile phase triggers the growth of nanowire as at 1,200 c when the anatase phase re - appears , the wire morphology gives way to a fibrous structure encompassing a regular granular phase . mechanism showing different microstructural transformations on annealing at temperatures : aas deposited , b700 c , c1 ,100 c , andd1 ,200 c xrd patterns of tio2films annealed at different temperatures are shown in fig .10 . for the as - deposited film , the intense peaks due to the planes ( hkl ) : 101 , 103 , 004 , 200 , 105 , 211 , 204 , 116 , 220 , 215 , 303 , 312 of the anatase phase of tio2 in accordance with pdf number 21 - 1272 corresponding to the interplanar spacings ( d ) : 0.35 , 0.242 , 0.237 , 0.187 , 0.169 , 0.166 , 0.148 , 0.136 , 0.134 , 0.126 , 0.12 , 0.117 nm , respectively , are marked on the diffractogram ( fig . the phase transformation from anatase to rutile structure is complete as peaks corresponding to single phase rutile crystal structure with the planes ( hkl ) : 110 , 101 , 200 , 111 , 210 , 211 , 220 , 310 , 221 , 301 , 112 , 321 , corresponding to interplanar spacings ( d ) : 0.323 , 0.247 , 0.229 , 0.218 , 0.205 , 0.166 , 0.162 , 0.148 , 0.145 , 0.136 , 0.134 , 0.117 nm , are seen in the diffractogram ( fig .10 b ) as per pdf number 21 - 1276 from the jcpds library of spectra . the partial transformation of rutile phase into anatase ( as seen from tem in fig .8 b ) on annealing the sample at 1,200 c is also supplemented by the xrd data , as an extra peak at interplanar spacing of 0.35 nm corresponding tohkl : 101 of anatase phase is seen in the diffractogram of this sample ( fig . all other peaks in the xrd pattern at this temperature ( 1,200 c ) still belong to the rutile phase . xrd patterns from tio2 in different conditions ; aas deposited , bandcannealed at 1,100 and 1,200 c , respectively . photoluminescence ( pl ) spectra recorded at room temperature from the different annealed samples ( at 700 , 1,100 and 1,200 c ) are depicted in fig . the emission of the samples was recorded at excitation wavelength of 200 nm , under similar excitation conditions . in all three samples , three peaks corresponding to uv , blue , and green are observed . euveb , and eg are energies corresponding to the emission bands maxima for the uv ( 414422 nm ) , blue ( 470483 nm ) , and green ( 518526 nm ) , respectively . the uv emission originates from interband transition of electrons and the visible emission is due to transition of electrons from shallow donor level of the oxygen vacancies in the valence band . the oxygen vacancies evolved during growth of the material , trap electrons and thus become paramagnetic and give the characteristic electron spin resonance signal . when the material gets exposed to ultravioletthe recombination of hole with the electron already trapped at the oxygen vacancies emits light , which is generally in the visible region . a net energy - peak shifts in all these samples , showed that the blue shift is significant ( e = 0.072 ev , table 1 ) with the annealing temperature . however , we did not observe considerable change in intensity of various bands with annealing at these temperatures ( 700 , 1100 , and 1,200 c ) . in our previous study , the emission bands recorded up to maximum annealing temperature of 700 c showed a trend of decreasing pl intensity with increasing temperature and the observations were understood on the basis of the various processes such as self - trapped excitons recombination which is a combined effect of defect centres generated from oxygen vacancies and particle size variation . in the present case , a dominant blue shift with increasing annealing temperature with considerable variation in pl intensity may be attributed to structural transformation from anatase to rutile and then partial transformation of rutile to anatase on increasing annealing temperature . photoluminescence spectra of tio2 in different annealed conditions : 700 , 1100 , and 1,200 c . symbols : excitation at 205 nm ( - - - ) ; 700 c ( ) ; 1100 c ( ) ; 1200 c ( ) schematic showing a general energy band diagram describing the photoluminescence of nanostructured tio2 effect of annealing conditions on different photoluminescent emission peaks of tio2 raman spectra of tio2 films are shown in figraman bands in anatase phase ( in as - deposited condition ) exist at raman shifts corresponding to 398 ( b1 g ) , 515 ( a1 g ) and 640 ( eg ) cm of vibrational modes . in contrast , the raman bands in rutile phase ( annealing at 1,100 c ) reveals frequencies at 448 ( eg ) and 612 ( a1 g ) cm of corresponding vibrational modes . however , the prior studies have further been confirmed by studying the samples annealed at 1,200 c . a weak raman shift ( 515 cm , a1 g of anatase phase ) in addition to strong peaks ( 448 , 612 cm : eg and a1 g of rutile phase ) shows that there is a partial phase transition of rutile to anatase at 1,200 c . the peak shifts arise due to different influences on change in the polarizability of electronic structures of rutile and anatase ( although both are tetragonal with the same group : d4h ) .14 ) in the present work shows the peak due to anatase at high temperatures ( 1,200 c ) although this phase is not a thermodynamically stable phase and is not revealed between 700 and 1,100 c . the optical phonon energies corresponding to different vibrational modes in anatase and rutile phases are very small , but the fine structural changes at lattice scale are significantly visible in the energy band diagram . the fine energy shifts in uv , blue , and green emissions in photoluminescence are also dependent on these vibrational states upon photoexcitation . for examplethe energy - shifts in photoluminescence at different annealing conditions in uv , blue , and green as plotted in fig .4 , 0.048 , 0.072 , and 0.038 ev , respectively , ( table 1 ) are of the order of raman active vibrations ( fig . this implies that the raman active optical phonons are excited due to external energy and subsequently assist the band - to - band recombination ( uv region ) and transitions due to different surface states and defects ( blue and green region ) . it has been stated that the band - to - band recombination ( anatase phase ) can be considered as a two phonons ( eg ( 5 ) : 0.017 ev + eg ( 6 ) : 0.024 ev = 0.041 ev ) one photon ( 0.04 ev ) coupling course . the kinetics of the conversion of anatase to rutile has been studied in the past by raman spectroscopy . authors in observed a sequential change in intensity of the anatase form were observed with laser irradiation time and it was noticed that there is a rise of 236 cm ( rutile ) and fall of 515 cm ( anatase ) . but in the present work at high temperature ( 1,200 c ) the initiation of 515 cm ( anatase ) and a sharp decrease in intensity of 44 and 612 cm ( rutile ) bands has been observed for the first time . this is possible only if the tio6 octahedra ( rutile at 1,100 c ) is distorted at 1,200 c in such a way that it tends to achieve anatase - crystallographic symmetry and in this process a vibrational mode of anatase at 515 cm is seen in the raman spectrum . since the transformation of rutile to anatase is not complete at this temperature ( 1,200 c ) , bands at 448 and 612 cm of rutile phase continue to exist in the spectrum . raman spectra of tio2 in different conditions ; aas deposited , bandcannealed at 1,100 and 1,200 c , respectively vibrational energy level diagrams for raman scattering from tio2 in different conditions ; aas deposited , bandcannealed at 1,100 and 1,200 c , respectivelynano - scaled morphological and crystallographic transformations in a sol gel derived tio2have been studied employing highly precise and complementary techniques like tem , xrd , and raman spectroscopy . the nanostructural transformations from particles to wires initiate at 700 c and significant growth of wires takes place at 1,100 c . however , our further investigations have delineated that at 1,200 c the wires undergo a nanostructural instability and leads to branching on nanowires . nano - scaled features obtained on annealing at different temperatures are related with the different crystal structures of tio2 . wire formation takes place when the anatase phase transforms to rutile structure of tio2 ( annealed at 7001100 c ) . a noteworthy feature was delineated as the rutile phase partially transforms to anatase again at 1,200 c . moreover these different nano - objects have been further evaluated for their performance as luminescent materials . one of the authors ( md ) acknowledges the financial support from department of science and technology ( grant no . singh , d. gupta and d. harnath are gratefully acknowledged for recording xrd , raman spectroscopy , and photoluminescence data .\noutput:\n" }, { "from": "agent", "value": "controllable nanostructures in spin coated titanium oxide ( tio2 ) films have been achieved by a very simple means , through change of post deposition annealing temperature . electron beam imaging and reciprocal space analysis revealed as - deposited tio2films to be characterized by a dominant anatase phase which converts to the rutile form at 600 c and reverts to the anatase modification at 1,200 c . the phase changes are also accompanied by changes in the film microstructure : from regular nanoparticles ( as - deposited ) to nanowires ( 600 c ) and finally to dendrite like shapes at 1,200 c . photoluminescence studies , raman spectral results , and x - ray diffraction data also furnish evidence in support of the observed solid state phase transformations in tio2 ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: cellulases have versatile applications in textile , laundry , pulp and paper , fruit juice extraction , and animal feed additives . in addition , they find use in saccharification of lignocellulosic agroresidues to fermentable sugars which can be used for production of bioethanol , lactic acid , and single - cell protein . bacteria have been widely explored for cellulase production owing to their high growth rate , expression of multienzyme complexes , stability at extreme temperature and ph , lesser feedback inhibition , and ability to withstand variety of environmental stress . among them , bacillus sp . continues to be dominant bacterial workhorse due to the capacity to produce and secrete large quantities of extracellular enzymes . however , physical process parameters such as temperature , ph , and agitation speed play a vital role for the cellulase production efficiency of the microorganisms . agitation speed is an important factor which governs the dissolved oxygen level in the culture broth that affects cell growth of cellulase producing microorganism . however , higher agitation speed has been shown to inhibit cellulase activity . analogous profile in growth and enzyme activity with change in ph and temperature is also a well - known fact . the traditional one - variable - at - a - time approach for optimization disregards the complex interactions among various components . statistically based experimental designs such as placket - burman design and response surface methodology ( rsm ) can be effectively used to study the effects of factors and to search for optimum levels of parameters for desired response . statistical design techniques have been successfully applied in many studies such as cellulose production by trichoderma reesei , bacillus subtilis as3 , and xylanase production by bacillus pumilus . simultaneous saccharification and fermentation ( ssf ) process combines enzymatic hydrolysis of cellulose with subsequent fermentation of reducing sugar ( glucose ) to ethanol . ssf studies from lignocellulosic biomass such as wheat and rice straw , corn stalk , corn cobs , and forestry wastes using cellulase from natural sources have been reported . owing to the inherent key enzymes for ethanol fermentation , alcohol dehydrogenase and pyruvate decarboxylase found in zymomonas mobilis , research has been focused on it as a promising alternative ethanol producer for its high sugar uptake and improved ethanol tolerance . in the present study , the physical process parameters such as initial ph , temperature , and agitation speed of the culture were optimized by central composite design technique using multiresponse analysis to enhance the alkaline cmcase activity from newly isolated b. subtilis ( as3 ) . the optimal levels of physical process parameters predicted by the model were verified both in flask and bioreactor . subsequently , the bacterial cellulase was employed for ssf trials on pretreated wild grass in shake flask and bioreactor with z. mobilis , respectively . carboxymethylcellulose ( cmc ) was purchased from sigma - aldrich ( st . louis , usa ) . all other chemicals and reagents of analytical grade like potassium dichromate ( k2cr2o7 ) , glucose , yeast extract , and peptone used in the study were procured from merck and himedia laboratories ( india ) . lignocellulosic biomass wild grass ( achnatherum hymenoides ) was provided by professor dinesh goyal , department of biotechnology and environmental sciences , thapar university , patiala , punjab , india . the biomass was washed thrice with water to remove adhering dust particles , dried at room temperature , and finally ground in a mixer grinder to 1 mm mesh size . eu754025 ) isolated from cow dung and used for cellulase production was a kind gift from professor d. goyal , thapar university , patiala , punjab , india . the culture was maintained in nutrient agar slant at 4c and subcultured every 2 weeks . the inoculum was prepared by taking a loop full of culture from the nutrient agar slant in a 100 ml erlenmeyer flask containing 25 ml of nutrient broth and incubated at 37c and 180 rpm for 1618 h ( od600 nm = 0.60.8 ) .2 % ( v / v ) of the fresh inoculum culture was added to 50 ml of optimized medium containing ( g / l ) : cmc , 18 ; peptone , 8 ; yeast extract , 5 ; k2hpo4 , 1 ; mgso47h2o , 0.25 ; feso47h2o , 0.25 ; and mncl24h2o , 0.5 in 250 ml erlenmeyer flask at different initial ph of the medium and incubated at different temperature and agitation as per the central composite experimental design presented in table 1 . samples were collected at regular intervals of time for measurement of cell growth and cmcase activity .2427 ) for fermentation was procured from institute of microbial technology ( imtech ) , chandigarh , india . z. mobilis was inoculated in autoclaved medium containing ( g / 100 ml ) glucose , 2 ; yeast extract , 1 , and kh2po4 , 0.2 with incubation at 30c , 120 rpm . aliquots measuring 1 ml from actively growing culture of z. mobilis ( 2.110 cells / ml ) were transferred to 100 ml of fermentation medium . in order to determine the best set of culture conditions to obtain maximum cellulase activity by bacillus subtilis as3 , experiments were performed by varying the levels of culture conditions as per the central composite design ( ccd ) . the culture conditions chosen for optimization study were ph , agitation speed ( rpm ) , and temperature ( c ) ; the total number of treatment combinations ( experiments ) was 20 = 2 + 2k + n0 , where k was the number of independent variables and n0 the number of replicates performed at center point of the variables . fourteen experiments were run with six replications at the center points to evaluate the pure error . table 1 shows the range and levels of these three factors where the levels ( 1 , 0 and + 1 ) of these culture conditions were chosen in such a way that the center point values ( 0 ) represented the factor levels mostly reported in the literature used for cellulase production . on the basis of the center point values , the low ( 1 ) and high ( + 1 ) levels of the culture condition were determined in such a step change that the center point remains middle values of the low ( 1 ) and high ( + 1 ) range of these factors . furthermore , as per ccd to test all these factors in five ranges including coded value + and , the uncoded values of these respective factors were calculated by solving the following equations : ( 1 ) xi = xix0xi , i = 1,2,3 , , k , where xi is the dimensionless value of an independent variable , xi is the real value of an independent variable , x0 is the value of xi at the center point , and xi is the step change , and where default alpha value for the 3 factor ( = 1.682 ) was chosen as per the ccd design . for fitting the experimental results by response surface regression procedurethe following second order polynomial equation was used : ( 2 ) y = o + i = 1kixi + i = 1kixi2 + ijijxixj , where y is the predicted response , k is the number of factor variables , xi and xj are independent variables , 0 is the offset term , i is the ith linear coefficient , ii is the iththe statistical software package minitab ( release 15.1 , pa , usa ) was used for regression analysis of the experimental data . multiple response or desirabilityfunction is an analysis in which a number of responses ( output variables ) are measured simultaneously for each setting of a group of parameters ( input variables ) and is also called multiresponse analysis . in systems having a large number of input variables and responses , the single response analysis has serious limitations as the optimum conditions for one response may not be suitable or practical for other responses and thus the meaning of optimum becomes unrealistic . the optimal conditions evaluated by this analysis are sometimes called near optimal for all responses . the optimization methodology based on the individual desirability using a desirability functionthese values are combined to determine the composite or overall desirability of the multiresponse system . it was reported earlier that although higher cell growth was achieved at favorable agitation speed , ph , and temperature , at the higher biomass concentration , the cellulase activity is inhibited . similar observation was also obtained in the present study . therefore , in order to optimize the cell growth for maximizing cmcase activity multiple response ( desirability function ) was applied by giving higher weight to enzyme activity as compared to cell growth . for this the following equation was used : ( 3 ) di ( y ^ i ) = { 0 , if y ^ li , ( y ^ ilitili ) ri , if liy ^ ti ,1 , if y ^ ti , where di ( y ^ i ) is desirability function of a response and li and ti are the lower and target values of response measured from experimental data . in the present study , while li for the two responses ( cmcase activity and cell growth ) were 0.104 u / ml and 1.65 mg / ml , respectively , ti values were set at 0.56 u / ml and 2.0 mg / ml , respectively . y ^ i is the value of a response predicted by the second - order polynomial equations generalized before ; ri is the weight of desirability function of a response . in this study , enzyme activity was given higher weight of 2 : 1 ratio as compared to cell growth . the overall desirability function ( d ) in turn was computed as shown below : ( 4 ) d = ( diwi ) 1 / w , where di is individual desirability for the ith response , wi = importance of the ith response , and w = wi . in the present study , wi was taken at 2 : 1 ratio for enzyme activity and cell growth . for solving the desirability function , the statistical software package minitab ( release 15.1 , pa , usa ) was used . in order to validate the model , experiments were performed in triplicate in a batch shake flask and 2 l stirred tank fermentor ( applicon , model bio console adi 1025 ) using optimal levels of culture conditions ( ph 7.2 , 39c , and 121 rpm ) and optimized medium . the laboratory scale bioreactor was operated at optimal levels of culture conditions and aeration rate of 1 vvm and 2 % ( v / v ) inoculum . after 48 h , 1.0 ml of sample was withdrawn and absorbance at od600 nm was measured . the samples were then centrifuged at 10,000 g for 10 min at 4c and supernatant analyzed for enzyme activity . all measurements were carried out in triplicates and results ' averages were taken as response .20 ml of 0.5 m naoh was added to one gram of the powdered wild grass in a 250 ml erlenmeyer flask . then , the mixture was autoclaved at 115c at 15 psi for 10 min . subsequently , the mixture was cooled to room temperature and treated with distilled water and 20 mm sodium phosphate buffer alternatively . final wash was done with sodium phosphate buffer ( 20 mm , ph 6.0 ) . each ablution was followed by centrifugation ( 8,000 g , 10 min ) till the ph became neutral and then the residues were dried in an oven at 70c for 24 h. one gram of substrate was incubated with 8 ml of concentrated phosphoric acid at 50c at 120 rpm for one hour . the slurry was then poured in to 24 ml of chilled acetone and thoroughly mixed . one gram of the pretreated wild grass was taken in a 250 ml flask to which 100 ml of sodium phosphate buffer ( ph 6.0 , 20 mm ) containing yeast extract ( 0.1 % , w / v ) and peptone ( 0.1 % , w / v ) was added . then , 1 ml of isolated b. subtilis cellulase ( 3.3 u / mg , 0.5 mg / ml ) along with 1 ml of z. mobilis inoculum ( 2.110 cells / ml ) was added to the fermentation media . the fermentation was carried out at 120 rpm 30c for three days and the sample was collected for every six hours with the monitoring of various parameters like cell od600 nm , ethanol concentration ( g / l ) , reducing sugar ( g / l ) , and specific activity ( u / mg ) . the ssf experiments were performed for alkali ( naoh ) and acid - acetone - pretreated substrate . batch ssf experiments were carried out in a 2 l lab scale fermenter ( applicon , model bio console adi 1025 ) with a working volume of 1 l. 1 % ( w / v ) of naoh - treated wild grass along with l l of autoclaved fermentation media containing sodium phosphate buffer ( ph 6.0 , 20 mm ) supplemented with yeast extract ( 0.1 % , w / v ) and peptone ( 0.1 % , w / v ) that was added in the fermenter . subsequently , there was addition of 10 ml of b. subtilis cellulase ( 3.3 u / mg , 0.5 mg / ml ) along with 10 ml of z. mobilis inoculum ( 2.110 cells / ml ) into the ssf media . the bioethanol production was performed at 120 rpm , 30c , and an aeration rate kept at 1 vvm which was controlled by a mass flow controller . the batch was run till 72 h with the sample collection at very 6 h interval . there was a constant monitoring of parameters like cell od600 nm , ethanol concentration ( g / l ) , reducing sugar ( g / l ) , and specific activity ( u / mg ) . similar ssf procedure was followed on scaling up the naoh - treated substrate concentration from 1 % ( w / v ) to 5 % ( w / v ) both at shake flask and reactor level . cell growth was determined by measuring absorbance at optical density of 600 nm using a uv - visible spectrophotometer ( perkin elmer , model lambda - 45 ) and the absorbance values were expressed as dry cell weight using a calibration curve of optical density ( od600 ) versus dry cell weight ( g / l ) of the sample . dry cells weight of the centrifuged sample ( 10,000 g for 10 min ) was measured by directly weighing the biomass after drying at 55c to a constant weight . the assay of cellulase was carried out in 100 l of reaction mixture containing 65 l of 2 % ( w / v ) cmc in 50 mm sodium phosphate buffer ( ph 6.0 ) and 35 l of cell - free supernatant and incubated at 45c for 10 min . the cmcase activity was measured by estimating the liberated reducing sugar by the nelson - somogyi procedure . the absorbance was measured at 500 nm using a uv - visible spectrophotometer ( perkin elmer , model lambda - 45 ) against a blank of 2 % ( w / v ) cmc without enzyme . one unit ( u ) of cmcase activity is defined as the amount of enzyme that liberates 1 mole of reducing sugar ( glucose ) per min at 45c in 50 mm sodium phosphate buffer , ph 6.0 . for ethanolcontent estimation , dichromate method was used where ethanol produced was converted to acid by reaction with dichromate . the cell - free culture was diluted 10 times ( reaction volume 10 ml ) to which 2 ml of potassium dichromate ( k2cr2o7 ) ( 3.37 g / 100 ml ) was added and absorbance was measured on a spectrophotometer ( perkin elmer , model lambda - 45 ) at 600 nm . for maximizing cmcase activity , the levels of the three important factors , ph , agitation speed ( rpm ) , and temperature ( c ) , were varied using the central composite design of experiment . table 1 represents the experimental and the model predicted values of cmcase activity along with cell growth , clearly depicting the close agreement of the experimental and predicted values with each other . the second - order response surface model outcomes were analyzed in the form of analysis of variance ( anova ) . tables 2 ( a ) and 2 ( b ) present anova of cmcase activity and cell growth profile of the culture , respectively . the fisher 's f value ( 21.18 ) for cmcase activity in the model owing to regressionis found to be higher than the critical f value ( f0 .059 , 3 = 2.54 ) ( table 2 ( a ) ) , indicating that most of the variations in the response could be explained by the regression model equation for cmcase activity . generally , a large f value with a corresponding small p value indicates a high significance of the respective coefficient . the associated p values are used to judge whether f was large enough to indicate statistical significance or not . the linear and square terms of both the regression models for cmcase activity and cell growth were found to be highly significant at p = 0.000 . in the present study , the model f values of 21.18 ( table 2 ( a ) ) and 37.48 ( table 2 ( b ) ) for cmcase activity and cell growth , respectively , indicate that the respective regression models could explain most of the variation in the responses . these findings confirmed that the second - order polynomial models for cmcase activity and cell growth were adequate in predicting both the responses . these regression model equations are presented below : ( 5 ) y1 = 0.436816 + 0.071256 x1 + 0.146789 x20 .073141 x30 .005283 x12 + 0.218983 x220 .020083 x320 .068413 x1x2 + 0.014319 x1x30 .123355 x2x3 , y2 = 3.18098 + 0.21897 x1 + 0.27103 x2 + 0.50635 x30 .86722 x121 .32722 x220 .53722 x320 .02828 x1x2 + 0.03536 x1x3 + 0.33941 x2x3 , where , y1 = cmcase activity ( u / ml ) , y2 = cell growth ( g / l ) , x1 is ph , x2 is temperature ( c ) , and x3 is agitation speed ( rpm ) . further , to determine significance of the regression coefficients in the two models , the results were subjected to student 's t - test as presented in table 3 . from table 3 , it could be seen that the regression coefficients of linear and quadratic terms for all the factors in the models for cmcase activity and cell growth were found to be highly significant ( p 0.007 ) ; however , the quadratic coefficient due to ph and agitation speed for cmcase activity indicated insignificance on the responses ( p 0.4 ) . from the student 's t - test of cmcase activity , the regression coefficient terms for interaction between temperature and agitation speed were found to be highly important ( p 0.009 ) ; however , interaction effects between ph and temperature revealed slightly less significance ( p 0.095 ) . other coefficient terms in the models did not seem to be have considerable significance ( p 0.7 ) on cmcase activity . in case of cell growth , the regression coefficient terms for interaction between temperature and agitation speed revealed some significance ( p 0.05 ) whereas no significant interaction was observed with other factors on cell growth of the culture . such observations on significance of interaction effects between the variables would have been lost if the experiments were carried out by conventional methods . in order to determine the optimal levels of the variables for maximum cmcase activity , three dimensional response surface plots as shown in figure 1were constructed by plotting the response against any two of the three independent variables and by maintaining the other variable at their middle ( zero ) levels . figure 1 ( a ) representing the effects of temperature and agitation speed on cmcase activity at constant ph ( 7.0 ) demonstrated that although the enzyme activity was found sharply increasing with the temperature , beyond the agitation speed of 190 rpm , a sharp decline of the enzyme activity was observed indicating a strong negative interaction between the factors . figure 1 ( b ) signifying the interaction effect between ph and temperature on enzyme activity at constant agitation speed ( 180 rpm ) showed that the enzyme activity stridently increased with increase of ph when temperature was lower than 40c whereas reverse trend was observed with increase in temperature from 4044c revealing a negative interaction effect between these factors at their higher level . figure 1 ( c ) displayed the effects of ph and agitation speed ( rpm ) on cmcase activity at constant temperature ( 37c ) . the surface plot was found to be curvilinear clearly revealing no significant change in enzyme activity with change in the culture conditions and the optimum was observed near the central values of ph and agitation speed . to illustrate the above mentioned interaction effect between the variables in the study , typical contour plots between temperature and agitation speed and that between ph and temperature are depicted in bottom of the response surface plots of figures 1 ( a ) and 1 ( b ) . in general , the contours in such plots help in proper identification of the type of interactions between test variables ; the surface confined in the smallest curve of such contour diagram can also be used to predict optimum response of the system . hence , from the given plot in figure 1 ( a ) , the corresponding coordinates in the region of the contour diagram gave the optimum values of the respective factors . also , the response surface contour plots of mutual interaction between the variables temperature and agitation speed and that between ph and temperature , figures 1 ( a ) and 1 ( b ) , respectively , were found to be elliptical indicating significant interaction between these pairs of factors . besides the two contour plots showing interaction between the variables , response surface contours drawn between ph and agitation speed in figure 1 ( c ) was circular indicating nonsignificant nature of their interactions . agitation speed is one of the important culture parameters that maintains homogenous conditions and disperses dissolved oxygen into smaller bubble thereby increasing the interfacial area and oxygen mass transfer rate for enhancing both substrate utilization and microbial activity . however , any further increase in the agitation speed more than 121 rpm did not improve the enzyme activity by the culture in the present study , which may be attributed to increased shear stress on the cells thus leading to reduced enzyme production . similar observations are also reported using bacillus amyloliquefaciens , trichoderma reesei , and thermomyces lanuginosus , where cellulase production declines at higher agitation rates . temperature is also one of the most important parameters that influences enzyme activity and is essential for a fermentation process . it was observed that when the culture temperature increased to an optimum level of 39c an enhancement in cmcase activity was achieved . similar observations on enhancement of cellulase activity were reported in other papers where optimum medium temperature for production of cellulase by bacillus subtilis cy5 and bacillus circulans were 40c , and for b. amyloliquefaciens dl - 3 and bacillus pumilus eb3 , it was 37c which is , within the range , as obtained in the present study . however , temperature above and below the optimum level inhibited the cellulase activity by the microorganism probably due to inhibition of the multienzyme complex system of the cell . at low temperature substrate transport across the cells is suppressed and lower product yields are attained . similarly , at higher temperature , the thermal denaturation of enzymes of the metabolic pathway could result in decreased enzyme production . the ph of the growth medium influences many enzymatic reactions by affecting the transport of chemical products and enzymes across the cell membrane . similar finding was also reported by ariffin et al . and rastogi et al . for cellulase enzyme production . at the optimized physical parameters of ph 7.2 , temperature 39c , and agitation speed 121 rpm , the fermentation by bacillus subtilis showed 33 % enhancement in cmcase activity as compared to unoptimized parameters . the maximum cmcase activity obtained using the optimized physical process parameters was 0.57 u / ml which was higher than many other reported values . bacillus sp . produced maximum cmcase activity of 0.074 u / ml and 0.12 u / ml , respectively , under optimized conditions . in another study , brevibacillus sp . reported maximum cellulase activity of 0.02 u / ml under optimum culture conditions . bacillus pumilus eb3 and bacillus megaterium recorded maximum cellulase activities of 0.076 u / ml and 0.102 u / ml , respectively , under optimized conditions in a 2 l stirred tank reactor . in order to determine the optimal levels of each variable for maximizing cmcase activity , the method of desirability function was applied . the desirability function study in this multiple response optimization method shown in figure 2 revealed that the overall desirability functions for cmcase activity and cell growth were close to 1 indicating the fact that the function increases linearly towards the desired target values of the two responses . in addition , individual desirability values of the two responses were calculated ; while the value for cell growth was computed to be 1 with a maximum predicted response of 2.01 mg / ml , the value for cmcase activity was also found to be 1 with maximum predicted value of 0.56 u / ml . thus , using the desirability function method for optimizing both the responses ( discussed earlier ) , optimum values of the culture conditions were estimated to be ph 7.2 , temperature 39c , and agitation speed 121 rpm . the cmcase activity was experimentally verified in batch shake flask and at 2 l stirred tank fermentor using optimized medium and optimum values of physical parameters . the maximum cmcase activity and cell growth by bacillus subtilis as3 was 0.57 u / ml and 2.1 mg / ml in shake flask ( figure 3 ( a ) ) which are in very good agreement with the value predicted by the model ( 0.56 u / ml and 2.01 mg / ml ) . the enzyme activity with unoptimized physical parameters and optimized medium was 0.43 u / ml . this showed 33 % enhancement of cmcase activity after physical process parameter optimization ( table 4 ) . the scale - up of batch cultivation from shake flask to bioreactor containing 1.0 l of the same optimized medium and optimized culture conditions yielded maximum cmcase activity of 0.75 u / ml ( figure 3 ( b ) ) . a significant increase of 32 % was observed due to controlled ph and maintenance of aeration in the fermentor throughout the cultivation which is not possible in shake flask ( table 4 , figure 3 ( b ) ) . shake flask experiments have limitations to control ph and dissolved oxygen level in the broth as compared to the fermentor . it was observed that in shake flask the ph of the culture medium showed variations with initial decline and then increasing trend in consensus with rise in enzyme activity at the end of cultivation ( figure 3 ( a ) ) . ph control during fermentation was reported to be essential for increased cellulase production . in scaleup at 2 l bioreactor level , a maximum activity of 0.75 u / ml was observed with controlled ph at 7.2 after 48 h of fermentation ( figure 3 ( b ) ) . the cell growth also showed a similar profile as cellulase production and reached its highest value at the late log phase ( figure 3 ( b ) ) . the cell growth and cmcase activity data inferred the growth associated production of cellulase . a considerable increase in enzyme activitywas observed in bioreactor as compared to flask level which may be due to the control of ph . the consequences of alkali ( naoh ) and acid - acetone pretreatments were evaluated on wild grass ( 1 % , w / v ) subjected to simultaneous saccharification by b. subtilis cellulase and fermentation by z. mobilis . these ssf trials were investigated to determine the outcome of various pretreatments on enzymatic hydrolysis and , in turn , the best ethanol titre ( g / l ) . in case of alkali ( naoh ) method , maximum ethanol concentration of 0.98 g / l from a reducing sugar content of 1.25 g / l with a yield coefficient of 0.098 ( g of ethanol / g of substrate ) was obtained ( table 5 ) . with acid - acetone pretreatment , an ethanol concentration of 0.93 g / l ) with a yield coefficient of 0.093 ( g / g ) ( table 5 ) . on the basis of ethanol titre ( g / l ) obtained from ssf experiments involving two pretreatments , alkali ( naoh ) treatment was found to be better over acid - acetone technique . consequently , on increasing the wild grass concentration to 5 % ( w / v ) , an ethanol concentration of 7.56 g / l was achieved from a reducing sugar content of 9.08 g / l ( table 5 ) . owing to the controlled conditions of ph and aeration in batch reactor ssf , using 1 % ( w / v ) wild grass with same enzyme and microbial combination , an ethanol titre of 2.23 the ethanol yield ( g of ethanol / g of substrate ) was 0.46 ( table 5 ) . the ssf profile of 5 % ( w / v ) wild grass involving b. subtilis cellulase and z. mobilis showed an interesting relationship between cell growth , specific activity of the enzyme , rate of sugar utilization , and in turn rate of ethanol formation . as evident from figure 4 there has been a sigmoidal increase in cell biomass after 24 h with a decrease after 66 h. during initial hours of fermentation there has not been a sharp increase in cell biomass owing to the acclimatization of the cells for further growth . the specific activity of the saccharifying cellulase was high during the early hours of ssf ( 18 h ) ( figure 4 ) thereby releasing a maximum amount of utilizable sugars for the ready uptake of z. mobilis for its growth and acclimatization . it is also observed that the specific activity of the enzyme decreased gradually during the late hours depicting an inhibition by the sugars released ( 3042 h ) ( figure 4 ) . there was a gradual increase in the amount of reducing sugars ( 18 h ) ( 13.22 g / l ) ( table 5 , figure 4 ) with a substantial decrease after 30 h thereby depicting a sinusoidal behaviour between the rate of sugar utilization and ethanol formation . a gradual decline in sugar concentration after 48 h without any further rise in ethanol concentration indicated its utilization for maintenance and survival of the fermentative microbes . the ethanol formation in batch ssf at reactor level implicated a contrasting relationship between reducing sugar content and activity of bacterial cellulase . as observed from figure 4 , there was a sharp increment in ethanol formation from 24 h to 42 h after which a steady increase till 66 h ( 11.65 g / l ) ( table 5 , figure 4 ) with a decline in the later stages of fermentation occured . thus , on increasing the substrate concentration from 1 % ( w / v ) to 5 % ( w / v ) , a 5.2-fold augmentation in ethanol titre ( g / l ) was witnessed on scaling up the ssf process at reactor level . all these values of ethanol production are comparable with the other reported literature . an ethanol concentration of 0.09 g / l was obtained from 1 % paper sludge waste using z. mobilis . an ssf experiment involving 30 % solid content with commercial cellulase enzyme and z. mobilis as fermentative organism gave an ethanol concentration of 60reactor level aerobic batch fermentation with optimized process conditions offered a maximum ethanol concentration of 0.06 g / l from 1the results demonstrated the effect of physical parameters such as initial ph , agitation ( rpm ) , and temperature ( c ) for cellulase production from bacillus subtilis as3 . central composite design of experiments followed by multiple desirability function was applied for the optimization of cmcase activity and cell growth . among the three independent variables , the maximum activity and cell growth predicted by the model were in consensus with values obtained using optimized medium and optimal values of physical parameters . after optimization , an enhancement in cmcase activity was recorded . on scale - up of cellulase production process with all the optimized conditions in bioreactor , an elevated activity was achieved . consequently , the bacterial cellulase employed for bioethanol production expending pretreated wild grass with zymomonas mobilis yielded a good ethanol titre at shake flask and bioreactor level , respectively . the present study , thus , clearly demonstrated , employing the statistical - based design technique , a significant enhancement in cmcase activity by bacillus subtilis as3 under optimized culture and medium conditions with subsequent usage in bioethanol production .\noutput:\n" }, { "from": "agent", "value": "effect of physical parameters such as initial ph , agitation ( rpm ) , and temperature ( c ) for cellulase production from bacillus subtilis as3 was investigated . central composite design of experiments followed by multiple desirability function was applied for the optimization of cellulase activity and cell growth . the effect of the temperature and agitation was found to be significant among the three independent variables . the optimum levels of initial ph , temperature , and agitation for alkaline carboxymethylcellulase ( cmcase ) production predicted by the model were 7.2 , 39c , and 121 rpm , respectively . the cmcase activity with unoptimized physical parameters and previously optimized medium composition was 0.43 u / ml . the maximum activity ( 0.56 u / ml ) and cell growth ( 2.01 mg / ml ) predicted by the model were in consensus with values ( 0.57 u / ml , 2.1 mg / ml ) obtained using optimized medium and optimal values of physical parameters . after optimization , 33 % enhancement in cmcase activity ( 0.57 u / ml ) was recorded . on scale - up of cellulase production process in bioreactor with all the optimized conditions , an activity of 0.75 u / ml was achieved . consequently , the bacterial cellulase employed for bioethanol production expending ( 5 % , w / v ) naoh - pretreated wild grass with zymomonas mobilis yielded an utmost ethanol titre of 7.56 g / l and 11.65 g / l at shake flask and bioreactor level , respectively ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: population - based and autopsy studies report that the incidence of intracranial aneurysms ( ias ) may be as high as 10 % and peaks in the sixth decade of life . subarachnoid hemorrhages ( sahs ) due to ruptured ias account for 10 % and 40 % of deaths before hospitalization and after a 1 - month hospital stay , respectively . more than 35 % of patients with sah develop major neurological deficits preceding hospital discharge , even if they demonstrated favorable glasgow coma scores . although it is easier to detect unruptured ias with various imaging modalities , it is difficult to predict if or when they will rupture , which poses a dilemma for both patients and physicians . acquired and hereditary risk factors contribute to the multifactorial etiology of unruptured ia , including sex , hypertension , atherosclerosis , alcohol consumption , and smoking . parameters utilized for rupture assessment include aneurysm size , shape , and location , in addition to angle and flow hemodynamics . cumulative arterial wall deterioration as a result of constant remodeling characterized by degeneration and inflammatory cell infiltration lead to ia rupture and subsequent sah . altered arterial wall elastic properties and hypertrophic remodeling might predispose ias to rupture . arterial wall elasticity and intima - media thickness can be estimated non - invasively via ultrasound to indirectly evaluate arterial wall strength . we hypothesized that hypertrophic intimal remodeling and impaired elastic properties detected in the right carotid artery might co - occur with ia rupture and thus may predict an impending ia rupture . a total of 49 patients consecutively admitted with a diagnosis of ia ( n = 23 ) or ruptured ia ( n = 26 ) between january and december 2010 were included in this study . study subjects were screened and removed from the study if they qualified for the following exclusion criteria : history of stroke , heart failure , severe heart valve disease , renal dysfunction , diabetes mellitus ( dm ) , and local or systemic acute infection . the study protocol was designed in accordance with the helsinki declaration and was approved by the institutional ethics committee . written informed consent was obtained from all participants . maximum blood pressure ( bpmax ) was the systolic bp and minimum blood pressure ( bpmin ) was the diastolic bp . blood pressure was measured from the right brachial artery with a sphygmomanometer ( omron hem 705cp , colson ) after a 10 - minute resting period . heart rate and bp were measured just before ultrasound examination , and within the first 3 days following ia rupture to avoid falsely elevated bps from sah - induced vasospasm . ultrasound examinations were performed for patients with ruptured ias within the first 3 days of rupture to avoid sah induced vasospasm and following dsa . specifically , the aplio xg scanner equipped with a 10 mhz linear array transducer ( toshiba medical systems , tokyo , japan ) was used . a pulse repetition frequency of 3 khz with an automatic cutoff filter ranging from 1 to 3 khz was utilized . m - mode ultrasound was performed at a speed of 50 mm / sec . the right common carotid artery ( cca ) the transducer was positioned parallel to the cca such that the lumen s diameter was maximized in the longitudinal plane . maximum ( dmax ) and minimum ( dmin ) internal lumen diameters were measured at 1 to 2 cm proximal to the cca bifurcation in magnified m - mode during systole and diastole . intima - media thickness measurements were taken at this same location , but were derived in b - mode . arterial elastic properties , including distensibility , strain , stiffness index , and elastic modulus , were measured to determine the stress on the right cca wall during diastole and systole . strain was defined as the percent change in cca artery lumen diameter during systole and diastole . the following calculations were performed to determine the aforementioned measures : statistical package for the social sciences for windows ( spss ver .18 , chicago , il , usa ) software was used to analyze all data . correlation analyses were performed with the spearman test . a p - value less than 0.05 was considered significant . the right cca internal diameter was measured by an expert , blinded observer ( a.d . ) . to evaluate inter - observer reliability , minimum and maximum cca internal diameter and distensibility were also calculated by a second observer ( m.i . ) . maximum blood pressure ( bpmax ) was the systolic bp and minimum blood pressure ( bpmin ) was the diastolic bp . blood pressure was measured from the right brachial artery with a sphygmomanometer ( omron hem 705cp , colson ) after a 10 - minute resting period . heart rate and bp were measured just before ultrasound examination , and within the first 3 days following ia rupture to avoid falsely elevated bps from sah - induced vasospasm . ultrasound examinations were performed for patients with ruptured ias within the first 3 days of rupture to avoid sah induced vasospasm and following dsa . specifically , the aplio xg scanner equipped with a 10 mhz linear array transducer ( toshiba medical systems , tokyo , japan ) was used . a pulse repetition frequency of 3 khz with an automatic cutoff filter ranging from 1 to 3 khz was utilized . m - mode ultrasound was performed at a speed of 50 mm / sec . the right common carotid artery ( cca ) the transducer was positioned parallel to the cca such that the lumen s diameter was maximized in the longitudinal plane . maximum ( dmax ) and minimum ( dmin ) internal lumen diameters were measured at 1 to 2 cm proximal to the cca bifurcation in magnified m - mode during systole and diastole . intima - media thickness measurements were taken at this same location , but were derived in b - mode . arterial elastic properties , including distensibility , strain , stiffness index , and elastic modulus , were measured to determine the stress on the right cca wall during diastole and systole . strain was defined as the percent change in cca artery lumen diameter during systole and diastole .18 , chicago , il , usa ) software was used to analyze all data . correlation analyses were performed with the spearman test . a p - value less than 0.05 was considered significant . the right cca internal diameter was measured by an expert , blinded observer ( a.d . ) . to evaluate inter - observer reliability , minimum and maximum cca internal diameter and distensibility were also calculated by a second observer ( m.i . ) . a comparison between unruptured ia and ruptured ia groups in terms of demographics and aneurysm characteristics is provided in table 1 . patients with unruptured ia had a mean age of 47.112.0 years , with ages that ranged from 26 to 68 years . patients with ruptured ia had a mean age of 48.611.5 years , ranging from 31 to 67 years . unruptured ia and ruptured ia characteristics included shape , size , angle , aspect ratio , and bottleneck factor . for the entire study population , unruptured ia and ruptured ia locations included the internal carotid artery ( ica ) in 14 % of cases , the anterior communicating artery ( acoa ) in 20 % of cases , the middle cerebral artery ( mca ) in 41 % of cases , and the vertebral and basilar arteries ( v - b ) in 25 % of of cases ( figures 1 and 2 ) . the unruptured ia group exhibited a decreased mean cca intima - media thickness at 0.520.12 cm vs. 0.610.13 cm for the ruptured ia group ( p = 0.013 ) . however , the unruptured ia group exhibited increased mean cca lumen diameter change ( d ) at 0.70.1 cm as compared to 0.50.1 cm for the ruptured ia group ( p = 0.04 ) ( figures 3 and 4 ) . mean cca stiffness index was greater for the ruptured ia group at 6.00.5 vs. 6.70.5 for the ia group ( p = 0.044 ) . this was also true for the mean cca elastic modulus , as this measure was higher for the ruptured ia group at 0.90.3 compared to the ia group at 0.70.2 ( p = 0.026 ) . mean cca strain was decreased for the ruptured ia group at 6.11.7 vs. 8.11.9 for the ia group ( p = 0.013 ) . this same trend was observed for mean cca distensibility , as the ruptured ia group mean value was lower at 1.80.4 than the ia group at 2.30.5 ( p = 0.024 ) . the risk of rupture per year for patients with asymptomatic ias has been reported at 0.05 % . in population - based studies , , much research has been devoted to studying ias and the factors that facilitate rupture . reduced arterial elasticity was observed in patients with ruptured ias in a recent ex vivo study . patients with ia rupture exhibit decreased arterial wall distensibility compared to those with unruptured ias . this phenomenon is widely accepted , even though one ex vivo study asserted the opposite upon measuring arterial wall distensibility in the anterior cerebral , radial , and dorsalis pedis arteries . moreover , arterial distensibility measurements have been commonly performed on the cca . in agreement with most studies , therefore , we designed an in vivo study using measurements from the right cca , such that our outcomes might aid in advancing the clinical management of patients with unruptured ia . numerous studies have been performed that focused on parameters predicting rupture , such as aneurysm location , size , shape , and angle . ias with an irregular shape and multilobular contours are associated with increased focal stress and distensibility . elliptical ias are more prone to rupture than spherical ias . decreased bottleneck and aspect ratiosare also correlated with increased rupture risk . however , once rupture has occurred , spherical aneurysms become more oval - shaped ; thus , an aneurysm s elliptical quality may not be distinctive of increased rupture risk . a recent study based on biomechanical models of rupture reported that rupture risk is associated with increased aneurysm size . the cutoff value for increased rupture risk was determined to be 10 mm ; however , the vast majority of ias reported in other studies range between 5 to 9 mm . because of the high prevalence of ias less than 10 mm in diameter , it is important to use criteria other than size to determine rupture risk . it has been postulated that rupture occurs in small - sized ias if they rapidly expand . however , surgical interventions are not indicated for small ias , since the rupture risk is relatively low . an experimental study focusing on biomechanical alterations between unruptured ias and ruptured ias showed that patients with greater arterial wall rigidity were more prone to ia rupture . rigidity can be determined by the elastic properties of the arterial wall tissue , and a reduction in elasticity significantly contributes to the pathobiology of ia rupture . it has been widely reported that arterial distensibility with comorbid vasculopathy predisposes patients to abdominal aortic aneurysm formation , dissection , and rupture . these studies asserted that aneurysmal rupture occurred when wall tension exceeded the strength limit of the artery wall . another study evaluating the aneurysmal expansion limit demonstrated a correlation between the extent of distensibility and rupture . increased arterial wall stiffness , loss of elasticity , and decreased perivascular supportmight be associated with vasculopathies resulting from aging , essential hypertension , diabetes mellitus , and vasculitis . intimal remodeling and arterial stiffness might be associated with defects in elastin , collagen , and extracellular matrix . specifically , defective collagen contributes to arterial wall weakness due to decreased wall distensibility , which facilitates ia rupture . hemodynamic studies also highlight parameters that modulate aneurysmal wall rigidity , growth , and rupture . diminished arterial wall elasticity has been associated with a large discrepancy between diastolic and systolic bp ( p ) , which contributes to increased arterial resistance . this phenomenon of continuous , increased mechanical loading augments ia wall stress , which facilitates ia fatigue and rupture . our results were in accordance with these data , as a high p was associated with ia rupture . overall , our results are in parallel with most in vivo studies performed on the extracranial arteries . we found that patients with ia rupture exhibit impaired cca elasticity , which is associated with hypertrophic remodeling not observed in unruptured ias . impaired distensibility might not be completely attributed to ia rupture , as vasculopathy may also contribute to ia rupture . our data suggest that decreased cca elasticity and increased intima - media measurements might be associated with an increased likelihood of ia rupture , which may be helpful in decision - making for ia clinical management . the study sample size was small , lacked a healthy control group , and no long - term follow - up was performed . the study sample size was small , lacked a healthy control group , and no long - term follow - up was performed . our findings demonstrate that patients with ruptured ias exhibit impaired cca wall distensibility and increased intima - media thickness , which suggests hypertrophic remodeling . thus , determining cca distensibility and intima - media thickness might be useful in determining whether an ia may rupture in the future . to better determine whether cca elastic properties predispose patients to ia rupture , a larger prospective study design might be more informative , as the development of rupture may be correlated with changes in these factors over time . it is our hope that developing a set of predictive parameters for ia rupture will guide clinical management so to prevent complications such as subarachnoid hemorrhage .\noutput:\n" }, { "from": "agent", "value": "backgrounda risk factor assessment that reliably predicts whether patients are predisposed to intracranial aneurysm ( ia ) rupture has yet to be formulated . as such , the clinical management of unruptured ia remains unclear . our aim was to determine whether impaired arterial distensibility and hypertrophic remodeling might be indicators of risk for ia rupture.material / methodsthe study population ( n = 49 ) was selected from consecutive admissions for either unruptured ia ( n = 23 ) or ruptured ia ( n = 26 ) from january to december 2010 . hemodynamic measures were taken from every patient , including systolic and diastolic blood pressure using a sphygmomanometer . unruptured ia and ruptured ia characteristics , including aneurysmal shape , size , angle , aspect ratio , and bottleneck factor , were measured and calculated from transverse brain ct angiography images . with ultrasound , the right common carotid artery intima - media thickness was measured , as well as the lumen diameter during systole and diastole . arterial wall strain , distensibility , stiffness index , and elastic modulus were calculated and compared between patients with unruptured ias and ruptured ias . a p - value less than 0.05 was considered statistically significant.resultsgeneral demographic data did not differ between patients with unruptured ias and ruptured ias . greater mean intima - media thickness ( p = 0.013 ) , mean stiffness index ( p = 0.044 ) , and mean elastic modulus ( p = 0.026 ) were observed for patients with ruptured ias . moreover , mean strain ( p = 0.013 ) and mean distensibility ( p = 0.024 ) were decreased in patients with ruptured ias.conclusionspatients with ruptured ias demonstrated decreased arterial distensibility and increased intima - media thickness at the level of the carotid arteries . by measuring these parameters via ultrasound , it may be possible to predict whether patients with existing ias might rupture and hemorrhage into the subarachnoid space ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: myopia is a worldwide common ocular disorder and the prevalence rate of myopia was reported to be 26.7 % and 26.2 % in the handan eye study and the beaver dam study , respectively . during the past decades , laser in situ keratomileusis ( lasik ) has been developed as one of the most important techniques of refractive correction in myopic eyes . however , there have been reports of keratectasia developed after lasik , possibly resulting from thickness and biomechanical changes of the cornea . understanding of the corneal biomechanical properties in myopic eyes might help refractive surgeons identify eyes at risk of developing keratectasia after refractive surgery . although measurement of corneal thickness has been proposed to be a useful parameter for the clinical identification of keratoconus , our knowledge about corneal properties is far from complete . recently , the ocular response analyzer ( ora , reichert ophthalmic instruments , depew , ny , usa ) has been developed to measure in vivo corneal biomechanical properties , which has been reported to be useful in the differentiation of healthy and diseased corneas . however , variations of corneal biomechanical properties , which may confound the detection of cornea disease , have been shown in healthy subjects . andconflicting data regarding the relationship between myopia and corneal hysteresis has been reported in previous studies . while some studies show that lower ch was associated with longer axial length , a number of studies reported that no significant relationship between myopia status and ch was detected . thus , controversies exist regarding the association between corneal biomechanical properties and myopic status . in view of the clinical importance of corneal hysteresis and the controversies about the relationship between corneal hysteresis and myopic status , we aimed to investigate the potential factors that affect the corneal biomechanics in healthy myopic eyes . one hundred and forty - six chinese healthy myopic subjects with a spherical equivalent less than 0.5 diopters ( d ) were consecutively recruited from the refractive surgery clinic of joint shantou international eye center . all the included subjects received a full ophthalmic examination including the measurement of visual acuity , refraction , central corneal thickness ( a - ultrasound pachymeter ; reichert ophthalmic instruments , depew , ny , usa ) , axial length ( iolmaster ; carl zeiss meditec , dublin , ca ) , and a dilated fundus stereoscopic examination . none of the included eyes had any concurrent ocular disease other than a refractive error . subjects with best corrected visual acuity less than 20/20 , intraocular pressure over 21 mmhg , positive family history of glaucoma , contact lens used , ocular surgery , glaucoma , or diabetes were excluded . the study was conducted in accordance with the ethical standards stated in the declaration of helsinki and approved by the local clinical research ethics committee . the principle of ora has been described elsewhere . in brief , ora works by pushing a precisely metered collimated - air - pulse onto the surface of the cornea . it causes the cornea to move inwards , past applanation , and into a slight concavity and then return to its normal configuration after the air pump shuts off and as the pressure decreases . during the entire 20 - millisecond measurement process , two independent pressure values ( p1 and p2 ) derived from the inward and outward applanation eventsfour main parameters including corneal hysteresis ( ch ) , corneal resistance factor ( crf ) , cornea - compensated intraocular pressure ( iopcc ) , and goldmann - correlated intraocular pressure ( iopg ) are provided by the device . according to the manufacturer , ch is thought to be the quantitative measurement of viscous damping in the corneal tissue while crf is a measurement of the cumulative effects of both the viscous and elastic resistance . to ensure accurate measurement , the ora software ( software version 2.02 , reichert ophthalmic instruments , depew , ny , usa . ) provides a quality check score ( waveform score , ranging from 0 to 10 ) based on the measurement curves . disqualified measurements ( the waveform score less than 5 ) and irreproducible values were discarded and retaken . one - sample kolmogorov - smirnov test was used to evaluate if each parameter had a normal distribution . univariate and multivariate regression analyses were performed to determine the effects of axial length / refractive error , cornea curvature , age , iop , and cct on the measurements of corneal biomechanics . eleven subjects were excluded because of repeatable visual field defects ( 4 ) and unacceptable ora measurements ( 7 ) . as a result , 135 eyes from 135 subjects were finally included in the analysis . the mean age , axial length , and spherical equivalent were 23.254.58 years ( range , 18 to 40 ) , 25.631.07 mm ( range , 23.25 to 29.45 ) , and 5.052.02 d ( range , 1 to 13.25 d ) , respectively . all parameters included in the univariate regression analysis were found to have a normal distribution ( one - sample kolmogorov - smirnov normality test , all with p 0.59 ) . axial length , spherical equivalent , cct , and iopcc were significantly correlated with ch ( all with p 0.006 ) . both iopcc and cct were significantly correlated with crf ( r = 0.203 , p = 0.018 and r = 0.521 , p 0.001 , resp . ) . crf did not vary significantly with age , axial length , or spherical equivalent . figure 2 presents the relationship between ch , crf , and age . in the multivariate analysis , axial length , cct , and iopccmean ch decreased by approximately 0.23 mmhg ( p = 0.014 ) for every 1 mm greater axial length and by approximately 0.24 mmhg ( p 0.001 ) for every 10 m thinner cct . both cct and iopcc were independently and significantly associated with crf ( table 4 ) . in the present study , we assessed the determinants of corneal biomechanics in healthy myopic subjects . we found that ch but not crf and cct decreased with increasing degree of myopia . by using multivariate analysis , our results indicated that decreased ch was significantly associated with increasing degree of myopia and thinner cct independent of iop level . associations between ch , crf , and cct have been investigated . significant and positive relationships between ch , crf , and cct were reported in most of the previous studies . in concordance with previous reports , we found that cct was significantly associated with both ch and crf . moreover , cct was found to be the most prominent predictor for variations of ch and crf . as ch and crfare thought to be the measurements of viscous damping and overall elastic resistance of the cornea , one would not feel surprised to find significant associations between ch , crf , and cct . the current results indicate that evaluation of ch and crf should be interpreted in light of cct . previous studies have reported the association between ch and refractive status in healthy subjects . although no significant correlation was detected between ch and refractive error in some of the previous studies , most of the studies reported that ch was significantly associated with refractive error or axial length . reported that longer axial length was significantly associated with lower corneal hysteresis in chinese children . in another study by shen et al . , refractive errors of spherical equivalent were found to be significantly correlated with ch in 135 normal chinese adults . in 293 healthy spanish children , bueno - gimeno et al. found that lower levels of ch were associated with longer axial length . in a recent study , a negative and weak correlation between axial length and ch was reported in 312 eyes of 177 spanish healthy subjects . in a population - based study , narayanaswamy et al . reported that ch was significantly influenced by axial length in 1136 chinese adults . consistent with most of the previous studies , we found a significant relationship between ch and axial length / refractive error in 135 chinese myopic subjects . in the present study , ch was significantly correlated with axial length / refraction , cct , and iopcc in the univariate analysis . thus , analyzing these factors with multivariate analysis is crucial in determining their relative effects on measurement of ch . by using the multivariate regression analysis , we found that axial length , cct , and iopcc were significantly associated with ch . the decrease of ch with increased axial length could be explained by the stretch of the periphery sclera observed in myopic eyes . due to elongation of the globe , the cornea is also stretched which may result in decrease of viscoelastic properties observed in the present study . further studies are warranted to investigate the underlying mechanism for the association between myopia and ch . decrease of ch and crf has been observed in eyes after photorefractive keratectomy ( prk ) and lasik . moreover , the amount of biomechanical change was found to be associated with the amount of myopic correction and different flap creation techniques . although the clinical significance of alteration in corneal biomechanics has not been well studied , previous studies have shown that keratoconic eyes had significantly lower ch compared with control eyes . these results indicate that assessment of corneal biomechanics may provide additional information on keratoconus screening and grading . previous studies have already reported the usefulness of corneal biomechanics in the differentiation of healthy and diseased corneas . in the present study , as decreased ch was found to be associated with increasing degree of myopia , evaluation of corneal biomechanics in corneal disorders should take axial length into consideration . interestingly , axial length was found to be associated with ch but not with crf in the current study . according to the manufacturer , ch is a measurement of viscous damping in the corneal tissue while crf is a measurement of the overall elastic resistance . as ch and crfare both generated from p1 and p2 ( ch = p1 p2 , crf = p10 .7 p2 ) , they are both expected to be influenced by viscoelastic changes . however , our findings in the present study indicated that the change of ch may be independent of crf . although the exact underlying mechanism for the present finding is not clear , our results were similar to findings of previous studies . shen et al . reported that ch but not crf was significantly correlated with refractive errors in 135 normal chinese adults . in a recent study , wong and lam also reported that axial length was significantly associated with ch but not with crf . as the differences between ch and crf have not been fully understood , these findings indicated that further research is needed to investigate precisely what biomechanical properties are represented by ch and crf . in the current study , ch was significantly decreased by increasing degree of myopia without significant changes of crf . our results indicated that the myopia - related structural change of ch may be independent of crf . age - related changes of the corneal structure have been observed in previous histological studies . it has been reported that interfibrillar spacing reduced with age and collagen fibril cross - linking increased with age . the relationship between age and in vivo corneal biomechanical properties has been investigated . reported that age was negatively and significantly correlated with ch in 204 normal eyes of 204 healthy japanese volunteers ( age range , 19 to 89 years ) . in another study , kotecha et al . also found that both ch and crf were negatively associated with age . in contrast , we did not detect a significant correlation between ch , crf , and age in our study population . one possible explanation is that the age range in our study is relatively narrow . of note , most of the subjects included in our study are young myopic subjects ( 95 % confidence intervals for age : 22.3523.69 years ) . in conclusion , both ch and crfa clinical assessment of cornea biomechanical properties should be interpreted in the context of cct and the myopic status .\noutput:\n" }, { "from": "agent", "value": "purpose . to determine the corneal biomechanical properties by using the ocular response analyzer and to investigate potential factors associated with the corneal biomechanics in healthy myopic subjects . methods . 135 eyes from 135 healthy myopic subjects were included in this cross - sectional observational study . cornea hysteresis ( ch ) , corneal resistance factor ( crf ) , cornea - compensated intraocular pressure ( iopcc ) , and goldmann - correlated intraocular pressure ( iopg ) were determined with the reichert ocular response analyzer ( ora ) . univariate and multivariate regression analyses were performed to investigate factors associated with corneal biomechanics . results . the mean ch and crf were 9.82 1.34 mmhg and 9.64 1.57 mmhg , respectively . in univariate regression analysis , ch was significantly correlated with axial length , refraction , central corneal thickness ( cct ) , and iopg ( r = 0.27 , 0.23 , 0.45 , and 0.21 , resp . ; all with p 0.015 ) , but not with corneal curvature or age ; crf was significantly correlated with cct and iopg ( r = 0.52 and 0.70 , resp . ; all with p < 0.001 ) , but not with axial length / refraction , corneal curvature , or age . in multivariate regression analysis , axial length , iopcc , and cct were found to be independently associated with ch , while cct and iopg were associated with crf . conclusions . both ch and crf were positively correlated with cct . lower ch but not crf was associated with increasing degree of myopia . evaluation of corneal biomechanical properties should take cct and myopic status into consideration ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: globally , the number of people living with hiv is estimated to be nearly 33.4 million as per year 2008 data . number of estimated people with newly infected hiv and aids - related death stood at 2.7 million and 2.0 million . nearly , 40 % of new hiv infection was among the age group of 15 - 24 years . in india , overall hiv prevalence among different population groups continues to reflect the concentrated epidemic situation in the country with 2.3 million people living with hiv / aids and estimated adult prevalence of 0.34 % ( 0.25 - 0.43 % ) . the epidemic is greater in urban areas than rural areas , greater among males than females , decreases with increasing education level , and is found to be highest among women whose spouses work in transport industry . as majority of the population in indiais considered to be free from infection , comprehensive preventive strategies would continue to be the main pillars of action of stakeholders in controlling disease progression . information education ( iec ) / behavior change communication ( bcc ) is one such critical element under this strategy . therefore , it is imperative to continue to gauge the level of hiv / aids knowledge at regular interval so as to provide feedback to planners for fine tuning the educational activities . with this background , a study was conducted to assess level of knowledge regarding hiv / aids among first year professional students in a health university , india for the admission year 2009 . university of health sciences , rohtak ( haryana ) has a sanctioned seats of 150 ( mbbs ) , 60 ( nursing ) and 60 ( pharmacy ) at undergraduate level , in addition to post - graduation and other para - medical courses . it is one of the premiere teaching and training public institution of northern india that provides specialist 's tertiary care services to patients largely belonging to lower / middle socio - economic strata of the society with rural and urban background . the attached medical college hospital caters to an average daily out - patient ( opd ) attendance of more than 5,000 patients and 80,000 annual admissions supported by near about 1,750 in - patient beds . this cross - section descriptive study was undertaken using pre - designed , pre - tested , anonymous , self - administered , semi - structured questionnaire among available 129 , 53 and 55 first - year mbbs , nursing and pharmacy students in the age - group of 17 - 19 years on 1 , 5 and 7 oct 2009 , respectively . remaining professional seats were either vacant or students were absent on the day of data collection , and hence , could not be covered . after explaining study objective , seeking informed verbal consent and ensuring confidentiality , students were given 45 minutes to complete the questionnaire without mutual consultation under the supervision of investigator . students were given the option to withdraw from the study any time during the data collection without any fear or obligation , if they felt to do so ; however none of them refused to participate . they were requested to scrutinize the questionnaire for completeness before return and all doubts clarified subsequently . it is noted that students were not formally exposed to topic in the university prior to conduct of study at any forum . the study variables were related to demography , gender and native place ; professional stream ; full form and difference between hiv / aids , routes of transmission , methods of prevention , behavioral risk category , opportunistic infection , and anti - retroviral therapy , etc . data entry and management were carried out using ms excel sheet and software statistical package ( spss - 16 ver . ) . analysis was carried out by calculating proportion , chi - square test with p value shown against statistically significant ( p 0.05 ) items only and results depicted according to professional streams . out of the total 237 students , there were 123 ( 51.9 % ) females and 103 ( 44.0 % ) students from the rural native place . a majority of students were able to correctly write the full form of aids ( 95.8 % ) in comparison to hiv ( 72.6 % ) and the difference between the two terminologies were known to 87.6 % , 81.1 % and 70.9 % of mbbs , nursing and pharmacy students , respectively . all four common routes of transmission of infection and methods of prevention were known to majority of the lot [ table 1 ] . however , injecting drug users ( idu ) and truck driver as a risk category was correctly reported by 67.5 % and 55.3 % students only , whereas 35.9 % incorrectly mentioned that smoking is a risk factor for acquiring infection . a statistically significant proportion of mbbs followed by nursing and pharmacy students were aware that infection does not spread by social activities like handshake / or playing nor mosquito bite . however , low level was ascertained with regard to items related to non - curability of infection ( 57.4 % ) and availability of anti - retro viral therapy ( 27.4 % ) . a cross - sectional descriptive study was undertaken among first - year professional ( mbbs , nursing and pharmacy ) students in a health university in india to determine level of hiv / aids awareness . in our study , all the students were aware of the terms hiv / aids , however higher proportion could write correctly the full form of aids ( 95.8 % ) in comparison to hiv ( 72.6 % ) with a statistically significant difference ( p 0.05 ) noted between the three professional streams . national behavioral surveillance survey ( bss ) conducted on 78,916 indian youths ( 15 - 24 years ) by national aids control organization ( naco ) also reported higher proportion being familiar with the terminology aids ( 86 % ) than hiv ( 72 % ) . most of the youth who were aware of hiv / aids also knew that hiv / aids could be transmitted through unprotected sexual contacts ( 92 % ) , transfusion of infected blood ( 95 % ) and sharing of used / infected needles ( 94 % ) . more than two - fifths of the youths could correctly identify three common misconceptions on transmission of hiv / aids . similar observations were noted in this study albeit with comparatively lower proportion reporting infected blood transfusion ( 81.4 % ) as a risk for acquiring infection . similar and / or higher level of correct knowledge with regard to routes of transmission , prevention , and myths / misconception was recorded in this study when compared to other studies conducted in india or at international platform . in a south indian study conducted on first year medical students , it was noted that 25.7 % believed that mosquitoes bite could transmit infection while this study recorded 16.9 % among all students . this wrong belief was present among 28.3 % , 25.5 % and 8.5 % of nursing , pharmacy and mbbs students respectively ( p 0.05 ) . the difference between hiv / aids was known to 82.3 % of students in this study whereas it was 54 % in university students at kazakhstan . in an another study conducted in nigeria and delhi , proportion of respondents who were aware about existence of anti - retroviral drugs for hiv / aids was 52.6 % and 28.6 % respectively . present study recorded 27.4 % for the same indicator inspite of availability of free art in india since 2004 . similar to our study , researcher in china also reported higher hiv / aids knowledge amongst medical students in comparison to non - medical students . the students in various professional streams pass a highly competitive exam to get admission in this prestigious university , and hence , may have a higher level of knowledge . however , with immediate educational background of students being similar ( 10 + 2 ) , a clear difference in level of knowledge was noted among three professional streams in the present study . ignorance and erroneous beliefs may impact an individual to behave and communicate in a particular manner . but there is ample opportunity in enhancing comprehensive knowledge , instilling positive attitude and changing behavior amongst students during their period of training in the institute with higher attention required on pharmacy and nursing students . although current study is limited to gauge the depth of knowledge it did not dwell upon other important factors related to attitude , behavior or practices . to conclude , the main focus of communication activities in the country till few years has been on informing community about hiv / aids , risk of transmission , methods of prevention and promoting good practices , however as this study points out that educational endeavors could be broadened to lay focus on myths / misconception , opportunistic infection and availability of anti - retroviral therapy also .\noutput:\n" }, { "from": "agent", "value": "objective : to determine level of hiv / aids knowledge among first - year mbbs , nursing and pharmacy students of a health university.materials and methods : a pre - designed , pre - tested , anonymous self - administered , semi - structured questionnaire was circulated among available 129 , 53 and 55 first - year mbbs , nursing and pharmacy students during oct 09 . data entry , management and analysis were carried out using ms excel and software statistical package.result : out of the total 237 students , there were 123 ( 51.9 % ) female and 103 ( 44.0 % ) students from rural native place . a majority of students were able to correctly write the full form of aids ( 95.8 % ) in comparison to hiv ( 72.6 % ) and the difference between two terminologies were known to 87.6 % , 81.1 % and 70.9 % of mbbs , nursing and pharmacy students , respectively . all four common routes of transmission of infection and methods of prevention were known to majority of the lot . however , injecting drug users ( idu ) and truck driver as a risk category was correctly reported by 67.5 % and 55.3 % students , whereas 35.9 % incorrectly mentioned that smoking is a risk factor for acquiring infection . a statistically significant ( p < 0.05 ) proportion of mbbs followed by nursing and pharmacy students were aware that infection neither spreads by social activities like handshake / playing nor by mosquito bite . however , low level was ascertained with regard to items related to non - curability of infection ( 57.4 % ) and availability of anti - retro viral therapy ( 27.4 % ) . conclusion : overall high level of knowledge was recorded in the present study with a difference noted among students in three professional streams ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the incidence of bcc is about 80 per 100,000 inhabitants each year for germany and reaches 884 in australia . the incidence of scc reaches 2.3 for the netherlands and 387 for australia . despite all efforts in skin cancer campaigns , there is a subpopulation of patients presenting with giant nmsc . by definition , they are also a great challenge considering surgical treatment . we analyzed our data from 2008 to 2011 for giant bcc and scc . we analyzed data from the files of the department of dermatology and allergology , academic teaching hospital dresden - friedrichstadt , germany . the hospital primarily cares for patients in eastern saxony , but patients from neighboring states brandenburg , thuringia , and saxony - anhalt also belong to the catchment area of the hospital . surgical risk was assessed by american society of anesthesiology ( asa ) physical status classification system . the asa differentiates six scores : a normal healthy patient.a patient with mild systemic disease.a patient with severe systemic disease.a patient with severe systemic disease that is a constant threat to life.a moribund patient who is not expected to survive without the operation.a declared brain - dead patient whose organs are being removed for donor purposes . a normal healthy patient . a patient with severe systemic disease that is a constant threat to life . a moribund patient who is not expected to survive without the operation . a declared brain - dead patient whosefollow - up was performed according to the german guidelines once a year in cooperation with outpatient dermatologists . demographics , treatment , and outcome of patients with giant basal cell carcinoma demographics , treatment , and outcome of patients with giant squamous cell carcinoma during the 3 - year period , about 2,500 nmscs were treated at the department of dermatology and allergology based on published data of the regional tumour centre , dresden . we identified a total of 20 patients , 10 with giant bcc and 10 with giant scc . the frequency of giant nmsc among our patients was estimated as 0.4 % for each tumor entity . the gender distribution was different in both groups : 80 % of giant bcc patients were female . the age distribution was not different between the two groups , i.e. , 81.58.5 ) years ( mean standard deviation ) for bcc and 79.511.4 years for scc . a rough estimation of mean delay was 7.53.1 years ( bcc ) and 2.11.2 years ( scc ) , respectively . the bccs were localized on the scalp ( 6 ) , the extremities ( 3 ) , and the abdominal skin ( 1 ) . sccs were localized on the scalp ( 8 ) , the lower leg ( 1 ) , and the hand ( 1 ) . the size was 35.065.8 cm ( bcc ) and 38.076.0 cm ( scc ) . two patients with scc presented with myiasis . among the scalp tumors , scull infiltration was suspected in preoperative imaging in four sccs , in one patient with cranial infiltration . a single scc patient presented with two cutaneous satellite metastases at the first visit . for tnm classification [ table 3 ] . demographics and tnm classification of patients with giant nmsc bccs were classified either basosquamous ( metatypic ; 4x ) , two with perineural infiltration , or nodular ( 6x ) . thirteen of 20 patients were classified 3 ( 65 % ) . comparing bcc and scc , the rate of asa 3 was 80 % and 60 % , respectively . all patients had a detailed clinical examination , imaging to exclude metastatic spread , and laboratory investigations as needed . imaging techniques had been selected on an individual base with diagnostic ultrasound as primary technique , and high - resolution x - ray and magnetic resonance imaging when necessary . for scalp tumors with suspicion of scull infiltration , cranial computerized tomography ( ct ) and vascular ct were used . surgery has been performed in general anaesthesia in five ( bcc ) and six ( scc ) patients , respectively . blood transfusions were necessary in five patients , who had pre - existent anemia [ tables 1 and 2 ] . all bccs were excised with delayed mohs technique to assess r0 resection with tumor - free surgical margin [ table 1 ] . r0 resection was achieved in all but one patient with a large metatypic bcc in a longstanding leg ulcer . defect closure was realized with rotational flaps in most cases [ figures 1 and 2 ] . neoadjuvant chemoimmune therapy with capecitabine and interferon - was performed in one patient with an advanced metatypic bcc of the hand to reduce the tumor mass . capecitabine 950 mg m body surface on days 114 was combined with interferon alpha 33 miou s.c . after three courses , delayed mohs surgery was performed and the defect was closed by a pedicled ulnar myocutaneous flap based on superior ulnar collateral artery . during follow - up , this patient developed cutaneous metastases ( primary tumor of the hand , metastases on the ipsilateral arm ) treated by palliative radiotherapy . giant metatypic ( basosquamous ) basal cell carcinoma of the scalp ; ( a ) clinical presentation ; ( b ) defect after complete excision ; ( c ) preparation of dual rotational flaps ; ( d ) eight days after surgery giant basal cell carcinoma of the scalp ( a ) defect after tumor removal and preparation of windmill flaps ; ( b ) defect closure ; ( c ) seven days after surgery in one scc patient , no major surgery was possible because of significant comorbidities ( chronic lymphatic leukemia with anemia needing regular transfusions , colon cancer , and heart disease ) . the patient refused any treatment of his skin cancer except the tumor - associated myiasis causing repeated bleeding . another patient with a giant scc of his left hand was referred to our hand surgeons for second opinion . eventually , he denied amputation . palliative radiotherapy was performed . in six of the remaining eight patients , delayed mohs surgery achieved r0 resection status . = 4 ) or split skin mesh graft transplantation in sandwich technique , in two patients in combination with osmotic tissue expanders [ figures 36 ] . surgery was realized in cooperation with the neurosurgery unit in a multiple - step approach . just before the last operationdesmoplastic squamous cell carcinoma of the scalp ; ( a ) clinical presentation of an ill defined nodular tumor ; ( b ) defect after mohs delayed surgery ; ( c ) preparation of a rotational flap ; ( d ) defect closure giant squamous cell carcinoma of the scalp ; ( a ) clinical presentation ; ( b ) after complete excision preparation of the outer tabula by diamond drill ; ( c ) defect closure was achieved by combined tissue advancement and extension . the primary defect has already been closed ; ( d ) five days after surgery giant tricholemmal squamous cell carcinoma ; ( a ) clinical presentation ; ( b ) osmotic expander ; ( c ) implantation of two expanders in the occipital region ; ( d ) after 6 weeks of tissue expansion with a final volume of 300 ml each giant squamous cell carcinoma of the scalp ; ( a ) ulcerated , ill - defined tumor ; ( b ) after complete excision with removal of periost and partial removal of the outer tabula . only some minor bleedings can be seen to feed the transplant ; ( c ) sandwich transplantation : elastin - collagen template was placed above the bone and a split skin mesh - graft transplant was fixed above in the same session ; ( d ) stable transplant after 8 days among all 20 patients , there was a single patient with primary failure of split skin mesh graft . two patients with high - risk scalp tumors were treated with adjuvant combined cetuximab / radiotherapy . targeted therapy with monoclonal anti - epidermal growth factor receptor ( egfr ) antibody cetuximab ( erbitux ; bristol - meyers sqibb ) was started with a loading dose of 400 mg / m , thereafter 250 mg / m was given once a week for 6 weeks . , 4 mg dimetindene maleate i.v . , 50 mg ranitidine i.v . and 8 mg ondansetron p.o . one traffic accident and a death related to chronic lymphatic leukemia . in the bcc group , one female patient died from a heart attack . demographics , treatment , and outcome of patients with giant basal cell carcinoma demographics , treatment , and outcome of patients with giant squamous cell carcinoma during the 3 - year period , about 2,500 nmscs were treated at the department of dermatology and allergology based on published data of the regional tumour centre , dresden . we identified a total of 20 patients , 10 with giant bcc and 10 with giant scc . the frequency of giant nmsc among our patients was estimated as 0.4 % for each tumor entity . the gender distribution was different in both groups : 80 % of giant bcc patients were female . the age distribution was not different between the two groups , i.e. , 81.58.5 ) years ( mean standard deviation ) for bcc and 79.511.4 years for scc . a rough estimation of mean delay was 7.53.1 years ( bcc ) and 2.11.2 years ( scc ) , respectively . the bccs were localized on the scalp ( 6 ) , the extremities ( 3 ) , and the abdominal skin ( 1 ) . sccs were localized on the scalp ( 8 ) , the lower leg ( 1 ) , and the hand ( 1 ) . the size was 35.065.8 cm ( bcc ) and 38.076.0 cm ( scc ) . two patients with scc presented with myiasis . among the scalp tumors , scull infiltration was suspected in preoperative imaging in four sccs , in one patient with cranial infiltration . a single scc patient presented with two cutaneous satellite metastases at the first visit . for tnm classification [ table 3 ] . bccs were classified either basosquamous ( metatypic ; 4x ) , two with perineural infiltration , or nodular ( 6x ) . thirteen of 20 patients were classified 3 ( 65 % ) . comparing bcc and scc , all patients had a detailed clinical examination , imaging to exclude metastatic spread , and laboratory investigations as needed . imaging techniques had been selected on an individual base with diagnostic ultrasound as primary technique , and high - resolution x - ray and magnetic resonance imaging when necessary . for scalp tumors with suspicion of scull infiltration , cranial computerized tomography ( ct ) and vascular ct were used . surgery has been performed in general anaesthesia in five ( bcc ) and six ( scc ) patients , respectively . blood transfusions were necessary in five patients , who had pre - existent anemia [ tables 1 and 2 ] . all bccs were excised with delayed mohs technique to assess r0 resection with tumor - free surgical margin [ table 1 ] . r0 resection was achieved in all but one patient with a large metatypic bcc in a longstanding leg ulcer . defect closure was realized with rotational flaps in most cases [ figures 1 and 2 ] . neoadjuvant chemoimmune therapy with capecitabine and interferon - was performed in one patient with an advanced metatypic bcc of the hand to reduce the tumor mass . capecitabine 950 mg m body surface on days 114 was combined with interferon alpha 33 miou s.c . after three courses , delayed mohs surgery was performed and the defect was closed by a pedicled ulnar myocutaneous flap based on superior ulnar collateral artery . during follow - up , this patient developed cutaneous metastases ( primary tumor of the hand , metastases on the ipsilateral arm ) treated by palliative radiotherapy . giant metatypic ( basosquamous ) basal cell carcinoma of the scalp ; ( a ) clinical presentation ; ( b ) defect after complete excision ; ( c ) preparation of dual rotational flaps ; ( d ) eight days after surgery giant basal cell carcinoma of the scalp ( a ) defect after tumor removal and preparation of windmill flaps ; ( b ) defect closure ; ( c ) seven days after surgery in one scc patient , no major surgery was possible because of significant comorbidities ( chronic lymphatic leukemia with anemia needing regular transfusions , colon cancer , and heart disease ) . the patient refused any treatment of his skin cancer except the tumor - associated myiasis causing repeated bleeding . another patient with a giant scc of his left hand was referred to our hand surgeons for second opinion . eventually , he denied amputation . palliative radiotherapy was performed . in six of the remaining eight patients , delayed mohs surgery achieved r0 resection status . defect closure was realized by rotation or transposition flaps ( n = 4 ) or split skin mesh graft transplantation in sandwich technique , in two patients in combination with osmotic tissue expanders [ figures 36 ] . surgery was realized in cooperation with the neurosurgery unit in a multiple - step approach . just before the last operationdesmoplastic squamous cell carcinoma of the scalp ; ( a ) clinical presentation of an ill defined nodular tumor ; ( b ) defect after mohs delayed surgery ; ( c ) preparation of a rotational flap ; ( d ) defect closure giant squamous cell carcinoma of the scalp ; ( a ) clinical presentation ; ( b ) after complete excision preparation of the outer tabula by diamond drill ; ( c ) defect closure was achieved by combined tissue advancement and extension . the primary defect has already been closed ; ( d ) five days after surgery giant tricholemmal squamous cell carcinoma ; ( a ) clinical presentation ; ( b ) osmotic expander ; ( c ) implantation of two expanders in the occipital region ; ( d ) after 6 weeks of tissue expansion with a final volume of 300 ml each giant squamous cell carcinoma of the scalp ; ( a ) ulcerated , ill - defined tumor ; ( b ) after complete excision with removal of periost and partial removal of the outer tabula . bleeding was stopped by bony wax . only some minor bleedings can be seen to feed the transplant ; ( c ) sandwich transplantation : elastin - collagen template was placed above the bone and a split skin mesh - graft transplant was fixed above in the same session ; ( d ) stable transplant after 8 days among all 20 patients , there was a single patient with primary failure of split skin mesh graft . two patients with high - risk scalp tumors were treated with adjuvant combined cetuximab / radiotherapy . targeted therapy with monoclonal anti - epidermal growth factor receptor ( egfr ) antibody cetuximab ( erbitux ; bristol - meyers sqibb ) was started with a loading dose of 400 mg / m , thereafter 250 mg / m was given once a week for 6 weeks . , 4 mg dimetindene maleate i.v . , 50 mg ranitidine i.v . and 8 mg ondansetron p.o . all bccs were excised with delayed mohs technique to assess r0 resection with tumor - free surgical margin [ table 1 ] . r0 resection was achieved in all but one patient with a large metatypic bcc in a longstanding leg ulcer . defect closure was realized with rotational flaps in most cases [ figures 1 and 2 ] . neoadjuvant chemoimmune therapy with capecitabine and interferon - was performed in one patient with an advanced metatypic bcc of the hand to reduce the tumor mass . capecitabine 950 mg m body surface on days 114 was combined with interferon alpha 33 miou s.c . after three courses , delayed mohs surgery was performed and the defect was closed by a pedicled ulnar myocutaneous flap based on superior ulnar collateral artery . during follow - up , this patient developed cutaneous metastases ( primary tumor of the hand , metastases on the ipsilateral arm ) treated by palliative radiotherapy . giant metatypic ( basosquamous ) basal cell carcinoma of the scalp ; ( a ) clinical presentation ; ( b ) defect after complete excision ; ( c ) preparation of dual rotational flaps ; ( d ) eight days after surgery giant basal cell carcinoma of the scalp ( a ) defect after tumor removal and preparation of windmill flaps ; ( b ) defect closure ; ( c ) seven days after surgeryin one scc patient , no major surgery was possible because of significant comorbidities ( chronic lymphatic leukemia with anemia needing regular transfusions , colon cancer , and heart disease ) . the patient refused any treatment of his skin cancer except the tumor - associated myiasis causing repeated bleeding . another patient with a giant scc of his left hand was referred to our hand surgeons for second opinion . eventually , he denied amputation . palliative radiotherapy was performed . in six of the remaining eight patients , delayed mohs surgery achieved r0 resection status . defect closure was realized by rotation or transposition flaps ( n = 4 ) or split skin mesh graft transplantation in sandwich technique , in two patients in combination with osmotic tissue expanders [ figures 36 ] . surgery was realized in cooperation with the neurosurgery unit in a multiple - step approach . just before the last operationdesmoplastic squamous cell carcinoma of the scalp ; ( a ) clinical presentation of an ill defined nodular tumor ; ( b ) defect after mohs delayed surgery ; ( c ) preparation of a rotational flap ; ( d ) defect closure giant squamous cell carcinoma of the scalp ; ( a ) clinical presentation ; ( b ) after complete excision preparation of the outer tabula by diamond drill ; ( c ) defect closure was achieved by combined tissue advancement and extension . the primary defect has already been closed ; ( d ) five days after surgery giant tricholemmal squamous cell carcinoma ; ( a ) clinical presentation ; ( b ) osmotic expander ; ( c ) implantation of two expanders in the occipital region ; ( d ) after 6 weeks of tissue expansion with a final volume of 300 ml each giant squamous cell carcinoma of the scalp ; ( a ) ulcerated , ill - defined tumor ; ( b ) after complete excision with removal of periost and partial removal of the outer tabula . only some minor bleedings can be seen to feed the transplant ; ( c ) sandwich transplantation : elastin - collagen template was placed above the bone and a split skin mesh - graft transplant was fixed above in the same session ; ( d ) stable transplant after 8 days among all 20 patients , there was a single patient with primary failure of split skin mesh graft . two patients with high - risk scalp tumors were treated with adjuvant combined cetuximab / radiotherapy . targeted therapy with monoclonal anti - epidermal growth factor receptor ( egfr ) antibody cetuximab ( erbitux ; bristol - meyers sqibb ) was started with a loading dose of 400 mg / m , thereafter 250 mg / m was given once a week for 6 weeks . , 4 mg dimetindene maleate i.v . , 50 mg ranitidine i.v . and 8 mg ondansetron p.o . we observed two deaths in the scc group one traffic accident and a death related to chronic lymphatic leukemia . in the bcc group , one female patient died from a heart attack . giant nmsc ( bcc and scc ) is defined as tumors with a diameter 5 cm . the presence of myiasis in some tumors can be considered a symptom of the neglect . scalp nmsc is most often seen in elderly patients . among 51 cases of giant bccs , another study from italy reported more cases in the head and neck region as we observed . closure various flaps and transplants have been used . since after removal of periostal the scull bone is not a useful place for mesh grafts as exposed tendons as well , we used a sandwich technique to overcome these problems . in the case of scull , a small rose drill was used to reach diploe veins for transplant nutrition before sandwich transplantation . in all cases , a dermal template was used to cover exposed bone or tendons . the split - thickness mesh graft placed over the template in the same session . in contrast to bcc , there is no accepted system for defining high - risk scc . multivariate analysis of scc identified major risk factors for metastasis : tumor thickness 2 mm , tumor size 6 mm , and desmoplastic growth pattern . a part of the patients with giant nmsc needs an adjuvant treatment , i.e. , patients with r1 resection , rapid relapse after primary surgery , and high - risk tumors . egfr - antagonists and radiotherapy offer a treatment option in particular for the group of elderly patients with significant comorbidities , who could not tolerate classical chemotherapy . it becomes obvious that patients with giant nmsc often need an intensive care due to the complexity of the surgical procedures , anemia , and other comorbidities . neglect of patients is the major reason for delayed diagnosis and treatment . obviously , the primary care by gps is not efficient to detect such tumors earlier .\noutput:\n" }, { "from": "agent", "value": "background : among nonmelanoma skin cancer ( nmsc ) , basal cell carcinoma ( bcc ) , and squamous cell carcinoma ( scc ) are the most common . giant nmscs have occasionally reported in the medical literature with particular problems related to diagnosis and treatment . the aim of this study was to analyze patients , treatment , and outcome with giant bcc / scc.materials and methods : we analyzed our files between january 1 , 2008 , and december 31 , 2011 , of an academic teaching hospital in the dermatology department . patients were analyzed according to demographic factors , clinical presentation , histopathology , treatment , and outcome . american society of anesthesiology physical status system was used to assess the fitness of patients before surgery.results : the frequency of giant nmsc was estimated as 0.4 % for both tumor entities . 80 % of giant bcc patients were female and 100 % of giant scc patients were male . the mean age was 81.5 8.5 years for bcc ) and 79.5 11.4 years for scc . the major anatomical site was the scalp . four of 10 bccs were classified metatypic ( basosquamous ) . perineural infiltration was seen in 5 nmscs . seventy percent of patients had an asa score 3 . surgery was performed in general anaesthesia in 5 ( bcc ) and 6 ( scc ) patients , respectively . all other patients were operated in local or tumescence anesthesia . blood transfusions were necessary in five patients . the primary treatment was delayed mohs technique . defect closure was realized with rotational flaps in most cases . neoadjuvant chemoimmune therapy and adjuvant combined cetuximab / radiotherapy have been performed in three patients . we observed three deaths , all unrelated to nmsc . 75 % of patients achieved complete remission.conclusions : giant nmsc is uncommon but not rare . these tumors are high - risk subtypes . treatment needs an interdisciplinary approach ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: it is a safe technique ; however , occasional complications like horner 's syndrome may occur . it is a benign condition normally but may also reflect presence of a variety of acute neurological conditions that may require urgent intervention to prevent permanent damage . we present report of a patient who developed weakness of right upper - limb and horner 's syndrome during epidural anaesthesia . we discuss possible causes of this coincidental observation which was short lived and did not require further investigation or treatment . a 27 - year - old ( 74 kg , 160 cm ) female patient , primigravida with no co - morbid conditions was admitted to labour room in active labour and requested pain relief . examination revealed adequate pelvis , 3.5 cm cervical dilatation with good effacement ( approximately 80 % ) . epidural analgesia was administered by inserting 18 g epidural catheter at l3 / l4 interspace in sitting position using loss of resistance to saline technique , and fixing - up the catheter at skin keeping 5 cm in epidural space . after negative aspiration of catheter for blood or cerebrospinal fluid , 3 ml test dose of 0.25 % bupivacaine was given . after 5 min when subarachnoid injection was ruled out ( sensory or motor effects in lower limbs ) , 9 ml 0.125 % bupivacaine was given and infusion of 0.08 % bupivacaine with fentanyl ( 1.66 g / ml ) was started at the rate of 10 ml / h . initial visual analogue scale ( vas ) score ( vas 0 - 10 , 0 = no pain and 10 maximum pain ) was 10/10 and after 20 min it was 5/10 and after 30 min it came down to 3/10 . she had good pain relief and progress during next 4 h. during 5 h decision for operative delivery was taken due to signs of foetal distress . epidural infusion was stopped ( after 4 h and 18 min of initiation ) and patient was shifted to operation theatre . oxygen 3 l / min with nasal cannulae was started , monitors for electro cardio - graphy , non - invasive blood pressure and oxygen saturation ( oximeter ) connected and 16 ml , 2 % lignocaine with adrenaline ( 1:200 , 000 ) was slowly injected through epidural catheter after negative aspiration . after cleaning and draping sensory block level was tested ( at 12 min ) and incision was given as pinprick sensations were absent till sub - costal margin . on deeper dissection patient complained of pain and intravenous ketamine - 25 mg and midazolam - 1 mg were administered and 4 ml lignocaine with adrenaline ( 1:200,000 ) was given through epidural catheter . neonatal status was satisfactory and paediatrician decided to shift the baby to nursery as per the protocol . before that when baby was shown to mother , she was unable to hold her baby with her right hand and we noticed congestion , ptosis and miosis on right side . she also complained of blurring of vision and became very anxious and restless due to weakness in her right arm and difficulty in focusing . vitals remained stable except for two episodes of hypotension ( blood pressure - 89/54 mm hg and 90/50 mm hg ) late in intraoperative period and managed with 6 mg injection mephentermine . after 45 min , at the end of surgery neurologist 's opinion was sought . the power in proximal muscles ( arm and forearm ) was normal ; there was improvement in hand grip with some weakness , vision was normal , anhydrosis of right eye was present , and ptosis in right eye was also improving [ figure 1 ] . in view of clinical improvement it was decided to continue observation and patient was shifted to post - operative recovery room . patient was re - examined by neurologist in postoperative ward after 8 h after fully recovery from spinal anaesthesia . epidural catheter was kept for 2 days and 3 ml 0.125 % bupivacaine and 3 mg morphine was given whenever vas score was 3 . postoperative course was uneventful except for one episode of vomiting within first 24 h , which was treated by injection ondansetron 4 mg . patient was advised magnetic resonance imaging to rule out any spinal cause for this event , but she refused due to financial constraints . horner 's syndrome , a triad of miosis , ptosis , and enophthalmos , occurs when the sympathetic nerve supply to face / eye is interrupted . sympathetic preganglionic fibres of face and eye originate from the anterior horn cells of c8 and t1 , and occasionally as low as t4 . these are small fibres and very sensitive to even very low concentration to local anaesthetics . it is easy to understand that large volume of local anaesthetic during epidural anaesthesia can block these fibres and may cause horner 's syndrome . however , horner 's syndrome is not rare and many cases have been reported in labouring mothers given epidural analgesia with low volume and low concentration of local anaesthetics . horner 's syndrome associated with epidural is benign ; however , it may be an indication of serious medical condition which may require immediate medical or surgical management . horner 's syndrome seen with labour epidural analgesia has been reported in association with maternal hypotension , foetal bradycardia and trigeminal nerve palsy due to high sympathetic blockade . the cranial nerve involvement is thought to be a more serious consequence than horner 's syndrome alone , because it could signify further cephalad spread of the anaesthetic agent . finally , cases of recurrent horner 's syndrome and persistent horner 's syndrome requiring eyelid surgery have been described after epidural analgesia as well . in the present case , weakness of upper - limb with horner 's syndrome and visual disturbanceshowever , all the features were transient , recovered spontaneously and did not require any treatment . the anatomical and physiological changes during pregnancy and labour which favours cephalic spread of local anaesthetics injected in the epidural space may predispose to development of horner 's syndrome . as most of the cases are seen during labour - analgesia and caesarean section it is thought that the gravid uterus increases the intra abdominal pressure and results in partial occlusion of the inferior vena cava , thus diverting blood through the epidural venous plexus , and lead to a decrease in the epidural space . in the present casecombined effect of local anaesthetic through continuous infusion and bolus could be the cause of higher block . cases of horner 's syndrome during epidural analgesia in labour in spite of not giving any top - up dose has been reported . weakness in upper arm of same side associated with visual disturbances could also be possible due to high block on one side . reduced sensation over the left hemi facial region and upper arm has been reported earlier . unilateral horner 's syndrome along with weakness of upper arm on the same side is difficult to explain and presence of midline septum has been suggested as the cause . we could not provide the evidence for the same in our case as patient refused to undergo mri . regarding test dose , there is no consensus on the exact nature of the epidural test dose in obstetrics , as no single regimen has been proven to be completely effective as an epidural test dose . for pregnant women , the epinephrine test dose might not be justified when a multiorifice catheter is inserted to induce labour analgesia . we used 3 ml 0.25 % bupivacaine without epinephrine as test dose by convention , and use of 3 - 5 ml of 0.25 % bupivacaine is practiced by many specialists . however , we agree that test dose per - se has no role in evidence - based practices and every epidural dose is a test dose . horner 's syndrome is not rare after epidural analgesia particularly during labour or caesarean section . physiological reasons like engorged epidural venous plexus and anatomical factors like midline septum may be responsible in this group of patients . horner 's syndrome is usually benign and self - limiting but may be associated with severe medical conditions and therefore should be investigated if does not resolve spontaneously in few hours .\noutput:\n" }, { "from": "agent", "value": "horner 's syndrome is not rare during labour epidural analgesia or in pregnant patients receiving epidural anaesthesia for caesarean section as thought previously . it occurs due to blockade of sympathetic fibres supplying the eye and face area . most of the times it is a benign and self - limiting condition ; however , it may become a serious systemic manifestation . we present a case where patient had weakness of upper - limb and horner 's syndrome of same side with visual disturbances . these symptoms were transient and resolved spontaneously without any treatment ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: - synuclein is a 140 amino acid brain protein , mainly localized in presynaptic terminals . although the detailed physiological functions of - synuclein are still elusive , recent studies suggest that it plays a key role in synaptic functions cooperated with cysteine - string protein - ( csp ) , which contains a typical domain for hsp40 - type molecular cochaperones . in the subgroup of neurodegenerative disorders termedsynucleinopathies , - synuclein is known to polymerize into fibrils and to accumulate in pathologic hallmark inclusions , such as lewy body ( lb ) , lewy neuritis ( ln ) , and glial cytoplasmic inclusions ( gcis ) . the lb and ln are characteristic of parkinson 's disease ( pd ) , and point mutations or gene multiplications of - synuclein are responsible for familial pd . moreover , transgenic flies overexpressing mutated human - synuclein showed progressive locomotor disability with dopaminergic neuronal cell death with intracytoplasmic inclusions . these findings suggest that abnormal - synuclein metabolism plays a key role in neurodegenerative processes in pd and other synucleinopathies , but the precise underlying mechanisms still remain unknown . to elucidate the possible roles of - synuclein in neurodegeneration , we have developed cells that overexpress wild - type or mutant - synucleins in dopaminergic or inducible catechol - quinone producing cell lines . the inclusions in synucleinopathies were proved to be composed of - sheet rich fibrils formed by nitrated species of - synuclein . several lines of evidence suggested that reactive oxygen species ( ros ) play a key role in the conformational change of - synuclein and the following aggregate formation . we developed human dopaminergic sh - sy5y cells overexpressing wild - type or mutant - synucleins , and established experimental models of intracellular aggregate formation following the exposure to various ros . the aggregates thus formed were immunopositive for ubiquitin , nitrotyrosine , and dityrosine , and positive for thioflavin s staining , which was in good agreement with the pathological features of inclusion bodies in synucleinopathies . the - tubulin and molecular chaperones coexisted as well , suggesting that the aggregate formation was associated with the intracellular transport system for protein turnover responses against the toxic effects of misfolded proteins . such mechanisms are called aggresome and are suggested to represent one of the cytoprotective responses . interestingly , the recent study on huntingtin showed that inclusion body formation reduced the risk of neuronal death . however , it is still controversial whether the aggregate formation of - synuclein has cytotoxicity in the neuronal cell or sequesters toxic species . we established a cellular model in which intracellular - synuclein aggregations were efficiently formed in response to various types of ros exposure . under these conditions , a significant number of cells showed caspase 3 activation . to explore possible relationships between the aggregate formation and apoptosis , first we investigated whether - synuclein aggregates colocalized with activated caspase - 3 using a double immunostaining method . following the combined exposure of the cells to a no donor and rotenonesurprisingly , immunocytochemical analyses revealed that the aggregate positive cells did not show any caspase 3 activations and , conversely , that caspase 3 activated cells did not contain any - synuclein aggregates . iron was able to induce - synuclein aggregates more effectively than any other ros inducers and no donors , suggesting the iron plays a key role in the aggregate formation . when using both ros and no inducers , the addition of ferric iron triggered further aggregate formation , but cells positive for activated caspase 3 were not coincident with aggregate positive cells . in quantification experiments , it was revealed that caspase 3 - positive cells were decreased by the addition of ferric iron . on the other hand , by chelating ferric iron , the aggregate formation was decreased with concomitant increases of caspase 3 activation . these data suggest that the ferric iron plays a key role in the - synuclein aggregation . furthermore , these data also imply that the aggregate formation may be cytoprotective against various cellular insults including oxidative stress . since - synuclein is ubiquitously expressed at high levels in all brain regions , the mechanisms responsible for the preferential and selective neurodegeneration of dopaminergic neurons in the substantia nigra remain to be determined . previous studies suggested that the specific vulnerability of dopaminergic neurons may be linked to the cytotoxic oxidative potential of dopamine . highly reactive oxygen species ( ros ) are generated not only in dopamine oxidation but also during the decay of catechol - derived orthoquinones which covalently incorporate into a variety of molecules including proteins and nucleic acids . on the other hand , previous reports demonstrated that - synuclein might regulate dopamine metabolism by direct interaction with the tyrosine hydroxylase , the dopamine transporter and vesicular monoamine transporter ( vmat2 ) , key proteins in the regulation of the dopamine content within nerve terminals . therefore , the pathological metabolism of - synuclein may be closely linked to the misregulation of dopamine , consequently leading to neuronal death . in support of this notion , catechol - derived orthoquinones ( eg , dopamine - quinone or dopa - quinone ) accelerate and stabilize the formation of - synuclein protofibrils by inhibiting the conversion of toxic protofibrils into fibrils . to shed light on the pathophysiological mechanisms underlying - synuclein - mediated neurodegeneration in dopamine neurons , we developed novel neuronal cell lines coexpressing - synuclein ( wild - type or a53 t ) and tyrosinase that produces catecholamines and their oxidized metabolites . investigating the effects of wild - type or mutant - synuclein expression , we found that the coexpression of wild - type and a53 t mutant - synuclein in tyrosinase - overexpressing cells exacerbated dna damage and successive apoptotic cell death compared to the cells overexpressing cat or antisense - synuclein . both wild - type and a53 t mutant - synucleins coexpressed with tyrosinase resulted in the gradual accumulation of high - molecular weight complexes immunopositive for - synuclein . this band , possibly representing oligomerized forms , corresponded to the size of - synuclein tetramer and was also detected by the nbt / glycinate redox - cycling staining , suggesting that it was modified by quinones . moreover , during these processes , the mitochondrial membrane potential was specifically decreased without the activation of map kinases . although the underlying mechanism ( s ) of neuronal cell death following the coexpression of tyrosinase and - synuclein are still elusive , it is likely that - synuclein modified by the oxidized catechol metabolites forms cytotoxic intermediates , that is , recent reports suggested that protofibrillar - synuclein tightly binds to lipid bilayers and increases the membrane permeability by forming pore - like structures . while the membranous structures damaged by protofibrils in dopaminergic nerve terminals remain unknown , intracellular organelles , such as synaptic vesicles and mitochondria , are possible candidates . in thisregard , disruption of synaptic vesicle membranes would result in an increase of the cytoplasmic dopamine levels that would trigger the further accumulation of dopamine - quinone and dopamine - derived oxyradicals and thus lead to a vicious cycle . likewise , mitochondrial enzymes in the electron transport chain and the functional permeability transition pores are impaired by dopamine oxidation products making it plausible that the early damage of mitochondria observed in this cellular model reflects the actions of - synuclein protofibrils and the subsequent increase of the membrane permeability in the presence of oxidized catecholamine metabolites . we further analyzed the resting membrane potential and whole - cell membrane conductance using the ramp voltage in the cell lines expressing wild - type or mutant - synuclein . interestingly , the cells expressing a53 t - synuclein have the most depolarized membrane potential . by the application of the ramp voltage under the whole cell voltage - clamp condition , we obtained an almost linear current - voltage ( i - v ) relationship in each cell line . the slope of the i - v relationship in the cells expressing mutant - synuclein was significantly steeper than that in the cells expressing the vector alone or wild - type - synuclein , indicating that the expression of mutant - synuclein results in higher ion permeability of the plasma membrane . because it has been suggested that abnormal intracellular calcium homeostasis plays a crucial role in the pathogenesis of neurodegenerative disorders , the intracellular free calcium concentrations in - synuclein - transfected cells were quantified using a calcium indicator dye , fura - 2 . notably , both the intracellular calcium concentrations under basal conditions and after depolarization induced by potassium chloride application were significantly higher in the mutant - synuclein expressing cells than in cells expressing the empty vector or wild - type - synuclein . these results suggest that mutant - synuclein is involved in the perturbation of the intracellular calcium homeostasis . taken together , our data from cellular models of synucleinopathy suggest that oligomer or protofibril , but not aggregate or fibril , formation of - synuclein plays a key role in the pathomechanisms of synucleinopathy ( figure 1 ) . the iron specifically triggers the aggregate formation of - synuclein , but this seems to be a cytoprotective process . the cytotoxic protofibril formation may be facilitated by not only gene mutations , but also the modification of - synuclein by catechol - derived quinones . the cellular membranes are the primary targets injured by protofibrils , and the mitochondrial dysfunction seems to be an initial step in the neurodegeneration of synucleinopathy . obviously , protofibrils or oligomers of - synuclein are heterogeneous in size and stability and exist as mixtures in the cytosol . therefore , at present it is difficult to specify the detailed molecular structures that may be responsible for the cellular injuries . however , from these data , it is plausible that the reduction of the protofibril pool may rescue neurons from death ( figure 1 ) . if this is the case , not only the acceleration of degradation ( c in figure 1 ) but also the facilitation of aggregate formation ( d in figure 1 ) , may be a novel strategy for the treatment of synucleinopathy . of course , the most important way would be to decrease the input ( a in figure 1 ) into the protofibril pool . the inclusions in synucleinopathies were proved to be composed of - sheet rich fibrils formed by nitrated species of - synuclein . several lines of evidence suggested that reactive oxygen species ( ros ) play a key role in the conformational change of - synuclein and the following aggregate formation . we developed human dopaminergic sh - sy5y cells overexpressing wild - type or mutant - synucleins , and established experimental models of intracellular aggregate formation following the exposure to various ros . the aggregates thus formed were immunopositive for ubiquitin , nitrotyrosine , and dityrosine , and positive for thioflavin s staining , which was in good agreement with the pathological features of inclusion bodies in synucleinopathies . the - tubulin and molecular chaperones coexisted as well , suggesting that the aggregate formation was associated with the intracellular transport system for protein turnover responses against the toxic effects of misfolded proteins . such mechanisms are called aggresome and are suggested to represent one of the cytoprotective responses . interestingly , the recent study on huntingtin showed that inclusion body formation reduced the risk of neuronal death . however , it is still controversial whether the aggregate formation of - synuclein has cytotoxicity in the neuronal cell or sequesters toxic species . we established a cellular model in which intracellular - synuclein aggregations were efficiently formed in response to various types of ros exposure . under these conditions , a significant number of cells showed caspase 3 activation . to explore possible relationships between the aggregate formation and apoptosis , first we investigated whether - synuclein aggregates colocalized with activated caspase - 3 using a double immunostaining method . following the combined exposure of the cells to a no donor and rotenone , - synuclein aggregates were efficiently formed in the cytoplasm as previously reported . surprisingly , immunocytochemical analyses revealed that the aggregate positive cells did not show any caspase 3 activations and , conversely , that caspase 3 activated cells did not contain any - synuclein aggregates . iron was able to induce - synuclein aggregates more effectively than any other ros inducers and no donors , suggesting the iron plays a key role in the aggregate formation . when using both ros and no inducers , the addition of ferric iron triggered further aggregate formation , but cells positive for activated caspase 3 were not coincident with aggregate positive cells . in quantification experiments , it was revealed that caspase 3 - positive cells were decreased by the addition of ferric iron . on the other hand , by chelating ferric iron , the aggregate formation was decreased with concomitant increases of caspase 3 activation . these data suggest that the ferric iron plays a key role in the - synuclein aggregation . furthermore , these data also imply that the aggregate formation may be cytoprotective against various cellular insults including oxidative stress . since - synuclein is ubiquitously expressed at high levels in all brain regions , the mechanisms responsible for the preferential and selective neurodegeneration of dopaminergic neurons in the substantia nigra remain to be determined . previous studies suggested that the specific vulnerability of dopaminergic neurons may be linked to the cytotoxic oxidative potential of dopamine . highly reactive oxygen species ( ros ) are generated not only in dopamine oxidation but also during the decay of catechol - derived orthoquinones which covalently incorporate into a variety of molecules including proteins and nucleic acids . on the other hand , previous reports demonstrated that - synuclein might regulate dopamine metabolism by direct interaction with the tyrosine hydroxylase , the dopamine transporter and vesicular monoamine transporter ( vmat2 ) , key proteins in the regulation of the dopamine content within nerve terminals . therefore , the pathological metabolism of - synuclein may be closely linked to the misregulation of dopamine , consequently leading to neuronal death . in support of this notion , catechol - derived orthoquinones ( eg , dopamine - quinone or dopa - quinone ) accelerate and stabilize the formation of - synuclein protofibrils by inhibiting the conversion of toxic protofibrils into fibrils . to shed light on the pathophysiological mechanisms underlying - synuclein - mediated neurodegeneration in dopamine neurons , we developed novel neuronal cell lines coexpressing - synuclein ( wild - type or a53 t ) and tyrosinase that produces catecholamines and their oxidized metabolites . investigating the effects of wild - type or mutant - synuclein expression , we found that the coexpression of wild - type and a53 t mutant - synuclein in tyrosinase - overexpressing cells exacerbated dna damage and successive apoptotic cell death compared to the cells overexpressing cat or antisense - synuclein . both wild - type and a53 t mutant - synucleins coexpressed with tyrosinase resulted in the gradual accumulation of high - molecular weight complexes immunopositive for - synuclein . this band , possibly representing oligomerized forms , corresponded to the size of - synuclein tetramer and was also detected by the nbt / glycinate redox - cycling staining , suggesting that it was modified by quinones . moreover , during these processes , the mitochondrial membrane potential was specifically decreased without the activation of map kinases . although the underlying mechanism ( s ) of neuronal cell death following the coexpression of tyrosinase and - synuclein are still elusive , it is likely that - synuclein modified by the oxidized catechol metabolites forms cytotoxic intermediates , that is , protofibrils . recent reports suggested that protofibrillar - synuclein tightly binds to lipid bilayers and increases the membrane permeability by forming pore - like structures . while the membranous structures damaged by protofibrils in dopaminergic nerve terminals remain unknown , intracellular organelles , such as synaptic vesicles and mitochondria , are possible candidates . in thisregard , disruption of synaptic vesicle membranes would result in an increase of the cytoplasmic dopamine levels that would trigger the further accumulation of dopamine - quinone and dopamine - derived oxyradicals and thus lead to a vicious cycle . likewise , mitochondrial enzymes in the electron transport chain and the functional permeability transition pores are impaired by dopamine oxidation products making it plausible that the early damage of mitochondria observed in this cellular model reflects the actions of - synuclein protofibrils and the subsequent increase of the membrane permeability in the presence of oxidized catecholamine metabolites . we further analyzed the resting membrane potential and whole - cell membrane conductance using the ramp voltage in the cell lines expressing wild - type or mutant - synuclein . interestingly , the cells expressing a53 t - synuclein have the most depolarized membrane potential . by the application of the ramp voltage under the whole cell voltage - clamp condition , we obtained an almost linear current - voltage ( i - v ) relationship in each cell line . the slope of the i - v relationship in the cells expressing mutant - synuclein was significantly steeper than that in the cells expressing the vector alone or wild - type - synuclein , indicating that the expression of mutant - synuclein results in higher ion permeability of the plasma membrane . because it has been suggested that abnormal intracellular calcium homeostasis plays a crucial role in the pathogenesis of neurodegenerative disorders , the intracellular free calcium concentrations in - synuclein - transfected cells were quantified using a calcium indicator dye , fura - 2 . notably , both the intracellular calcium concentrations under basal conditions and after depolarization induced by potassium chloride application were significantly higher in the mutant - synuclein expressing cells than in cells expressing the empty vector or wild - type - synuclein . these results suggest that mutant - synuclein is involved in the perturbation of the intracellular calcium homeostasis . taken together , our data from cellular models of synucleinopathy suggest that oligomer or protofibril , but not aggregate or fibril , formation of - synuclein plays a key role in the pathomechanisms of synucleinopathy ( figure 1 ) . the iron specifically triggers the aggregate formation of - synuclein , but this seems to be a cytoprotective process . the cytotoxic protofibril formation may be facilitated by not only gene mutations , but also the modification of - synuclein by catechol - derived quinones . the cellular membranes are the primary targets injured by protofibrils , and the mitochondrial dysfunction seems to be an initial step in the neurodegeneration of synucleinopathy . obviously , protofibrils or oligomers of - synuclein are heterogeneous in size and stability and exist as mixtures in the cytosol . therefore , at present it is difficult to specify the detailed molecular structures that may be responsible for the cellular injuries . however , from these data , it is plausible that the reduction of the protofibril pool may rescue neurons from death ( figure 1 ) . if this is the case , not only the acceleration of degradation ( c in figure 1 ) but also the facilitation of aggregate formation ( d in figure 1 ) , may be a novel strategy for the treatment of synucleinopathy . of course , the most important way would be to decrease the input ( a in figure 1 ) into the protofibril pool .\noutput:\n" }, { "from": "agent", "value": "- synuclein is a key molecule in the pathogenesis of synucleinopathy including parkinson 's disease and multiple system atrophy . in this mini - review , we mainly focus on recent data obtained from cellular models of synucleinopathy and discuss the possible mechanisms of neurodegeneration . recent progress suggests that the aggregate formation of - synuclein is cytoprotective and that its precursor oligomer ( protofibril ) may be cytotoxic . the catechol - derived quinones are the candidate molecules that facilitate the oligomer formation of - synuclein . furthermore , the cellular membranes are shown to be the primary targets injured by mutant - synucleins , and the mitochondrial dysfunction seems to be an initial step in the neuronal death ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: interleukin - 18 ( il - 18 ) is produced by a wide range of cells , primarily macrophages , monocytes , and to a smaller degree by keratinocytes and osteoblasts . it strengthens cytotoxic properties of natural killer ( nk ) cells and cd8 + t cells . it also possesses a unique ability to increase the activity of both th1 - type as well as th2 - type cd4 + t cells and depends on local cytokine network . il - 18 contributes to inflammation and fever due to its potent inducing effects on the gene expression and synthesis of interferon - ( ifn - ) , granulocyte - macrophage colony - stimulating factor ( gm - csf ) , tumour necrosis factor ( tnf ) , interleukin - 1 ( il - 1 ) , fas ligand ( fasl ) , and several chemokines . being a pleiotropic cytokine , il - 18 can play an immunoregulatory role , especially in inflammatory , infectious , and autoimmune diseases . only a few studies analysed the role of il - 18 in psoriasis vulgaris , they did not , however , yield conclusive results . increased expression of il - 18 was demonstrated in keratinocytes from psoriatic lesions in comparison to keratinocytes from normal skin . however , neither the bioactivity of il - 18 nor the influence of ifn - on inflammatory processes in the peripheral blood mononuclear cells ( pbmc ) from psoriatic scales could be detected . the level of il - 18 mrna was demonstrated to be 2 - to 8-fold higher in extracts from psoriatic skin lesions than the one obtained from both uninvolved skin extracts in psoriasis patients and healthy subjects . similarly , 6 - to 8-fold higher concentrations of il - 18 receptors mrna were observed in psoriatic lesional skin in comparison to both uninvolved skin of psoriasis patients and healthy subjects . in the human peripheral blood , two distinct lineages of dendritic cells ( dcs ) were identifiedthese two subsets of dcs have been implicated in inducing diverse types of immune responses , with mdcs favouring th1 - and pdcs favouring th2 - type immune reactions profile . mdcs express specific antigen - blood dendritic cell antigen bdca - 1 , whereas pdcs express characteristic antigen bdca - 2 . recent data indicate that dcs may be involved in pathological processes in numerous diseases , including immune - mediated skin conditions . in psoriasis , bdca - 2 cells were detected in the basal layer of the epidermis and the papillary dermis . this observation is particularly interesting in the context of the most important immunopathogenic hypotheses of psoriasis focused on the synthesis and release of proinflammatory mediators by activated dcs and t cells , distorted function of the immune synapse leading to the emergence of self - reactive t cells or epidermal expression of chemokines attracting t cells and dcs into the skin . have recently demonstrated that human dcs express il - 18 receptors and that il - 18 has a direct chemotactic effect on dcs . increased il - 18 levels , observed in some diseases , might lead to dcs recruitment to the sites of inflammation . companjen et al . found that in the epidermis , il - 18 expression was detected not only in keratinocytes but also in the cells with a dendritic morphology , probably langerhans cells . the cellular infiltrate in the dermal papillae of psoriatic lesional skin , containing cells with dendritic and lymphocyte morphology , also expressed il - 18 . since several lines of evidence link the pathogenesis of psoriasis to both increased levels of il - 18 and dcs functions , we decided to investigate the relationship between plasma il - 18 and blood dcs in psoriasis patients . we hypothesized that such correlation may help to explain some of the pathogenic processes observed in the psoriatic skin . thirty - eight males with psoriasis and 21 healthy male volunteers took part in the study . patients were hospitalized at department of dermatology , venerology and paediatric dermatology , medical university of lublin , poland , due to psoriasis vulgaris . patients had a chronic active type of psoriasis of moderate severity with the mean psoriasis area and severity index ( pasi ) of 24.568.28 ( m sd ) and the average percentage of skin involvement of 28.4419.54 % . the patients treated with topical or systemic steroids , any form of dithranol or retinoid therapy prior to examination , were excluded from entering the study . subjects with other systemic , infectious , parasitic , neurological , or psychiatric diseases were also excluded from the study . an informed written consent was obtained after complete description of the study from each participant . the study was approved by the ethics committee of the medical university of lublin . the mononuclear cells were isolated from heparinised blood by density gradient centrifugation on lymphoprep ( nycomed , norway ) and washed twice in phosphate buffered saline without ca and mg containing 0.5 % bovine serum albumin and 2 mm edta . the phenotypes of dcs were analysed with double - colour flow cytometry using monoclonal antibodies : mouse antihuman bdca -1-fitc ( miltenyi - biotec , germany ) , cd19 - cychrome ( pharmingen , usa ) , bdca -2-fitc ( miltenyi - biotec , germany ) , cd123 - pe ( becton dickinson , usa ) , and matched isotype control ( caltag , usa ) . the cell staining was performed according to the manufacturers ' instructions in the presence of fcr blocking reagent ( miltenyi - biotec , germany ) . the immunolabelled cells were collected ( a total of 300000 events ) using an facscalibur flow cytometer equipped with 488 nm argon laser ( becton dickinson ) and analysed with cell - quest software . the numbers of myeloid and plasmacytoid dcs were quantified as the percentages of peripheral blood mononuclear cells . mdcs were defined as bdca - 1 positive and simultaneously cd19 negative cells , whereas pdcs as double bdca - 2 and cd123 positive cells ( figure 1 ) . plasma il - 18 concentration was determined by a commercially available human il - 18 elisa kit ( mbl , japan ) . plasma samples were collected on edta as anticoagulant and stored deep frozen at 80c until further evaluated . elisa reader elx800 ( bio - teck instruments ) was used for the examination . results are presented as mean , median , 25 percentile and 75 percentile , mean ( m ) , standard deviation ( sd ) . the fit of the data to the normal distribution was tested with kolmogorov - smirnov test . since the distribution of the data was significantly different from normal , nonparametric statistics were further used . mann - whitney u test was employed for comparison between patient and control groups , and spearman rho correlations coefficients were calculated between the assessed variables . the patients and healthy controls were homogeneous with respect to the number of demographic , physical , and behavioural variables including age , weight , height , body mass index ( bmi ) , blood pressure , wbc , frequency of smoking , and declared alcohol intake ( table 1 ) . none of the differences between the patients and healthy subjects in the mean values of these variables proved to be statistically significant ( p .05 ) . the mean plasma level of il - 18 was significantly increased in males with psoriasis as compared to the healthy control male group ( p = .027 ) . the counts of bdca - 1 + cells in psoriasis patients were not significantly different from those in healthy controls ( p .05 ) . the counts of bdca - 2 + cells were found to be significantly lower in patients with psoriasis than those in healthy controls ( p = .001 ) . the myeloid / plasmacytoid ratio was significantly higher in psoriatic patients compared to the control group ( figure 2 ) . in the correlations between il - 18 and bdca - 1 + cells , bdca - 2 + cells were examined separately for the patient and the control groups . in the latter , none of the correlation coefficients was found to be statistically significant . in the patient group , however , statistically significant negative correlations were found both between the bdca - 1 + cell counts and plasma il - 18 level ( rho = 0.38 ) as well as the bdca - 2 + cell counts and plasma il - 18 level ( rho = 0.41 ) ( table 2 , figure 3 ) . in the patient group , correlation coefficients were calculated between the dcs subpopulations , il - 18 , and clinical severity of the disease . neither dcs nor il - 18 showed statistically significant correlations with the severity of psoriasis expressed by pasi score . il - 18 and bdca - 2 + did not demonstrate statistically significant correlations with percentage of skin involvement in psoriatic patients either . however , the severity of the disease , expressed by percentage of skin involvement correlated negatively with bdca - 1 + cell counts ( rho = 0.39 ) ( table 3 ) . our patients with psoriasis showed significantly increased levels of plasma il - 18 as compared to healthy subjects , which confirms findings reported by other authors , and our previous ones . increased il - 18 levels found in our patientsseem to be in agreement with the widely accepted observation that il - 18 is a potent inducer of ifn - from t cells , nk cells , b cells , dendritic cells and , generally , is a trigger of the th1 immune response . taking into account the fact that psoriasis is a th1 - type disease , il - 18 may be regarded to be of some importance in its pathogenesis . this is further supported by studies demonstrating decrease of il - 18 levels after narrowband uvb therapy together with other parameters ' characteristics for th1 response . apart from stimulating the th1 responseil - 12 enhances ifn - production induced by il - 18 , whereas il - 18 alone induces il - 4 and il - 13 production . these unique properties of il - 18 could explain statistically significant negative correlations between the bdca - 1 + cell counts and plasma il - 18 level as well as the bdca - 2 + cell counts and plasma il - 18 level . kaser et al . showed that plasmacytoid dc lineage express an chain of il - 18 receptor ( il - 18r ) . therefore , il - 18 can directly down - regulate proliferation of plasmacytoid dc precursors ( pre - dc2s ) . this , in turn , can lead to a decrease in bdca - 2 + cells . ifn - was demonstrated to up - regulate the il - 18r on monocyte - derived dendritic cells . our results show the statistically significant decrease of bdca - 2 + cells and the significantly higher myeloid / plasmacytoid ratio in the psoriatic patients compared to the control group . spearman 's rank correlation coefficients indicated that negative correlation between il - 18 and bdca - 2 + is more pronounced ( figure 3 ) . this finding could be explained by both the direct influence of il - 18 on plasmacytoid dcs , which in psoriasis is enhanced by increased level of il - 12 , as well as additional function of il - 4 . the th2 - type cytokine - il - 4 is able to induce apoptosis of plasmacytoid dcs , but ifn - can protect bdca - 2 + cells from this process . observed a lower level of bdca - 2 + cells in the blood of psoriatic patients than in healthy subjects . they suggested that bdca - 2 + cells are decreased in the blood of psoriatic patients due to their migration into the lesional skin , a phenomenon similar to that observed in systemic lupus erythematosus . therefore , the decreased counts of bdca - 2 + cells we found in our patients might possibly be related to their presumed migration into the lesional skin . this remains in agreement with the findings of other authors who observed increased dcs counts in the lesional psoriatic skin . . found an elevated level of plasmacytoid dcs in both plaque lesions and uninvolved skin of psoriatic patients as compared to the skin of control subjects . analysed the role of il - 18 in the initial phase of th response and demonstrated that il - 18 interacts with the differentiation pathway of plasmacytoid dcs . through thismodulation , il - 18 shifts the th1 / th2 balance towards th1 response . the potent chemotactic activity of il - 18 on plasmacytoid dcs was also identified . further studies are , however , required to examine the chemotactic effect of il - 18 on plasmacytoid dcs in the psoriatic patients ' skin and blood . what is more is that investigation on the expression of il - 18r on plasmacytoid dcs in the patients ' skin and blood seems to be of considerable usefulness . the counts of bdca - 1 + cells were not significantly different in the blood of our psoriatic patients from that of healthy controls . however , our study demonstrated a significant negative correlation ( rho = 0.38 ) between plasma il - 18 and bdca - 1 + cell counts in patients with psoriasis . this negative correlation may be the result of myeloid dendritic cell downregulation driven by ifn - , as it was already demonstrated in systemic lupus erythematosus . in conclusion , based on the increased il - 18 levels in plasma of our patients , this cytokine seems to play a role in the etiopathogenesis of psoriasis which was already suggested by many authors . decreased blood plasmacytoid dcs in psoriatic patients might be related to the il - 18 down - regulation of plasmacytoid dc precursor proliferation . ifn - , by exerting its influence on myeloid / plasmacytid ratio , on the one hand could down - regulate myeloid dendritic cells and on the other hand can protect plasmacytoid dendritic cells from apoptosis . explanation of the exact mechanisms of interactions between il - 18 and dcs in psoriasis requires , however , further studies .\noutput:\n" }, { "from": "agent", "value": "peripheral blood dendritic cells seem to play a crucial role in psoriatic inflammatory processes . the aim of our study is to investigate the relationship between plasma interleukin - 18 ( il - 18 ) levels and blood dendritic cells in psoriatic patients . il - 18 plasma levels were measured by elisa . phenotypes of dendritic cell subsets were analyzed by double - colour flow cytometry . plasma il - 18 level in psoriatic males was significantly higher , whereas counts of bdca - 2 + cells were lower than in the control group . the myeloid / plasmacytoid ratio was significantly higher in the patient group compared to the control one . in the patient group , significant negative correlations between plasma il - 18 level and both the bdca - 1 + and bdca - 2 + counts were found . bdca - 1 + counts correlated negatively with percentage of skin involvement . il - 18 seems to play a role in psoriasis pathogenesis . the decreased counts of blood plasmacytoid dcs in psoriatic patients might result from il - 18 down - regulation of plasmacytoid dc precursor proliferation ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in the polish market there is currently a broad range of products for mouth washing and disinfection . these products differ in qualitative and quantitative composition and in the concentration of active substances . in antisepsis and disinfection , the chemical agents should provide a significant degree of microorganism reduction in a relatively short time period . the european committee for standardization ( cen ) has been developing standards for evaluation of the effectiveness of antiseptics and disinfectants for many years . the relevant en standards ( currently adopted as the polish standards pn ) allow comparison of antimicrobial activity of a number of products with the same application . previously , this comparison was impossible due to the use of various , diverse procedures ( different contact time , concentrations , and tested strains ) . the purpose of this study was to examine the bactericidal activity of selected herbal products and other products for mouth washing , possessing antibacterial activity as declared by the manufacturers , used in treatment of inflammation and for disinfection of the mouth . a total of 28 products for mouth washing and disinfection , available in department stores and pharmacies , were included in this study . chemical disinfectants and antiseptics quantitative suspension test for the evaluation of basic bactericidal activity of chemical disinfectants and antiseptics - test method and requirements ( phase 1 ) . it is assumed that the product possesses antibacterial properties if it causes minimum of 5 log reduction in the number of viable bacteria after 60 min or less , when the test organisms are staphylococcus aureus atcc 6538 and pseudomonas aeruginosa atcc 15442 . additionally , 2 other bacterial strains were included in the study : escherichia coli nctc 10538 and enterococcus hirae atcc 10541 . these strains are recommended by standard en 13727 chemical disinfectants and antiseptics quantitative suspension test for the evaluation of bactericidal activity in human medicine , the densities of bacterial suspensions were adjusted to a value of 1.5510 cfu / ml . two contact times were used : 5 min and / or 60 min . at the end of the contact time , bactericidal activity was immediately neutralized by using neutralizer consisting of lecithin ( applichem ) g / l , and water up to 1 l. during this study , the dilution - neutralization method was applied . the test procedure was as follows : 1 ml of water and 1 ml of bacterial test suspension were added to 8 ml of the examined product test solution . at the end of the contact time , 5 or 60 min 10 s , a 1 - ml sample of the test mixture was transferred into a tube with 8 ml of neutralizer mixed with 1 ml of water . after 5 min 10 s of neutralization time , a 1 - ml sample of neutralized test mixture was immediately taken in duplicate and inoculated using the pour plate technique . after 48 h of incubation , verification of the absence of toxicity of the neutralizer and validation of the dilution - neutralization method tests were performed at the same time and under the same conditions . an assessment of the effectiveness of the bactericidal activity in 2 contact times ( 5 and 60 min ) , was carried out on 4 herbal products listed in the register of medicinal products authorized in poland : dentosept a , salviae , stomatosol , and salviasept . after conducting a preliminary study of the efficacy of dentosept a , which was not diluted ( concentration recommended by the manufacturer ) , a reduction in the number of bacterial cells within all tested strains required by the standard was noticed . in the case of 70 % solution of this product , however , this result occurred for e. hirae after 5 min , but took over 60 min for other strains . the bactericidal efficacy of the salviae product based , on the preliminary studies , was insufficient at the concentration recommended by the manufacturer ( approximately 2 % ) . in accordance with pn - en 1040 , the product salviae possesses bactericidal activity for all tested strains at a concentration of 30 % . the analysis of the bactericidal activity of the product showed that a 10 % solution was effective only against e. coli after 60 min . a 20 % concentration of this product reduced the number of viable bacterial cells of s. aureus after 60 min . tests of the effectiveness of the salviasept product showed that , in the dilution recommended by the manufacturer ( 1.6 % ) , it meets the requirements of the pn - en 1040 standard after 5 min only for the e. coli strain . however , undiluted product caused a 5 log reduction of all tested bacteria after just 5 min of contact . the antibacterial activity of the product was tested in concentrations of 10 % , 20 % and 30 % . in the case of s. aureus , a 20 % concentration of salviasept had bactericidal activity in accordance with pn - en 1040 after 5 min , but a 10 % solution required a 60 min of contact time . in the case of e. hirae , this product , at a 10 % concentration , complied with the standard only after 60 min contact time and after 5 min at a concentration of 20 % . in the p. aeruginosa strain , a 10 % product solution caused the required reduction in the number of bacterial cells after 5 min contact time . preliminary investigations of the stomatosol product for mouth washing showed that this product , in concentrations recommended by the manufacturer ( approx .4 % ) , did not possess bactericidal activity meeting the standard , but when the product was used in undiluted form , the requirements of pn - en 1040 were met after just 5 min . analysis of the bactericidal activity of a 10 % concentration of stomatosol showed a reduction in the number of viable cells of s. aureus , e. coli , and p. aeruginosa to the level of 5 log after 60 min contact time . in the case of the e. hirae strain , five min of contact time was sufficient at the concentration of 20 % for the e. coli strain only . higher concentrations of this product were turbid and not homogeneous , making it impossible to carry out further investigations . due to the presence of ethanol in the tested herbal products , the antibacterial activity of ethyl alcohol at concentrations of 1050 % was conducted on 4 bacterial strains at 2 contact times : 5 and 60 min . a 5 log reduction in the number of bacterial cellsethanol at a 40 % concentration only completely eliminated s. aureus cells after 5 min contact time . for e. coli and p. aeruginosathe 5 log reduction of e. hirae cells was not achieved in any tested concentration . it was observed that ethanol concentrations of 30 % and lower did not show any bactericidal activity against the tested strains . the survey revealed that antimicrobial activity of ethanol can be excluded in the stomatosol , salviae , and salviasept products at concentrations of 50 % and lower . two other products from the group of medicinal products corsodyl and hascosept at the level of 5 log bactericidal activity against all tested strains after 5 min of contact time . studies of the effectiveness of 22 different products for mouth washing , commonly available in department stores and pharmacies , were performed against 4 test strains using 2 contact times : 5 and 60 min . study of the effectiveness of mouthwash with fluoride , elgydium , paroplak , and sensikin against 4 bacterial strains showed that they failed to achieve a 5 log reduction the number of viable bacteria , even after 1 h of contact time . the product mouthwash with fluoride was used as a control because the manufacturer has not declared any antibacterial activity . a 5 log reduction in the number of bacterial cells for all tested strains after 5 min of contact timewas proven for the following products : aquafresh , eludril , listerine freshmint , listerine cleanmint , oral b advantage mouth rinse , denivit , active oral care extra strength original , cepacol antibacterial mouthwash with ceepryn , and walgreens fresh breath antiseptic mouth rinse . in the study of the effectiveness of the products mouthwash antiseptic and elmex , reduction in the number of s. aureus cells , required by the standard , was noticed after 60 min of contact time , and for the other tested strains after 5 min of contact time . the evaluation of the efficacy of the hascosept , protefix dental antisept , and oreksyd products showed bactericidal activity in accordance with pn - en 1040 standard against the tested microorganisms after 5 min and after 60 min , only in the case of e. hirae . meridol and lacalut aktiv were effective against e. coli and p. aeruginosa after 5 min of contact time , but 60 min was required for s. aureus and e. hirae . studies of the bactericidal activity of orthokin did not show enough efficacy against e. hirae , but the 5 log reduction in number of viable bacteria for the other 3 strains was achieved after just 5 min . in the case of pearl drops , the effectiveness of the bactericidal activity against p. aeruginosa was demonstrated after 5 min ; however , the action against the other tested strains did not meet with the standard . figure 1 illustrates the antibacterial effectiveness of the products used for mouth hygiene and disinfection . a total of 13 out of 27 products ( 48 % ) , including 3 medicinal products , demonstrated bactericidal activity against all tested strains in accordance with the standard . up to 19 % of the products , including 2 medicinal products , did not demonstrate bactericidal activity against any of the tested strains according to pn - en 1040 . one - third of the tested products caused the reduction of bacterial cells required by pn - en 1040 , but only in 13 strains . the information provided by manufacturers on the packaging or in the leaflets of products for mouthwash and disinfection is important for consumers . the manufacturers of antiseptic products should provide data on the concentration , duration of application , and scope of the antimicrobial activity . our study investigated whether the common , commercially available medicinal products and cosmetics meet the current , basic bactericidal requirements of the pn - en 1040 standard for chemical disinfectants and antiseptics . it was assumed that a product intended for use as an oral antiseptic is effective when the reduction of bacterial cells is on the level of at least 5 log after 5 min of contact time , which corresponds with the standard and is actually a reasonable mouth washing time . the mouth washing time can be shorter , however , when washing with water is not done , as a substantial amount of the product remains on the mouth mucosa for some time and allows the antibacterial effect to last longer . antibacterial activity was also studied after 60 min of contact time , as it is the longest time specified by the standard pn - en 1040 for disinfectants and antiseptics . international , standardized test methods for evaluation of antimicrobial activity of preparations forthus , researchers generally use different bacterial strains ( ie , clinical isolates ) and different assay conditions to evaluate antibacterial activity of mouth disinfectants . the european committee for standardization ( cen ) has created several european standards for evaluation of antimicrobial activity of chemical disinfectants and antiseptics . standards concerning the test methods of phase 1 , for evaluation of basic antibacterial and antifungal activity ( en 1040 , en 1275 ) , are aimed at general applications . there is no differentiation between antimicrobial requirements for antiseptic preparations applied on living tissue ( skin and mucosa ) and disinfectants used in order to diminish the microbial count on surfaces and instruments ( medical devices ) . the cen standards relate to only a limited range of microbial species and a limited number of standard strains . these have been chosen as representative , taking into consideration their relative resistance and their relevance to practical use . the cen plans to evaluate the phase 3 tests performed under practical conditions , with usage of clinical isolates ; however , no single standard is available and only standard strains are recommended in the en . the oral microbes colonizing the surfaces of oral cavity mucosa , teeth , and tongue , as well as present in saliva , were not included in the study because of the diversity of strains . . these bacteria may be even more susceptible to the analyzed antiseptic preparations than standard strains recommended in the en . however , cen s idea was to use resistant rather than susceptible strains in tests . the incorporation of oral microbes in tests may be more appropriate , taking into consideration the possibility of control of oral health problem by use of antiseptics , but the aim of our study was to use the international , standardized , cen method dedicated for evaluation of antibacterial activity of antiseptics , and to compare this activity of the products for mouth washing and oral disinfection present on the polish market . this study involved 2 groups of products : 1 ) medicinal products containing herbal extracts used against infections and inflammation of the mucous membranes of the mouth and 2 ) popular , widely available , liquids ( rinses ) for oral hygiene . hayes et al . claimed that the active ingredients ( essential oils ) are used in medicinal products and antiseptics because of their antimicrobial activity and because of a lack of resistance mechanisms to these substances . antimicrobial activity of essential oils depends on their chemical composition and it is related to plant species , vegetative parts of the plant used , and phase of plant development , as well as soil and climate conditions . shapiro et al . showed a high efficacy of peppermint , sage , and tea tree oils , thymol and eugenol , against bacteria colonization of the mouth . adams and kunz proved that essential oils , due to their lipophilic properties , damaged the cell walls and cytoplasmic membranes of bacteria and fungi , leading to the leakage of cytoplasm . these oils inhibited the synthesis of dna , rna , proteins , and polysaccharides , as well as enzymatic activity . kalemba studied essential oils derived from plants in our climate zone , such as thyme , rosemary , yarrow , mint , sage , and clove . he showed that each of these essential oils possesses antimicrobial activity against at least 1 organism , and the efficacy increases with oil concentration . studied the susceptibility of pathogenic bacteria to various antiseptics used in the mouth , and proved that tea tree and eucalyptus oils were biocidal to bacteria that cause paradontosis and dental caries . it was shown that a 0.2 % solution of essential oils kills porphyromonas gingivalis and streptococcus mutans after 30 s. hammer et al. showed that tea tree oil inhibits the growth of other bacteria present in the mouth . the most sensitive bacteria belong to the genera porphyromonas and prevotella , and the least sensitive were streptococcus and lactobacillus . study demonstrated the efficacy of dentosept herbal product against anaerobic bacteria that cause periodontal disease . this product contains extracts of herbs such as chamomile , oak bark , sage , arnica , sweet flag , mint , and thyme . there is an important fact concerning the obtained results the author evaluated the smallest concentration ( mic ) of dentosept that inhibited the growth of microorganisms and interpreted the results after 48 h of culture . this method is used in studying antibiotic activity , but it should not be used in the case of antiseptics because of the increased length of contact time . in this publication , activity of the dentosepta product ( made by the same manufacturer ) against aerobic bacteria was studied ( the product contains the same set of plant extracts as dentosept , but in lower concentrations ) . in this study , the results described by kedzia , and obtained by this study , showed that dentosept a may be used for mouth prophylaxis and the treatment of oral infections caused by aerobic and anaerobic bacteria . the salviae , salviasept , and stomatosol products , used in significantly higher concentrations than recommended by the manufacturer , showed bactericidal activity against the 4 referenced strains tested in accordance with the standard . after 5 min of contact time , the salviae product in 40 % concentration ( approximately 28 % ethanol ) and the salviasept product in 20 % concentration ( approximately 10 % ethanol ) showed reduction of bacteria as required by the standard . the stomatosol product in 20 % concentration ( approximately 14 % ethanol ) was active after only 60 min of contact time . this study suggests the use of higher concentrations of plant extracts in products for mouth antisepsis than is recommended by the manufacturers . the second group of products tested in this study was commercially available mouthwashes with antibacterial activity declared by the manufacturers . two out of 23 of these products are included in the register of medicinal products in poland , and 16 out of 23 are included in the central register of cosmetics . bocian and tyski reported that solutions of ethanol in 6070 % concentrations were the most effective against s. aureus in dry or humid environments . research showed that survival of spores in ethanol depends on the species of bacteria and the concentration of alcohol . however , spores of anaerobic bacteria survived in 10 % ethanol for more than 10 months , but only as long as 4 weeks in 80 % ethanol . in the present study , we demonstrated that hascosept containing ethanol and benzydamine hydrochloride has antibacterial properties towards of tested microbial strains after 5 min contact time , but in the case of e. hirae , 60 min of contact time was required . other combinations of active substances are also used in mouth washing products , like the combination of 0.12 % chlorhexidine with 0.05 % acetyl - pyridine chloride ( perioaid ) , or alcohol with 0.2 % chlorhexidine ( corsodyl ) . van strydonk et al . demonstrated the comparable efficacy of both preparations in reducing dental plaque . the products aquafresh , cepacol and active oral care extra strength original were proven to act as good oral antiseptics . the product named pearl drops tested in this study did not show bactericidal activity in accordance with the standard . due to the fact that manufacturers of the tested rinses did not provide quantitative information about the composition , it can be assumed that the ineffectiveness of pearl drops is caused by a concentration of active substances that is too low . as reported by bocian and tyski , antiseptic chlorhexidine gluconate is often used in dentistry and oral hygiene . apart from antimicrobial properties and the effect of prolonged activity , it also exhibits high affinity for the mucosa and the ability to inhibit the formation of dental plaque . at the same time , however , it is characterized as not very harmful . in the present study , the products eludril and denivit were found to be effective against tested microorganisms after 5 min . the product protefix dental antisept required 60 min of contact time for 1 of the strains ; this is a very long time and , therefore , not practical for an antiseptic mouth rinse . quirynem , who studied the effectiveness of chlorhexidine at 0.12 % and 0.2 % concentrations , achieved comparable reduction in the number of bacteria : 78 % and 89 % , respectively . despite the best results being observed for concentrations of 0.2 % , the obtained difference was not statistically significant . the author suggests the possibility of reducing chlorhexidine concentrations without a significantly negative influence on therapeutic effect . clinical studies performed with 0.12 % chlorhexidine solution showed an 8190 % reduction of tongue microflora and 8995 % reduction of saliva microorganisms . the products for mouth washing containing 0.2 % chlorhexidine are recommended for the control of dental plaque and for the support of periodontitis treatment . gos - slomka conducted research at the centre for pediatric pulmonology in karpacz and showed a significant efficacy of the product corsodyl ( chlorhexidine gluconate 0.2 % ) in reducing the amount of dental plaque and reducing gingivitis . this decrease was noticeable most clearly for children aged 812 years , after the first 3 days of washing . a significant improvement in gingivitis was obtained both by decline in the amount of dental plaque as a major etiological agent of gingivitis and by the antibacterial activity of corsodyl . limited studies of antimicrobial activity according to custom methods on products containing chlorhexidine , benzydamine , salvia , and gel with polyvinylpyrrolidone - sodium hyaluronate were carried out using microbial strains colonizing the oral cavity enterococcus faecalis and candida sp . reduced incidence of such colonization took place when polyvinylpyrrolidone - sodium hyaluronate gel was applied . luc et al . studied biocidal activity of corsodyl using the dilution - neutralization method . they observed efficacy against s. mutans , lactobacillus acidophilus , fusobacterium nucleatum , prevotella intermedia , actinobacillus actinomycetemcomitans , and candida albicans after 1 min of contact time . chen et al . also demonstrated in vitro activity of the products corsodyl and listerine on s. mutans biofilm . our studies showed that corsodyl was effective against s. aureus , e. hirae , e. coli , and p. aeruginosa . this was confirmed by the results described in the literature regarding the antimicrobial activity of this product and chlorhexidine at the concentration of 0.2 % . luc et al . investigated the antimicrobial activity of the products eludril ( chlorhexidine gluconate and alcohol ) , meridol ( amine fluoride ) and lacalut ( chlorhexidine gluconate ) using the dilution - neutralization method after 1 min of contact time against s. mutans , l. acidophilus , f. nucleatum , p. intermedia , l. actinomycetemcomitans , and c. albicans . they observed the efficacy of eludril at dilutions of 1:2 and 1:3 against all tested strains . our studies showed a strong bactericidal activity of undiluted product against tested bacterial strains after 5 min of contact time . luc et al . showed that the product meridol was active after 1 min of contact time only against s. mutans and f. nucleatum . the results obtained i our study demonstrated that meridol met the requirements of the pn - en 1040 standard after 5 min against strains of e. coli and p. aeruginosa , but in the case of s. aureus and e. hirae the product was equally effective only after 60 min . the results in this publications show that the rinse was effective against s. aureus and e. hirae after only 5 min and effective against all tested reference strains after 60 min . the difference in the efficacy lacalut described in the above - mentioned study and our study may be caused by longer contact time and use of other microorganisms . investigated plant products with a declared antimicrobial activity registered as medicinal products , in most cases , did not exhibit the antibacterial activity required by the pn - en 1040 standard at the recommended concentrations . only some mouth washing products exhibit antimicrobial activity required by the standards . the information on the packaging or the leaflets for antiseptic products should be corrected by the manufacturers to include accurate information on antimicrobial activity .\noutput:\n" }, { "from": "agent", "value": "backgroundcurrently , there is a wide range of products for mouth washing on the polish market . they have different qualitative and quantitative compositions , and they differ particularly in the concentration of active substances . in antisepsis and disinfection , the significant reduction in number of cells of microorganisms in a particular environment is very crucial . the chemical agents should provide a significant decrease in number of microorganisms in a relatively short time . the purpose of this study was to examine the bactericidal activity of selected herbal products used for treatment of inflammation , and disinfection and washing of the mouth , having antibacterial activity as declared by the manufacturers.material / methodsthe study included 28 products for mouth washing and disinfection available in poland . bactericidal activity was studied using a quantitative suspension test according to the standard pn - en 1040 . resultsonly 1 of 4 tested herbal products , registered as medicinal products , showed satisfactory antibacterial activity when they were used according to the manufacturer s recommendations . a total of 13 preparations ( 48 % ) complied with the standard requirements against all tested strains . up to 19 % of products showed no bactericidal activity against bacterial strains , and up to 33 % were only effective against certain microorganisms.conclusionsthe informational literature accompanying most antiseptics should be corrected by the manufacturers , providing information about antimicrobial activity consistent with the requirements of applicable standards . the information on the packaging or in the leaflets for antiseptic products should be corrected by the manufacturers to include accurate information on antimicrobial activity ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: cyclin - dependent kinase inhibitor 1a ( p21 , cip1 ) mitochondria - associated membrane nuclear localization signalmaintenance of genome stability requires mobilization of the dna damage response ( ddr ) , both to repair the day - to - day chemical nicks and bruises and resolve acute damage following exposure to ionizing radiation ( ir ) or chemotherapeutics . cells respond to these chemical mishaps and overtly acute genotoxic insults by inducing the tumor suppressor protein p53 ( tp53 , known as p53 ) , whose role in the regulation of the ddr is complex , involving changes in the expression of more than 3,000 genes and activation of cell cycle checkpoints to allow dna repair . the most intensively studied p53 target genes include cyclin - dependent kinase inhibitor 1a ( cdkn1a , known as p21 ) , which promotes cell - cycle arrest or senescence , and p53 upregulated modulator of apoptosis ( puma , also known as bcl2 - binding component 3 [ bbc3 ] ) and bcl2 - associated x protein ( bax , also known as bcl -2-like protein - 4 ) , which are activated to induce apoptosis when cellular damage is irreparable . the transcriptional activity of p53 requires post - translational modifications , including phosphorylation and acetylation , to stabilize p53 and enhance its transactivation functions , respectively . the class iii histone deacetylase sirtuin 1 ( sirt1 ) represses p53 transcriptional activation by deacetylating p53 following dna damage . sirt1 can be regulated transcriptionally and post - transcriptionally and through interactions with other cellular proteins in diverse pathways . the complexity of these functions suggests that regulation of sirt1 activity probably requires additional cellular factors . we recently identified the multifunctional sorting protein phosphofurin acidic cluster sorting protein - 2 ( pacs - 2 ) as a novel mediator of p53 action in response to genotoxic insult ( fig . pacs - 2 was initially identified by its cytoplasmic roles in mediating mitochondria - associated membrane ( mam ) formation , autophagy , and protein traffic in the secretory and endocytic pathways ( fig .1 , panel b ) . in response to apo2 ligand / tumor necrosis factor - related apoptosis - inducing ligand ( apo2l / trail ) , pacs - 2 switches to a proapoptotic effector that promotes membrane permeabilization of mitochondria and lysosomes , which is required for the activation of executioner caspases and cell death ( fig . our finding that pacs - 2 is required for apo2l / trail - induced apoptosis led us to ask whether pacs - 2 would similarly be required for apoptosis induced by dna damage . surprisingly , we found that whereas sirna knockdown of pacs - 2 in hct116 human colon carcinoma cells reduced apo2l / trail - induced apoptosis , it sensitized cells to doxorubicin - induced apoptosis and this effect was dependent on p53 . thus , pacs - 2 has a proapoptotic role in apo2l / trail action but an anti - apoptotic role in response to genotoxic insult ( fig . ( a ) dna damage induces nuclear pacs -2-mediated cytoprotection through inhibition of sirt1 - mediated p53 deacetylation to promote p21 - dependent cell cycle arrest . ( b ) phosphorylation state - dependent homeostatic function of pacs - 2 to regulate either mam integrity or cargo trafficking in secretory and endocytic pathways . ( c ) signaling by death ligands triggers pacs - 2 dephosphorylation to induce mitochondria and lysosome membrane permeabilization , leading to caspase - 3 activation and cell death . ac , acetylated lysine ; p , akt - phosphorylated ser437 on pacs - 2 ; er , endoplasmic reticulum ; mam , mitochondria - associated membrane ; trail - r , trail receptor ; tbid , truncated bid . ( a ) dna damage induces nuclear pacs -2-mediated cytoprotection through inhibition of sirt1 - mediated p53 deacetylation to promote p21 - dependent cell cycle arrest . ( b ) phosphorylation state - dependent homeostatic function of pacs - 2 to regulate either mam integrity or cargo trafficking in secretory and endocytic pathways . ( c ) signaling by death ligands triggers pacs - 2 dephosphorylation to induce mitochondria and lysosome membrane permeabilization , leading to caspase - 3 activation and cell death . ac , acetylated lysine ; p , akt - phosphorylated ser437 on pacs - 2 ; er , endoplasmic reticulum ; mam , mitochondria - associated membrane ; trail - r , trail receptor ; tbid , truncated bid . to characterize this previously undescribed role for pacs - 2 in ddr , we used cell cycle analyses combined with western blotting ( wb ) and in vivo enterocyte migration studies in the gastrointestinal track of pacs - 2 mice . we observed that pacs - 2 knockdown reduced p53 acetylation in response to dna damage , thereby blunting the induction of p21 and cell cycle progression . this p21 repression increased apoptosis as previously described , which suggests a p21 - dependent cytoprotective role for pacs - 2 in ddr . consistent with the above data , we found that the migration of bromodeoxyuridine - positive ( brdu ) enterocytes along the crypt - villus following ir was restricted in wild - type mice but not in pacs - 2 mice . together , these data describe the functional importance of pacs - 2 as a specific in vivo regulator of the p53 - p21 axis in ddr . we confirmed that p53 acetylation and p21 induction levels in pacs - 2 depleted cells or tissues were sirt1 dependent , as sirt1 knockdown or addition of the sirt1 inhibitor ex-527 restored p53 acetylation and p21 induction , as observed by wb , as well as p21 - dependent cell cycle arrest , in pacs - 2 knockdown cells . the inhibition of sirt1 by pacs - 2 was also confirmed by in vitro assays showing that pacs - 2 directly binds to and inhibits sirt1 - catalyzed p53 deacetylation . together , these data support a previously undescribed role of pacs - 2the inhibition of sirt1 following dna damage as a cytoprotective component of the p53 signaling pathway , although the specific protein motifs or residues involved and the molecular mechanism by which pacs - 2 inhibits sirt1 catalytic activity are still not fully understood . the promotion of p53 - dependent p21 expression by pacs - 2 depended on its ability to traffic to the cell nucleus . sequence analysis of human pacs - 2 identified one nuclear localization signal ( nls ) and at least 2 putative nuclear export signals . correspondingly , mutation of the pacs - 2 nls blocked its nuclear trafficking . moreover , pacs - 2 responded to dna damage by increased translocation into the cell nucleus , where it repressed sirt1 - mediated p53 deacetylation . curiously , sequence alignment of the nls sequences in pacs proteins from different species reveals that pacs - 2 underwent a late evolutionary adaptation to acquire nuclear trafficking motifs . this new , and surprising , function of pacs - 2 parallels the role of p53 in directing cell cycle arrest found in higher metazoans but not in worms or flies , where p53 function is limited to apoptosis induction . thus , these findings described a new compartment - specific function of pacs - 2 following dna damage in response to the heightened need for p53 to resolve the damage . however , the mechanism by which pacs - 2 is mobilized from the cytoplasm to the nucleus in response to dna damage remains unclear . overall , our work characterizes pacs - 2 as a new inhibitor of sirt1 to specifically regulate the p53p21 axis in response to dna damage . interestingly , the role of the nuclear pool of pacs - 2 in promoting p21 - dependent cell cycle arrest could correlate with the role of the cytoplasmic pool of pacs - 2 in promoting autophagy . . future work will determine how the ratio of pacs - 2 pools is regulated in response to different stimuli and the crosstalk between them .\noutput:\n" }, { "from": "agent", "value": "sirt1 regulates p53 transcriptional activation in response to genotoxic insult by deacetylating key lysine residues . we recently identified the multifunctional protein pacs - 2 as a sirt1 inhibitor . after dna damage , pacs - 2 binds and inhibits sirt1 to increase p53 - dependent transactivation of the cdk inhibitor p21 ( cdkn1a ) and induce cell cycle arrest ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the number of hip arthroplasty procedures performed has been progressively increasing as the range of adaptation following hip arthroplasty has been expanded1 ) . among several complications associated with hip arthroplastythe use of cementless implants in hip arthroplasty instead of cemented implants has increased over recent years567 ) . as cementless hip arthroplasty is performed in elderly patients , who have poor bone quality , intraoperative fracture easily occur when strong compression is applied to achieve initial stability . moreover , periprosthetic femoral fractures are more likely to occur in patients who underwent cementless hip arthroplasty , despite poor bone quality , after falling down , compared to cemented surgery8 ) . periprosthetic femoral fractures following hip arthroplasty are mostly associated with trauma ; however , they may also be caused by local factors including osteoporosis , loosening of prosthesis , and osteolysis4910 ) . since the incidence of fractures is influenced by prosthesis design and surface treatment in cementless hip arthroplasty , and prosthetic loosening after operative treatment of vancouver type b1 fractures is frequently reported , caution is required in determining treatment options for patients with periprosthetic femoral fractures111213 ) . in this study , we aimed to identify the causes of periprosthetic femoral fractures in patients who underwent hip arthroplasty with cementless prostheses and to investigate considerations in managing fractures following cementless hip arthroplasty by evaluating clinical and radiological outcomes after operative treatment . from june 2002 to may 2012 , 40 patients who underwent cementless hip arthroplasty due to periprosthetic femoral fractures and could be followed - up for more than 1 year were enrolled in this study . the mean age at the time of surgery was 71.5 years ( range , 38 - 89 years ) and the patients included 27 males and 13 females . fractures occurred after primary hip arthroplasty using proximal fixation prostheses in 34 cases and during revision using distal fixation prostheses in 6 cases . the cause of fracture after hip replacement was slipping down in 33 cases and falling down in 1 case . on the basis of radiographs taken before and after fractures , the presence of risk factors of periprosthetic femoral fractures ( osteolysis , cortical defects , stem loosening , and stress riser ) was examined . the mean duration of the follow - up after surgery was 28.5 months ( range , 15 - 97 months ) ( table 1 ) . the types of intraoperative and postoperative fractures were determined by using the vancouver classification14 ) . three patients had intraoperative type a2 fractures , 2 patients had type b2 fractures , and 1 patient had a type b3 fracture . among postoperative fractures , type ag ( involving the greater trochanter ) was present in 5 hips , type al ( involving the lesser trochanter ) in 2 hips , type b1 in 15 hips , type b2 in 6 hips , type b3 in 3 hips , and type c in 3 hips . fracture location , degree of displacement , stem stability , bone quality around the prosthesis , causes of fracture , and other factors have to be taken into consideration in choosing surgical treatment of the fractures . according to the degree of fracture displacement , type ag and type al fractures were fixed with cerclage wiring or a greater trochanteric reattachment ( gtr ) plate . revision was done in 1 type ag case with extensive osteolysis in the proximal part of the femoral component . of 15 cases with type b1 fractures without femoral stem loosening , plate fixation was performed in 8 cases , and stem revision was performed using distal fitting stems in 7 cases with extensive osteolysis in the proximal part ( fig . stem revision was performed in patients with type b2 fractures with stem instability and those with type b3 fractures with bone loss ; these fractures were managed with plate fixation and bone grafting according to the degree of bone defects . type c fractures were managed with open reduction followed by plate fixation ( table 2 ) . revision surgery was performed using long cementless stems to achieve fixation at the femoral isthmus . plate fixation was performed in the proximal part using unicortical locking screws and cables , and in the distal part using bicortical locking screws . type a2 fractures , which occurred intraoperatively , were fixed using metal plates . in 1 case , a type b3 fracture with a bone defect occurred during revision due to infection ; this fracture was treated with bone grafting and plate fixation . early postoperative range of motion exercises were performed and ambulation with crutches was begun by allowing partial weight bearing at 3 postoperative weeks . bony union was defined as the presence of trabeculations across the fracture site and absence of pain on full weight - bearing on postoperative radiographs . clinical assessment was performed with the use of the harris hip score and postoperative complications . loosening of the femoral component was defined as the presence of pain during ambulation and progression of subsidence on radiographs . the risk factors of periprosthetic femoral fractures following total hip arthroplasty ( tha ) were osteolysis in 7 cases , a cortical defect in 1 case , weakening of the cortical bone due to stress shielding in 2 cases , and osteoporosis in 13 cases . the fractures occurred within a mean period of 7 years 8 months ( range , 2 months - 17 years 2 months ) after tha ( thr ) . bony union was achieved in all but 1 case and the average time for bony union was 21 weeks ( range , 16 - 40 weeks ) . even though fixation using a gtr plate was performed , non - unionsurgical treatment using plate fixation was performed in 1 patient with a type b1 fracture , but the patient underwent revision due to stem loosening at postoperative 27 months . the mean harris hip score was 86 ( range , 64 - 98 ) at the final follow - up . good or excellent clinical results were obtained in all cases , except for 1 case with revision due to stem loosening and 1 case with non - union . besides 3 cases of plate removal due to irritation that occurred after bony union , no other complications were observed such as infection or refracture . the incidence of periprosthetic femoral fractures following hip replacement varies according to authors , but the prevalence of hip arthroplasty has been on the rise in recent years , along with an expanded range of indications for surgery and growing number of older adults124 ) . in particular , surgical management needs to be considered carefully in older patients with osteoporosis , who are at high risk of fractures , since treatments that result in fractures are not satisfactory . the mean age of patients was 71.5 years in this study , and 13 of 40 patients were positive for osteoporosis . the increased incidence of periprosthetic fractures is related to the increased incidence of hip arthroplasty in older adults with poor bone quality . therefore , the incidence of periprosthetic fractures in the future will increase with the increasing elderly population . since revision has a very high fracture incidence , caution is required before surgery in patients at high risk of fractures1718 ) . in this study , we found the following risk factors of intraoperative fractures during revision : loosening of prosthesis , a cortical defect around the fracture site due to infection , and osteolysis . mcelfresh and coventry19 ) addressed inadequately inserted bone cement , cortical osteolysis , perforation , stress riser , as the risk factors of fractures after surgery . larsen et al. 20 ) suggested that loosening of the femoral component , osteoporosis , calcar resorption , and varus angular deformity of the prosthesis could be the fracture risk factors . in this study , postoperative fractures were most frequently caused by minor traumas including falls . at the fracture site , furthermore , a dual - energy x - ray absorptiometry scan revealed osteoporosis in 13 cases . although all fractures occurred after minor falls , they appeared to be influenced by multiple risk factors around hip implants . conservative treatment in patients with periprosthetic femoral fractures after thr results in a high rate of complications , which include atelectasis , pulmonary embolism , and non - union1417 ) . for this reason , surgical treatmentsurgical treatment is now most commonly performed and treatment options are chosen depending on the presence of stem loosening and the type of fracture21 ) . the authors of this study chose surgical management for all patients because of its advantages of early joint exercise and ambulation to avoid the problems of conservative treatment . surgical treatment were determined based on the location of the fracture , stem stability , and bone defect according to the vancouver classification , and internal fixation , bone grafting , or revision was performed . we achieved satisfactory results by conducting cerclage wiring in 3 patients with a2 type fractures , revision with a long femoral stem and plate fixation in 2 patients with type b2 fractures , and plate fixation and an allograft in 1 patient with a type b3 fracture . we suggest that favorable results can be anticipated when intraoperative periprosthetic femoral fractures are managed according to the above treatment principles . in the case of type a periprosthetic fractures after tha , conservative treatment can be performed in hips with minimal displacement according to the stability of fracture , while open reduction and fixation seem to be appropriate for hips with severe displacement . despite fixation using a gtr plate , non - union was seen in 1 case with a type ag fracture associated with osteolysis . bony union is expected to be obtained with a combination of curettage of osteolytic lesions and bone grafting . thus , different treatment options for type ag fractures can be considered according to the causes of the fractures . however , we performed revision in all patients with type b1 fractures , in cases of the use of proximal stem and extensive or fractures extended proximally . stem loosening occurred at postoperative 27 months after open reduction and plate fixation in 1 patient with a type b1 fracture , and revision surgery was performed ( fig . this case indicates that loosening of the stem component can occur over time , although a fracture is classified as type b1 on radiographs . abg ( anatomique benoist giraud ; howmedica , newbury , uk ) hydroxyapatite - coated femoral stems with coating on their proximal part , which were mainly used in this study , have severe problems with stem stability when a fracture occurs around the proximal part of the prosthesis . it will also occur in other proximally fitted prostheses1213 ) . unlike fractures developed in femoral stem components because of extensive ingrowth , type b1 fractures in proximal fitting femoral stems should be managed differently based on our experience . in type b2 fractures , a loosened femoral stem was revised using a long femoral stem . to manage type b3 fractures , composite reconstruction was performed using revision of the femoral stem and bone grafting , since proximal bone defects were severe due to osteolysis and comminuted fractures . type c fractures were managed with open reduction and internal fixation according to the treatment principles for general fractures222324 ) . as suggested by dennis et al. 25 ) , we fixed periprosthetic fractures using plates with cables . the proximal part was fixed using unicortical locking screws and cables and the distal part was fixed using bicortical locking screws . furthermore , stem stability was achieved by wire fixation after stem revision in 1 case of a type al fracture with osteolysis . possible complications of periprosthetic femoral fractures after thr include stem loosening , infection , malunion , non - union , refracture , and shortening of the lower extremity . in the present study , infection , refracture , and other complications were detected , excluding 1 non - union , 1 stem loosening , and 3 cases of plate removal due to metal allergy after bony union . satisfactory outcomes were obtained with a mean harris hip score of 86 at the final follow - up . surgical management according to treatment principles can achieve low incidence of complications and good clinical results in patients with periprosthetic femoral fractures after cementless hip arthroplasty . based on revision surgery standards , the stability and types of the femoral stem and the degree of osteolysis need to be taken into account .\noutput:\n" }, { "from": "agent", "value": "purposewe aimed to evaluate the results of surgical treatment of periprosthetic femoral fractures in cementless total hip arthroplasty ( tha ) . materials and methodsfrom june 2002 to may 2012 , 40 patients who could be followed - up for more than 1 year after surgery were enrolled in this study . the mean duration of follow - up was 28.5 months ( range , 15 - 97 months ) and the average age at the time of surgery was 71.5 years ( range , 38 - 89 years ) . the fracture types were determined by using the vancouver classification . among intraoperative fractures , there were type a in 3 hips , type b2 in 2 hips and type b3 in one . among postoperative fractures , type ag was present in 5 hips , type al in 2 hips , type b1 in 15 hips , type b2 in 6 hips , type b3 in 3 hips , and type c in 3 hips . evaluation of the results was based on bony union , stability of the prosthesis , postoperative complications , and harris hip score at the final follow - up.resultsbony union was achieved in all but one case and the average time for bony union was 21 weeks . the mean harris hip score was 86 at the final follow - up . clinical results were above good in 34 of 40 hips ( 85.0 % ) . stem loosening occurred in one patient with a type b1 fracture treated with open reduction and plate fixation . nonunion was observed in 1 patient with an ag type fracture.conclusionopen reduction and fixation using a plate with a screw and cerclage wiring provided good results for periprosthetic fractures in patients who had a stable femoral stem without bone defects . revision surgery with a cementless long stem should be considered in patients with an unstable stem or suspected stability in b1 type of tha using a proximal fixation type ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: guillain - barr syndrome ( gbs ) is an acute immune - mediated polyneuropathy , typically presenting with rapid ascending paralysis caused by an antecedent infection . sarcoidosis is a multi - system noncaseating granulomatous disorder of unknown etiology presenting with bilateral hilar lymphadenopathy , pulmonary reticulonodular opacities , and skin , joint , or ocular lesions . a minority of patients with known sarcoidosis develop neurological complications , making neurosarcoidosis a diagnostic consideration . a 43 - year - old australian presented with an acute progressive distal limb weakness and sensory alteration of both hands and feet . this information was subsequently unearthed during his readmission to the intensive care unit ( icu ) . inpatient investigations revealed elevated serum corrected calcium of 2.36 mmol / l ( n : 1.10 - 1.30 mmol / l ) and an angiotensin - converting enzyme ( ace ) level of 108 u / l ( n : 8 - 52chest x - rays and high - resolution computed tomography scan of the chest showed extensive fine nodular patterns on both lungs . the patient 's symptoms , apart from the blurred vision , improved with 50 mg of daily oral prednisolone . two weeks postdischarge , he re - presented to the hospital with acute progressive limb weakness which started distally with gradual proximal involvement over 2 days . differential diagnoses for acute flaccid paralysis relevant to an intensive care unit patient neurological examination of the upper and lower limbs showed global areflexia . magnetic resonance imaging ( mri ) of the brain and spine demonstrated abnormal enhancement of the cauda equina nerve roots and patchy white matter signal change representing inflammatory demyelination extending up to the t3 level of the thoracic cord , preferentially involving the ventral nerve roots [ figures 1 and 2 ] . cerebrospinal fluid ( csf ) findings showed acellular fluid with a mildly elevated protein level of 0.67 magnetic resonance imaging of the spine showing high signal and linear contrast enhancement of the cauda equina magnetic resonance imaging of the spine showing enhancement preferentially of the ventral nerve roots based on these findings , a diagnosis of gbs was made , and the patient was started on a 5 - day course of immunoglobulin . over the next 24 h , he clinically deteriorated to mrc power 0/5 in all his limbs , with respiratory failure requiring ventilatory support . his stay was complicated by ventilator - associated pneumonia and he underwent a tracheostomy . as he failed to improve after a full dose of immunoglobulin , plasmapheresis was initiated . sarcoidosis is a multisystem inflammatory disorder of unexplained etiology . in a prospective study from australia , allen et al . neurological manifestations in a patient with known sarcoidosis should always prompt a possible diagnosis of neurosarcoidosis . the most common brain mri finding of neurosarcoidosis is a basilar leptomeningeal involvement ( in about 30 - 40 % ) , which is usually seen as a thickening and diffuse or nodular enhancement . nonspecific anomalies that support a diagnosis of neurosarcoidosis are elevated ace , pleocytosis , reduced or normal glucose , high protein count ( 0.5 g / l ) , elevated beta - 2 microglobulin and increased igg index with possible oligoclonal bands . evidence of patchy demyelination with conduction block has been seen , which is most likely as a result of mechanical neural compression by granulomata . a risk estimate of one additional gbs case per million people vaccinated is found in the advisory committee on immunization practices recommendation and the vaccine information statement for influenza vaccine . the period between vaccination and first symptom onset ranged could potentially range from as short as 3 - 5 days to 6 - 18 weeks , and up to a few months and even years . this correlated with the peak incidence of vaccine - associated neuromuscular weakness as differential diagnoses , even though it was hard to prove that the vaccine had definitely caused the axonal neuropathy . the other speculation with regards to the vaccination as a precipitant of the inflammatory polyradiculoneuropathy was the axonal pattern on the nerve conduction study as opposed to the typical demyelinating pattern with conduction blockade and reduced amplitude which occurs with aidp . furthermore , the h response and f wave were not particularly abnormal keeping in with a typical gbs , which happens following an infectious prodrome . neuroimaging studies and csf analysis results were also consistent with gbs as opposed to neurosarcoidosis . peripheral nerve conduction studies hold a prognostic value and frequently show classical demyelination but can show axonopathy and inexcitability in certain subgroups of gbs . mri findings of gbs report marked enhancement of the thickened nerve roots in the conus medullaris and cauda equina , with no abnormalities on precontrast images . these mri features were in contradistinction to the pachymenigeal and leptomeningeal enhancement which is typical of neurosarcoidosis along with involvement of the perivascular spaces , the circle of willis , and the cranial nerves . corticosteroids are the first - line agents while other immunomodulatory and biological agents can be used . this is in stark contrast to the treatment of gbs in which steroid therapy has no proven benefit . starting with ivig or plasmapheresis would be a reasonable option in these patients , especially given the concern about a poor response with steroids for typical gbs . nevertheless , if there is an unexpectedly high pleocytosis in csf followed by additional confirmation of sarcoidosis , following up with further steroid treatment for neurosarcoidosis is highly recommended . the authors are happy to report this interesting case illustrating the neurological complications of sarcoidosis in a man with rapid onset peripheral neuropathy , which prompted further investigations for neurosarcoidosis and the eventual results that conversely supported a diagnosis of acute gbs . this case also illustrates the importance of accurate history taking in patients with extreme complexity , especially in an icu environment , wherein the art of history taking is regrettably sidelined due to the vagaries of time , conflicting commitments and the absence of a reliable historian . our report also highlights the temporal association between influenza vaccine and gbs , even though causality has not been proven .\noutput:\n" }, { "from": "agent", "value": "guillain barr syndrome ( gbs ) is an acute demyelinating polyneuropathy , usually evoked by antecedent infection . sarcoidosis is a multisystem chronic granulomatous disorder with neurological involvement occurring in a minority . we present a case of a 43 - year - old caucasian man who presented with acute ascending polyradiculoneuropathy with a recent diagnosis of pulmonary sarcoidosis . the absence of acute flaccid paralysis excluded a clinical diagnosis of gbs in the first instance . subsequently , a rapid onset of proximal weakness with multi - organ failure led to the diagnosis of gbs , which necessitated intravenous immunoglobulin and plasmapheresis to which the patient responded adequately , and he was subsequently discharged home . neurosarcoidosis often masquerades as other disorders , leading to a diagnostic dilemma ; also , the occurrence of a gbs - like clinical phenotype secondary to neurosarcoidosis may make diagnosing coexisting gbs a therapeutic challenge . this article not only serves to exemplify the rare association of neurosarcoidosis with gbs but also highlights the need for a high index of clinical suspicion for gbs and accurate history taking in any patient who may present with rapidly progressing weakness to an intensive care unit ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: fast food intake has been associated with poor dietary intake and weight gain among young population . fast food restaurants are becoming widespread worldwide , both in developed and even developing countries like iran . based on reports , one - third of adolescents consume fast foods three or more times during a week . fast food contains higher levels of calorie and fat compared to the home - prepared meals . our previous studies in isfahan , iran , showed that the majority of students consume high servings of fast food per week which was related to higher dietary energy density and higher weight and waist circumference . previous studies in isfahan , iran , showed that fast food consumption was associated with obesity and central adiposity . an important time for assessing and evaluating fast food intake and detecting the associated factors is from adolescents to younger adulthood , a high risk time for being overweight and obesity . determining the factors influence on dietary intakes among adolescents , such as food preferences , family eating patterns , and social norms , could be a guide for conducting interventions aimed to adopt healthy eating behaviors . one of the well - known models is the theory of planned behavior ( tpb ) . this theory could successfully predict intention and behavior in eating and has recently received great attention in determining the norms and beliefs related to fast food and snacks consumption . tpb model has been derived from the theory of reason action ( tra ) and explains health behaviors that are not completely under an individual 's control . according to a report , intention to a behavioris controlled by three concepts : attitudes ( favourable or unfavourable evaluations about the behavior ) , subjective norms ( perceived social pressure to perform behavior ) , and perceived behavior control ( pbc ) ( an individual 's perceptions of the ease or difficulty of performing the behavior of interest ) . this model has been examined in several studies on eating behavior and has been successfully applied , in a wide range of age groups , in the field of fast food consumption . one of the important age groups that are usually interested in fast food intake is adolescents . attitudes , pbc , and subjective norms are major parts of tpb , and further to these main parts , tpb could include additional variables if they constitute a large proportion of variance in behavior . two additional variables could be past behavior and actual behavior control ( abc ) which have been mentioned in previous studies in the field of fast food consumption . tpb model could increase the possibility of predicting intention and behavior . abc referres to those factors and resources that could affect people 's ability to do a behavior . dunn et al . found that intention , abc , and pbc explained 50 % of variance in the behavior related to fast food consumption . to our knowledge , no study has examined the utility of a theoretical framework of fast food consumption in an iranian population to date . as it was mentioned previously , fast food intake is a problem in iran and we are not aware of any research based on tpb in this population for determining the beliefs and norms related to fast food intake among iranian adolescents . although there is a large body of the literature on tpb , according to our knowledge , it is mostly conducted in developed countries and few studies have been conducted in developing countries . in developing countries , we are faced with the burden of diseases , so we have both malnutrition and over nourishment and chronic diseases due to high calorie intake . therefore , it is not clear that if a model is suitable in predicting some factors related to fast food intake in developed countries , it may also be successful in developing countries . so , it seems that examining the usefulness of the models in each population is necessary . the present research examines some predictors of fast food consumption using tpb model and additional variables to increase the predictability of intention and behavior among high school students in isfahan , iran . in 2011 , a sample of 521 high school students ( 244 boys and 277 girls ) was recruited from 3 regions in isfahan , iran . we used a randomized stratified sampling to choose the participants of the present study . at the first stage , six schools ( three boys ' and three girls ' schools ) were selected from each of the three regions in isfahan . at the second stage , classes were selected from all grades ( year of education in high school ) by using a simple random - sampling design . in this way , one class was randomly selected in each of the three grades ( first year , second year , and third year ) in each high school . thus , we had a total selection of at least 18 classes in each region ( 9 classes from the boys ' schools and 9 from girls ' schools ) . the explanations about the objectives of the present study were provided for principals of these schools . participants completed a simple questionnaire during school hours . in total , 600 questionnaires were distributed , and 521 were returned ( response rate , 86.83 % ) . this study was approved by the research council and ethics committee of the isfahan university of medical sciences . first , participants completed questions related to demographic data and the tpb variables , which included attitudes , pbc , subjective norms , additional variable past behavior , and abc . most of the measures used within the study were developed in a previous study published by blanchard et al . a panel of experts , consisting of 5 experts in the fields of health behavior , education , nutrition , and a healthy eating provider with field experience in nutrition , reviewed and assessed the questions of commitment to a plan of action scale orally by evaluating the appropriateness and relevance of the items and response format . they confirmed them as being representative of the construct in order to confirm content validity of the instrument . the feedback from the panel of experts which was mostly regarding the wording and phrasing of questions was used to revise and modify the instrument . a pilot study was conducted to examine the utility of the instruments and to identify the problems and benefits associated with the design . the data were used to estimate the internal consistency of the scales , using cronbach 's coefficient alpha . attitude to fast food consumption was assessed as the mean of twenty questions with 5 - point items including ten items for behavior beliefs and ten for outcome expectancies . beliefs such as fast food tastes good were measured on a 5 - point scale between 1 ( strongly disagree ) and 5 ( strongly agree ) . expectancies , directly related to the previous beliefs , were also measured on a 5 - point scale with participants responding to a sentence like eating fast food frequently is good for my health with a score between 1 ( extremely unimportant ) and 5 ( extremely important ) . participants rated on a scale of 15 with a higher score indicating a more positive attitude . for example most people who are important for me think that i should eat fast food regularly was typical of the items for this construct . each item was presented on a 5 - point scale from 1 ( strongly disagree ) to 5 ( strongly agree ) , with a higher score indicating higher normative pressure . for example it would be impossible for me not to eat fast food regularly during the next montheach item was presented on a 5 - point scale from 1 ( strongly disagree ) to 5 ( strongly agree ) , with a higher score indicating higher level of perceived control . for example where i live , i have no access to fast - food outlets . two items were measured on a 5 - point scale between 1 ( strongly disagree ) and 5 ( strongly agree ) . past behavior was measured with two items , on average , how often do you eat fast food ? and in the last week , how many times have you eaten fast food ? . responses were rated on a 7 - point scale , ranging from 0 ( never ) to 7 ( more than once per day ) for first item and the number for fast food intake in past week for second item . for example given my lifestyle , it is likely that i will eat fast food regularly over the next four weeks . each item was presented on a 5 - point scale from 1 ( strongly disagree ) and 5 ( strongly agree ) , with a higher score indicating higher intention of fast food intake . behavior ( fast food consumption ) was measured with a short self - report measure of fast food consumption during one week . eight items ( sandwich , berger - piroshky , hot dog , snack , pizza , chicken nugget , and fried chicken ) were used to assess consumption at each time point . scores from the eight items were summed to create a composite score of the fast food consumption during one week . all data analyses were performed using spss version 14.0 with an alpha level of 0.05 . to test normality of data , kolmogorov - smirnov test was conducted . pearson correlation was used to examine the associations among the variables of the tpb model . we applied multiple regression analysis to predict intention and behavior with and without the additional variables . finally , bivariate analysis and anova were used to link the results of the tpb with individual characteristics of the respondents . table 1 provides a summary of the demographic characteristics of the students in this study . there was a direct association between economic status and the amount of fast food intake in the present study ( r = 0.235 , p 0.001 ) . high levels of education of mother ( r = 0.154 , p 0.001 ) and father ( r = 0.138 , p 0.001 ) was positively correlated with fast food consumption . there was no significant association between parents ' job and family size with fast food consumption . table 2 shows means , standard deviations , range , and bivariate correlations among attitude , subjective norm , pbc , intention , behavior , past behavior , and abc regarding fast food intake among iranian high school adolescents . all of the tpb variables with the exception of pbc ( r = 0.21 ) and actual behavior control ( r = 0.09 ) were found to have significant positive correlations with intention to consume fast food ( p 0.01 ) . higher positive attitude toward fast food consumption ( r = 0.40 ) , and subjective norms ( r = 0.38 ) were significantly associated with a stronger intention to fast food consumption ( p 0.001 ) . furthermore , those who had a higher pbc towards eating fast food had a weaker intention to fast food intake . male students had higher perceived subjective norms than female students ( t ( 521 ) = 2.89 , p 0.05 ) , but no gender differences were found for attitude or pbc ( p 0.05 ) . figure 1 shows that attitude , subjective norm , and pbc explained 25.7 % of the variance in the intention to fast food consumption . attitude ( = 0.311 , p 0.001 ) , subjective norm ( = 0.294 , p 0.001 ) , and pbc ( = 0.102 , p 0.01 ) had the greatest influence on intention , respectively . regarding the association of pbc with attitude and intention to fast food consumption , less pbc toward fast food consumption was associated with a stronger positive attitude and intention . furthermore , pbc was a nonsignificant predictor of high school students ' behavior ( = 0.01 , ns ) . the direct and indirect effects of both attitude and subjective norms on behavior were also significant ( p 0.001 ) and subjective norms were the strongest predictive of behavior . high school students ' intention was positively related to their own behavior and accounted for 6 % of its variance ( p 0.001 ) . figure 2 shows the tpb model with additional variables of past behavior and abc as predictors of both intention and behavior . subjective norm ( = 0.269 , p 0.001 ) , attitude ( = 0.252 , p 0.001 ) , past behavior ( = 0.242 , p 0.001 ) , pbc ( = 0.096 , p 0.05 ) , and abc ( = 0.090 , p 0.05 ) had the greatest influence on intention . actual behavior control was found to be unrelated to behavior , and it was less effective than past behavior on intention ( p 0.05 ) . adding past behavior in this model significantly increased the variance in intention to 5.4 % and the variance in behavior to 15.1 % . therefore , both directly and indirectly , past behavior was most predictive of behavior ( p 0.001 ) . in total , 31 % of the variance in intention and 21 % of the variance in behavior could be predicted by the model presented in figure 2 . this study examined the applicability of tbp model and tpb model with additional variables of past behavior and abc to determine predicting factors of fast food intake . so this study investigated the direct and indirect effects of tpb constructs on intention and behavior . the major finding was that tpb with additional past behavior and abc had higher power compared to the classic tpb framework . in tpb model , this was lower than the reported value from other study which showed that attitude , subjective norms , and pbc explained 50 % of the variance in intention to fast food consumption in an australian sample . we found that intention to consume fast food was predicted by attitude ( direct effect ) , subjective norm , and pbc ( negative relationship ) , either directly or indirectly . interestingly , while some studies suggest that subjective norms are better predictors of intention to consume fast food than attitude , in the present study , attitude was a stronger predictor of intention than subjective norms and pbc in the tpb model , but in the tpb with additional variable model subjective norms were the strongest predictor . similar findings reported that attitude toward snacking was the strongest predictor of intentions , followed by subjective norm and pbc . in this study , a strong subjective norm was related to decreased perception of controllability to consume fast food , thus , indicating the importance of social influence in fast food consumption . consistent with the results of collins and mullan 's study intention was found to be a significant predictor of behavior , accounting for 28.8 % of variance in snacking among undergraduate psychology students from an australian university . this finding showed that the interventions to increase students ' motivation for reducing the frequency of fast food consumption may need to focus on creating more positive attitudes regarding healthy eating , social norms , and increasing pbc to limit fast food consumption . consequently , greater understanding of these determinants is likely to help in the development and implementation of future intervention for students , a group that consumes fast food more frequently than other age groups emphasizing supporting peers to engage in healthy eating behaviors . the tpb model with additional behavior in the present study showed that the model was more capable of explaining variation in behavior . another noteworthy finding in the path analysis was the direct and indirect effect of past behavior . past behavior had stronger direct and indirect effect on fast food consumption and significantly increased the amount of explained variance in both intention and behavior in our study . in the previous studies , past behavior improved the prediction of intention and behavior and it accounted for 13.6 % of variance in intention and 21.5 % of variance in snacking . the path model in the present study showed direct effect of abc and indirect effect of behavior on students ' intention to consume fast food . high school students in isfahan were more likely to report positive attitude toward fast food intake and more likely to consume fast food with their friends and parents . the results indicated that the older 15 to 18 year adolescents who reported the intention to consume fast food had a less pbc and actual control . all variables had a direct effect on behavior except for pbc and abc that exert indirect effects on behavior in the present study . although previous studies in iran emphasized on the role of dietary intake on the risk of chronic diseases as well as nutrients deficiency , we are not aware of studies mostly focus on the field of specific determinants such as norms and beliefs in iran . seo and lee examined fast food consumption status among middle school students and explored factors influencing fast food consumption using tpb . it has been suggested that higher intention , perceived behavior control , attitude , and subjective norm led to higher rates of fast food consumption behaviors among middle school students in seoul . the present study , however , focused on adolescents in iran . there might be some differences between the results in the researches in middle eastern countries and other countries in other parts of the world . thus , the discrepancy between our findings and other studies findings may be due to differences in the age , cultural context , or health motivations . in this study , both models performed better in explaining the intentions than fast food consumption . it is suggested that future studies focus on tpb model with additional variables to reduce fast food consumption among children and adolescents in iran . strengths of the current study were a novel investigation regarding the predictors of fast food intake of high school students in isfahan , iran that identified possible avenues for interventions . beaulieu and godin emphasized on the importance of using tpb to develop nutrition - based interventions for encouraging high school students to stay in school for lunch instead of eating in fast food restaurants . one limitation of the current study relates to the potentially biased sample of high school students aged 1518 years . we had access to just this age group among adolescents and according to our hypothesis that that fast food consumption is a problem among adolescents , we just focused on adolescents in this study . however , researches have shown that this age group had higher intake of fast foods . so , we should keep in our mind that the results of the present study could be specified for adolescents . future research in iran should involve another age group and obtain more detailed dietary information of various groups to better understand the relationship between beliefs and fast food consumption . in addition , self - report data and the cross - sectional design were used for this study . the present study basically confirmed the applicability of the tpb to adolescent students in isfahan , iran , and the effect of past behavior and abc on their intention to and behavior of fast food intake . thus , further studies could examine the effectiveness of various strategies in altering the psychological determinant of fast food intake among iranian students . findings indicate that tpb is useful for predicting factors directly and indirectly related to fast food consumption among high school students in isfahan by comparing two models of tpb . the study was the first to use the tpb to predict fast food consumption in an adolescent population in a developing country , iran . subjective norms in tpb model and past behavior in tpb model with additional variables ( past behavior and actual behavior control ) were the most powerful predictors of fast food consumption . this study suggests that a higher social pressure from peers or family and higher past behavior had the strong influence of fast food consumption . this difference between studies in other countries may be attributed to sociocultural differences and differing behavioral patterns in adolescents towards fast food consumption . it is concluded that the tpb may be used in developing countries , like iran , as a framework for planning intervention programs in order to predict and improve the healthy eating behavior of students . among iranian adolescents , eating fast foodmay be part of their lifestyles ; thus , our results suggest that intervention programmers should focus on the beliefs , social norms , and past behavior based on pbt model to help adolescents in deciding how often to eat fast food , controlling their energy intakes and improving their overall diet quality .\noutput:\n" }, { "from": "agent", "value": "objective . this study was conducted to identify some factors ( beliefs and norms ) which are related to fast food consumption among high school students in isfahan , iran . we used the framework of the theory planned behavior ( tpb ) to predict this behavior . subjects & methods . cross - sectional data were available from high school students ( n = 521 ) who were recruited by cluster randomized sampling . all of the students completed a questionnaire assessing variables of standard tpb model including attitude , subjective norms , perceived behavior control ( pbc ) , and the additional variables past behavior , actual behavior control ( abc ) . results . the tpb variables explained 25.7 % of the variance in intentions with positive attitude as the strongest ( = 0.31 , p < 0.001 ) and subjective norms as the weakest ( = 0.29 , p < 0.001 ) determinant . concurrently , intentions accounted for 6 % of the variance for fast food consumption . past behavior and abc accounted for an additional amount of 20.4 % of the variance in fast food consumption . conclusion . overall , the present study suggests that the tpb model is useful in predicting related beliefs and norms to the fast food consumption among adolescents . subjective norms in tpb model and past behavior in tpb model with additional variables ( past behavior and actual behavior control ) were the most powerful predictors of fast food consumption . therefore , tpb model may be a useful framework for planning intervention programs to reduce fast food consumption by students ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the population is aging worldwide1 , and approximately one - third of people aged 65 years or above fall at least once a year . studies show that the older the person , the more likely that a fall will result in an injury2 . one of the major consequences of falls by older adults is lower extremity fracture , which can lead to significant disability . although much of the research on falls has focused on falls that occur while standing or walking , falls from a seated position are of special concern for those with a disability involving the lower extremities . these individuals often need to perform functional activities from a sitting position ; therefore stability of movement in multiple directions is crucial for their safety and movement efficiency . indeed , simple daily tasks such as transferring or reaching can result in a fall , and one of the causes is a loss of sitting balance3 . although epidemiological information about the incidence of falls from a sitting position among older adults is still lacking , about one - third of wheelchair users were found to have one or more falls over the course of a year , and 14 % of patients with spinal cord injury were injured further as a result of falls4 . it is generally believed that the older adult population has a similar or higher incidence of injury from falls . previously , most sitting balance tests have been constructed around reaching abilities5 , 6 . however , such measurements have their limitations . the reaching ability only measures the spatial domain without consideration of the temporal domain ( i.e. , the time needed to complete the test ) or the quality of movement . indeed , the time to complete functional activities could reflect the efficiency of subjects with ambulation difficulties in accomplishing tasks , like the timed - up - and - go test . moreover , differences in anthropometrics between sitting heights and arm lengths also make comparisons between individuals difficult . most importantly , they involve only one orthogonal movement plane for each measure , which is not functionally adequate because many daily activities , such as putting on a sock located beside oneself , involve sequential diagonal movements of the trunk . in view of these limitations , functional or task - oriented approaches to the assessment of sitting balancenevertheless , these types of performance - based measures may be difficult for the tester to score or judge . moreover , no standardized or sequential protocol for the assessment of sitting balance has been explored . this study was conducted to determine the test - retest reliability of a newly developed test of dynamic sitting balance , the sequential weight - shifting ( sws ) test . the sws test is more functional in nature than previous tests and specifically incorporates the temporal domain without imposing a floor effect . older adults with physical dependence were recruited from four residential care homes in hong kong by convenience sampling . the participants characteristics are shown in table 1table 1 . characteristics of the subjects of studies 1 and 2demographic variablesstudy 1 ( n = 10 ) study 2 ( n = 23 ) age ( years ) 88.07.885.68.0 weight ( kg ) 48.38.452.310.7 body height ( cm ) 150.57.6149.19.5 sitting height ( cm ) 63.68.564.87.4 arm length ( cm ) 66.24.065.06.3 ems score 11.02.69.74.1 barthel index 66.612.467.915.4 mmse score 19.96.919.07.0 values are mean sd . their ambulation level as assessed by the functional ambulation classification ( fac ) 9 was used as one of the selection criteria : only older adults with fac scores of between 0 and 2 were included . these scores indicate a need for physical assistance for ambulation10 , and the candidates mainly remained sitting when performing daily activities . the candidates were excluded if they : had a progressive neurological disease or any unstable medical condition ; had any signs or symptoms consistent with major unstable cardiopulmonary disease ( i.e. , ischemic chest pain , unaccustomed shortness of breath , shortness of breath with mild exertion , recurrent episodes of syncope , orthopnea , paroxysmal nocturnal dyspnea , palpitations , tachycardia , claudication , or ankle edema with severe pitting ) ; were unable to follow instructions ; or had a terminal disease . all of the participants signed an informed consent form before participating in the study . ems : elderly mobility scale ; mmse : mini - mental status examination the assessments used in this study included the newly developed sequential weight - shifting ( sws ) test , a reaching test in the sitting position ( forward and lateral reach ) , tests of arm muscle strength ( shoulder flexor strength and hand grip strength ) , an eye - hand coordination test , a mobility test , and a pulmonary function test . in the sws test , two force platforms ( model 9286aa , kistler , gommiswald , switzerland ) were placed under the participants buttocks and feet to measure shifts in the resultant center of pressure ( cop ) while sitting . the force platforms were connected to a computer with labview software ( version 8.6 ; national instruments ) customized to display and store in real time the motion of the resultant cop during the sitting balance test . the participants initially sat on the force platform with their arms crossed on their chests and their hips and knees at approximately 90 degrees of flexion . their feet were placed shoulder - width apart and rested completely on the second force platform . the participants were required to sit quietly before the dynamic test began to record their baseline body sway . the test began when a target appeared on a visual display unit ( vdu ) in front of the participant ; the vdu also displayed the current position of the participant s cop . the participants were asked to shift their center of mass ( com ) as quickly as possible without losing their balance in order to propel the cop trace to reach 10 targets that appeared sequentially on the vdu . when each target was hit , it disappeared and the next target appeared . the unfilled square denotes the center of pressure of the subject at rest , filled squares denote the target locations ) . the distance from the center to each target was normalized according to the participant s individual height and was determined using the normalized body sway angle . the normalized body sway angles were calculated from the data of 22 older adults of similar mobility level ( fac = 02 ) , collected in a previous study , and twenty - fifth percentiles of their limits of stability were chosen to position the target locations . the unfilled square denotes the center of pressure of the subject at rest , filled squares denote the target locations visual feedback regarding the participants cop was provided continuously on the vdu as the participants adjusted their com to reach the targets . each participant performed the test only once , but a familiarization trial was performed to ensure that the participants fully understood the testing procedure .2 . equipment setup for the sequential weight - shifting ( sws ) test shows the equipment setup for the sws test . equipment setup for the sequential weight - shifting ( sws ) test the forward reach test in a sitting position ( sit - and - reach ) has been shown to be reliable ( test - retest reliability intraclass correlation coefficient [ icc ] , 0.79 ) 5 . tests of lateral reaching in a sitting position have also reported that it has excellent intrarater reliability ( icc , 0.96 ) 6 . in the forward reach test , a measuring tape was secured horizontally on a wall at the level of the participants acromion process . the participants sat on a wooden stool with their hips , knees , and ankles positioned at approximately 90 degrees of flexion , with about 5 cm ( 2 inches ) of clearance between the popliteal fossa and the edge of the stool11 . each participant was requested to sit up straight , make a fist with the dominant hand , straighten the elbow , and flex the shoulder to 90 degrees . the participants were allowed to use their other arm for counterbalance only ( i.e. , they were not allowed to hold on to the chair or to bear weight with their other arm ) . the placement of the end of the third metacarpal along the tape was recorded as the initial position . the participant then reached as far forward as possible without rotating the trunk or losing balance . the position of the end of the third metacarpal was then recorded as the final position . the distances achieved in the reaching test were defined as the difference between the initial and final positions . if the participant touched the wall or lost his or her balance during the test , the trial was repeated . the investigator sat beside the participants to record the measurements and to help prevent them from falling . the tests of lateral reach to the left and right were performed in a manner similar to that of the forward reach test by asking the participants to reach to the side using the left and right arms , respectively , with the shoulder abducted at 90 degrees . the participants were not permitted to lift their heels or any portion of their feet off the floor . if the feet moved , the trial was repeated . each participant was allowed to practice these two tests twice before performing the three test trials . shoulder flexor strength was measured with a nicholas mmt hand - held dynamometer ( model 01160 , lafayette instrument , lafayette , in , usa ) . the participants were asked to sit with the tested arm at approximately 90 degrees of shoulder flexion with the elbow extended12 . the force pad of the hand - held dynamometer was always held perpendicular to the arm being tested . for the participants comfort and because of the fragility of their skin , a towel was placed between the force pad and the arm being tested . the participants were then asked to flex their shoulder against the device , which was placed just proximal to the epicondyles of the humerus . the mean value of three trials was computed for the strength tests , because the use of three trials was shown to have greater test - retest reliability than the use of one trial or the use of the highest of the three scores13 . the duration of the contraction was 3 seconds , which was usually sufficient to register a maximum reading14 . hand grip strength was measured with a jamar hydraulic hand dynamometer ( sammons preston , abilityone co. , bolingbrook , il , usa ) . the reliability and high test - retest reliability of the jamar dynamometer have been confirmed13 . the participants were asked to adduct the shoulder in neutral rotation with the elbow flexed at 90 degrees , the forearm in a neutral position , and the wrist between 0 and 30 degrees of extension and between 0 and 15 degrees of ulnar deviation13 . for standardization , the grip strength was measured to the nearest kilogram . for the eye - hand coordination test , a vdu ( cleartek 3000 ; capacitive touchscreens , microtouch systems inc . , methuen , ma , usa ) and a force - sensing resistor were used , and the data were collected using customized tailored labview software ( labview , version 7.0 , national instruments , budapest , hungary ) . the participants were seated on a chair with the seat height adjusted so that the upper edge of the screen was at each participant s eye level . the hips , knees , and ankles were in approximately 90 degrees of flexion , and the feet were placed completely on the floor . the participants were instructed to sit erect with the trunk supported throughout the test . a mark was positioned at the center of the upper edge of the display unit , and the participants were asked to fix their eyes on it at the beginning and during the entire test . at the beginning of the test , the participants hands were positioned on hand - like markers on a table 10 cm from the screen . the force - sensing resistor connected to the computer system was located underneath the thumb of the hand - like marker for the participant s dominant hand ( i.e. , the side used for writing and for holding chopsticks ) . in each trial , the participants were instructed to point to the visual signal as quickly and as accurately as possible . spoken encouragement was delivered ( in cantonese ) at the middle of each set of tests to counter any decrease in attention span . the visual target was an image of a ball ( 1.2 cm diameter ) on the vdu . the participants were required to touch the ball with the index finger of their dominant hand . each of the 20 targets appeared as soon as the participant had touched the previous ball . the participants were asked to touch the visual targets as quickly and as accurately as possible . the movement time was measured from the time the participant s hand left the force - sensing resistor and the time the hand touched the 20th target . the test - retest reliability was evaluated using 20 individuals in a previous study16 , and the iccs for reaction time , movement time , and accuracy were 0.70 , 0.68 , and 0.71 , respectively . the elderly mobility scale ( ems ) was used to assess locomotion , balance ( functional reach ) , and key position changes ( sitting to standing , lying to sitting , sitting to lying , and standing with and without support ) . the maximum score possible , which represents independent mobility , is 20 , and the minimum score is 0 . individuals with a score below 10 on the ems are likely to need help with mobility and adl , whereas those with a score or 14 or more are likely to be independent in mobility . the ems has concurrent validity , exhibits high correlation with the barthel index and the functional independence measure , and demonstrates good inter - rater reliability , as no significant difference was found between testers17 . pulmonary function tests were performed with a spirometer ( microlab 3500 v6 , micro medical ltd . , the participants were asked to inhale a maximal breath and then to exhale into a mouthpiece as hard , as fast , and for as long as they could , so that the entire exchangeable gas volume was emptied from their lungs as quickly as possible . the values for forced vital capacity , forced expiratory volume in the first second , and peak expiratory flow were recorded . the best values of three attempts were used in the analysis18 . in study 1 , the participants repeated the sws test 1 week after first performing it under similar conditions . in study 2 , the participants underwent a series of physical and mobility assessments that included the sws test , forward and lateral reach tests in a sitting position , shoulder flexor and hand grip strength tests , an eye - hand coordination test , a mobility test , and pulmonary function tests . the results were entered into a database for analysis using the statistical package for the social sciences ( spss ) version 17 for windows . the test - retest reliability was determined using the intraclass correlation coefficient ( icc ) with trial as the random factor and rater as the fixed factor in a two - way mixed anova model . in the results , the notation icc ( 3,1 ) signifies that model 3 was used for the assessment of test - retest reliability , and 1 represents the number of trials used in the dynamic sitting balance test , in this case , a single rating . the correlations between the sws test results and the physical data were analyzed using pearson s product - moment coefficient of correlation . an value of less than or equal to 0.05 was considered significant in all statistical analyses . after administration of the sws test , the procedure was repeated 1 week later under similar conditions . the icc ( 3,1 ) value was found to be 0.67 ( 95 % confidence interval , 0.12 to 0.91 ) , which suggests moderate reliability of the sws test has moderate reliability within this population with a mean age of 88 years19 . table 2table 2 . pearson correlations between the physical measures and sequential weight shifting timesphysical dimensionr ( 95 % ci ) sitting balance forward reach test 0.740 * * ( 0.897 to 0.417 ) right reach test 0.533 * ( 0.789 to 0.118 ) left reach test 0.522 * ( 0.789 to 0.089 ) shoulder flexor strengthleft0 .456 * ( 0.731 to 0.054 ) right0 .472 * ( 0.740 to 0.074 ) hand grip strengthleft 0.615 * * ( 0.819 to 0.272 ) right0 .666 * * ( 0.846 to 0.350 ) eye - hand coordination time to complete the sequential target pointing task0 .458 * ( 0.045 to 0.737 ) physical mobility elderly mobility scale0 .529 * * ( 0.773 to 0.149 ) pulmonary functionforced expiratory volume in 1 second0 .544 * * ( 0.781 to 0.170 ) forced vital capacity0 .594 * * ( 0.808 to 0.241 ) peak expiratory flow0 .442 * ( 0.723 to 0.036 ) * indicates significance at the p0 .05 ( * * p0 .01 ) level of confidence shows the correlation coefficients between the results of the sws test and the physical data and the results of the mobility tests . the parameters that had the strongest correlations with the results of the sws test were the forward reach test ( r = 0.74 ) , the two tests of hand grip strength ( right , r = 0.666 ; left , r = 0.615 ) , and forced vital capacity ( r = 0.594 ) . * indicates significance at the p0 .05 ( * * p0 .01 ) level of confidencea new sequential weight - shifting test of sitting balance was developed and its psychometric properties were established in this study . the sequential weight - shifting test has acceptable test - retest reliability and correlations with forward reach in the sitting position , arm muscle strength , eye - hand coordination , mobility , and pulmonary function . the moderate reliability of the sws test can be considered to be acceptable among this population of older adults with a mean age of 88 years and some physical disability . a similar reliability ( icc = 0.69 ) was reported in another study with a similar assessment protocol , i.e. , an investigation of the dynamic sitting balance control of subjects with spinal cord injury20 . the lack of familiarity with the equipment setup and testing procedures may have affected the reliability result even though familiarization trials were conducted before the actual testing . moreover , greater inconsistencies in physical and cognitive performance among the old - old population may also contribute to the variable responses . furthermore , a more physical challenging test in the dynamic mode may contribute to the variations as more sensorimotor processing is required to maintain control of the balance . it is also worthwhile noting that only one sws test trial was conducted in this study in order to avoid fatigue among the older adults . the results show that the participants who had better performance in the tests of physical function were able to complete the sws test more quickly . the significant correlations of the times achieved in the sws test with the results of other dynamic sitting balance tests , such as the forward reach test in a sitting position , support its convergent validity . the analysis also found that the time domain ( as revealed in the sws test ) correlated with the spatial domain of balance control in a sitting position , particularly the forward reach test . a possible explanation for this is that stronger neck and trunk muscles were needed in the sagittal plane , than in the coronal plane , for greater excursion in the anteroposterior direction as well as the faster movement required by the sws test . significant correlations of the sws test with both shoulder flexor strength and hand grip strength were found in this study . traditional tests of balance control have shown it correlates with physical functioning21 , and with both shoulder flexor strength22 and hand grip strength23 . an individual s arm strength may reflect the general muscle strength of their entire body , which determines balance control while sitting . indeed , a positive correlation has been reported between lower extremity strength and standing balance control24 . the significant correlation between arm muscle strength and dynamic sitting balance control revealed by this study is a novel observation . a significant correlation was also found between eye - hand coordination and performance in the sws test . it has been shown that eye - hand coordination is one of the fitness components that is most strongly associated with the functional performance of older adults25 . subjects who have better balance while sitting may have better functional capability . specifically , the coordination of eye - hand movements requires coordinated truncal movement and stable sitting balance control , which are reflected in the sws test . this correlation may be the result of the positive relationship between pulmonary function and general physical fitness26 being reflected in sitting balance control27 . the time domain of the sws test significantly correlated with muscle strength , eye - hand coordination , mobility , and pulmonary function . this may imply that the sws test is to some extent functional in nature and that it involves many sensorimotor systems such as dynamic balance control , eye - head - trunk coordination , muscle strength ( especially that of the trunk muscles ) , and general mobility . this body of evidence makes it clear that all of these physical components are interrelated . in fact , the relationships between physical parameters and functional abilities have been studied and evidence is accumulating . the results of this study are of great clinical importance , because the overall correlation of the sws test results with many physical parameters further confirms that the sws test can assess many physical states ranging from impairment to a certain degree of functional capability . the results of this study suggest the potential use of the sws test both as a specific assessment of dynamic sitting balance , which does nt impose floor effects , and as a more generic assessment of general physical fitness . there are , however , several limitations to the use of the sws test in a clinical setting . the major limitations of this test are the involvement of sophisticated instruments which are expensive in terms of equipment ( e.g. force platforms ) and the necessity of technical expertise in clinical settings , even though the sws test can provide time domain and diagonal measurements . the force platform could possibly be tailored to purpose using four load cells mounted on the platform to reduce the cost . also , the size of the platform could be adjusted to suit different sizes of chair and even wheelchair20 . another issue is that it may be difficult for older adults with cognitive impairment to perform the sws test . the mini - mental status examination scores of the subjects were 19.9 and 19.0 in study 1 and study 2 , respectively . however , the cut - off point for the test remains to be determined . this study included a small sample size with convenience sampling rather than probability sampling . it is possible that some older adults who met the selection criteria and were representative of critical differences were not recruited . thus , a large random sample is suggested for future studies to avoid selection bias and to increase the generalizability of the study results . furthermore , the protocol tested here emphasized the time domain . the spatial domain of this test ( i.e. , different starting and ending locations and control of cop trajectory ) remains to be explored , and the test s psychometric properties also need to be explored further in different populations , such as patients who have experienced stroke or spinal cord injury . finally , the establishment of cutoff points for the results of the sws test may provide more information for the prediction of fall risk of chair - bound older adults . in conclusion , this study was designed to generate valuable , previously unavailable information regarding the measurement of dynamic sitting balance using a sequential protocol . the sws test was shown to provide a functional approach to the assessment of sitting balance control , with multidirectional and sequential movement components . the continuous scale of measurement is applicable to a wide range of capabilities and is not sensitive to floor effects . the sws protocol demonstrated satisfactory psychometric properties , including acceptable test - retest reliability and convergent validity with the forward reach test . it also showed correlation with arm muscle strength , eye - hand coordination , and pulmonary function . therefore , an aggregation of measures from various physical function domains may provide the initial screening criteria for exercise training for older adults .\noutput:\n" }, { "from": "agent", "value": "[ purpose ] the evaluation of sitting balance is important for the prevention of falls in older adults , especially those who have a disability involving the lower extremities . however , no studies have been designed to assess a patient s dynamic sitting balance using a sequential protocol . the objective of this study was to investigate the psychometric properties of the sequential weight - shifting ( sws ) test . [ subjects and methods ] twenty - three older adults who were physically dependent with regard to ambulation were recruited by convenience sampling . in study 1 , 10 participants performed the sws test and repeated the procedure 1 week later . in study 2 , 23 participants were assessed using the sws test , forward and lateral reach tests in a sitting position , tests of shoulder flexor and hand grip strength , an eye - hand coordination test , mobility tests , and pulmonary function tests . the test - retest reliability of the sws test and its correlations with the different physical dimensions were examined . [ results ] the intraclass correlation coefficient ( 3,1 ) of the sws test was 0.67 . the results of the sws test correlated significantly with forward reach in the sitting position , arm muscle strength , eye - hand coordination , mobility , and pulmonary function ( all p < 0.05 ) . [ conclusion ] the sws test demonstrated satisfactory psychometric properties and can be considered a useful functional approach for the measurement of sitting balance ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: recent advances in laboratory medicine have allowed for automated devices , like the cellavision dm96 ( ccs ; cellavision , lund , sweden ) , to screen for specific cell abnormalities at a much more efficient rate than without automation . previous evaluations of these types of systems have shown good correlations with the manual differentiation of normal cells . automated red blood cell ( rbc ) analysis and screening therefore presents clinical laboratories with the potential to process large sample volumes , while ensuring a high accuracy rate in diagnosis . in particular , routine identification of the absence or presence of abnormal morphological features in rbc can be an important diagnostic tool for many hematologic diseases . for example , the presence of acanthocytes in blood smears may indicate hemolytic anemia of severe liver disease . however , microscopic analysis is still needed when abnormal cells are present because automated analyzers offer limited morphological information for rbc 's . some institutions may choose to autoverify the results from the cellavision dm96 into their laboratory information system . however , at calgary laboratory services ( cls ) the rbc morphologic abnormalities identified by the system are sent for medical laboratory technologist ( mlt ) or pathologist review . therefore at cls , the cellavision dm96 is primarily used as a screening tool for rbc morphologic abnormalities . in this paperthe system scans a user - defined portion of a microscopy slide and automatically locates and presents images of cells on blood smears . a peripheral blood application is specified for differential count of white blood cells , classification of rbc morphology and platelet estimation . the cellavision dm96 system overlays the digitized image with a grid to facilitate accurate cell counting . the operator recognizes and verifies the recommended classification of all cells according to types specified in a preexisting database . for rbc morphology , the cellavision dm96 system scans one zone equivalent to eight fields using a 100 objective . the cellavision dm96 system is outfitted with four flag levels to discriminate between six morphological abnormalities of size and color of rbcs including hypochromasia , polychromasia , microcytosis , macrocytosis , anisocytosis and poikilocytosis , and has the ability to characterize several more , many of which are included in this study . peripheral blood smears performed as part of routine medical care were collected from five hematology labs in calgary , alberta , canada . four of the centers are acute care facilities : foothills medical center ( 50 smears ) , peter lougheed centre ( 50 smears ) , the rockyview general hospital ( 35 smears ) and the alberta children 's hospital ( 37 smears ) . the fifth lab is the diagnostic and scientific center ( 40 smears ) , which collects and analyses samples from the calgary community and surrounding towns in the southern alberta region . however , some of the specific rbc abnormalities were not identified in cellavision dm96 run samples , such as malaria parasites , basophilic stippling , burr cells and howell jolly bodies in the count for that sample . the samples testing for malaria are not further analyzed in the hematology department and are then forwarded to microbiology for further testing . therefore , these individual results were excluded , reducing the number of samples to 198 for some rbc abnormality counts . the selection criteria for the study identified abnormal rbc morphological samples at each site . these samples were identified by randomly selecting abnormally screened rbc morphology samples by the initial screening device , the coulter lh 780 analyzer . the analyzer identifies nonspecific rbc abnormalities such as low / high hemoglobin or mean corpuscular volume . these nonspecific abnormalities trigger the analyzer to automatically create a peripheral smear on a glass slide . abnormal samples identified with rbc morphological defects were collected until a preselected amount of samples was met . once this amount was reached the slides were screened by the cellavision dm96 and also by the mlts at each site . slide smears of the abnormal slides were made using an automatic coulter lh slide maker and then stained with wright - giemsa by the coulter lh slide stainer . each site performed manual differentiation using standard microscopic techniques on each of the slides . for standard rbc morphology identification , the smears were evaluated , as per cls hematology department standards , by using a 100 objective lens scanning 10 separate fields [ table 1 ] . these standards were based on hematology reference materials and then established using international society for laboratory hematology guidelines for suggested action following automated complete blood count differential analysis . each slide was scored at each individual site by two experienced mlts . in cases of observer disagreement , rbc morphologic abnormalities examined in this study all of the sites had experienced mlts ( 25 + year 's experience ) evaluate the slides . the results were reported as either present or absent for 15 different rbc morphological abnormalities : acanthocytes , basophilic stippling , burr cells , howell jolly bodies , ovalocytes , pappenheimer bodies , polychromasia , rbc agglutination , rouleaux , schistocytes , sickle cells , spherocytes , stomatocytes , target cells and tear drop cells . each slide was scored and data was collected using the same criteria as the manual differential method where rbc morphology abnormalities were reported as present or absent . the classification of any of the rbc abnormalities studied is a manual addition from the instrument screen and is not automatic . the cellavision dm96 and glass slide classifications were then compared in truth tables and sensitivities and specificities calculated . the system scans a user - defined portion of a microscopy slide and automatically locates and presents images of cells on blood smears . a peripheral blood application is specified for differential count of white blood cells , classification of rbc morphology and platelet estimation . the cellavision dm96 system overlays the digitized image with a grid to facilitate accurate cell counting . the operator recognizes and verifies the recommended classification of all cells according to types specified in a preexisting database . for rbc morphology , the cellavision dm96 system scans one zone equivalent to eight fields using a 100 objective . the cellavision dm96 system is outfitted with four flag levels to discriminate between six morphological abnormalities of size and color of rbcs including hypochromasia , polychromasia , microcytosis , macrocytosis , anisocytosis and poikilocytosis , and has the ability to characterize several more , many of which are included in this study . peripheral blood smears performed as part of routine medical care were collected from five hematology labs in calgary , alberta , canada . four of the centers are acute care facilities : foothills medical center ( 50 smears ) , peter lougheed centre ( 50 smears ) , the rockyview general hospital ( 35 smears ) and the alberta children 's hospital ( 37 smears ) . the fifth lab is the diagnostic and scientific center ( 40 smears ) , which collects and analyses samples from the calgary community and surrounding towns in the southern alberta region . however , some of the specific rbc abnormalities were not identified in cellavision dm96 run samples , such as malaria parasites , basophilic stippling , burr cells and howell jolly bodies in the count for that sample . the samples testing for malaria are not further analyzed in the hematology department and are then forwarded to microbiology for further testing . therefore , these individual results were excluded , reducing the number of samples to 198 for some rbc abnormality counts . the selection criteria for the study identified abnormal rbc morphological samples at each site . these samples were identified by randomly selecting abnormally screened rbc morphology samples by the initial screening device , the coulter lh 780 analyzer . the analyzer identifies nonspecific rbc abnormalities such as low / high hemoglobin or mean corpuscular volume . these nonspecific abnormalities trigger the analyzer to automatically create a peripheral smear on a glass slide . abnormal samples identified with rbc morphological defects were collected until a preselected amount of samples was met . once this amount was reached the slides were screened by the cellavision dm96 and also by the mlts at each site . slide smears of the abnormal slides were made using an automatic coulter lh slide maker and then stained with wright - giemsa by the coulter lh slide stainer . each site performed manual differentiation using standard microscopic techniques on each of the slides . for standard rbc morphology identification , the smears were evaluated , as per cls hematology department standards , by using a 100 objective lens scanning 10 separate fields [ table 1 ] . these standards were based on hematology reference materials and then established using international society for laboratory hematology guidelines for suggested action following automated complete blood count differential analysis . each slide was scored at each individual site by two experienced mlts . in cases of observer disagreement , rbc morphologic abnormalities examined in this study all of the sites had experienced mlts ( 25 + year 's experience ) evaluate the slides . the results were reported as either present or absent for 15 different rbc morphological abnormalities : acanthocytes , basophilic stippling , burr cells , howell jolly bodies , ovalocytes , pappenheimer bodies , polychromasia , rbc agglutination , rouleaux , schistocytes , sickle cells , spherocytes , stomatocytes , target cells and tear drop cells . each slide was scored and data was collected using the same criteria as the manual differential method where rbc morphology abnormalities were reported as present or absent . the classification of any of the rbc abnormalities studied is a manual addition from the instrument screen and is not automatic . the cellavision dm96 and glass slide classifications were then compared in truth tables and sensitivities and specificities calculated . results from the classification into normal and abnormal were sorted into the categories in table 2 . in regards to sensitivity , we observed a wide range of results in identifying rbc morphological abnormalities . for some rbc abnormalities , such as stomatocytes and sickle cells , there was a 100 % sensitivity rate . however , for rbc agglutination and burr cells , there were low sensitivity rates of 33 % and 47 % , respectively . the other abnormalities ranged in sensitivity from 56 % to 84 % , respectively . sensitivities and specificities of 15 rbc morphologic abnormalities assessed through the cellavision dm96 system as compared to glass slide assessment in regards to specificity , we found more consistent results among the rbc abnormalities . the range of specificity was from 84 % for schistocytes to 99.5 % for both sickle cells and stomatocytes with the other rbc abnormalities within these two values . we observed generally very good specificities but variable sensitivities when the cellavision dm96 system was used to classify rbc morphologic abnormalities when compared to traditional glass slide microscopy . there is only very limited existing literature addressing this question , and reported results have varied widely . one prior study compared a different analytical system , the diffmaster octavia , with the cellavision dm96 . however , the two different systems were compared only to each other and not to a proper reference method such as the industry gold standard manual differential . another study showed that when direct microscopy was used as the reference method against , which the results of the cellavision dm96 were compared , with all discrepant results included in the analysis , the specificity was 8293 % and sensitivity was 2591 % , which was similar to the results of this study . finally , another study reported that blood cell and platelet morphology was judged to be adequate ; however it was not specific for rbc morphological abnormalities . first , the mlts participating at each laboratory involved in the study only analyzed the slides from their individual sites . as a result , although the slides were presented in a blinded fashion to the mlts , there is a large probability that the same technologist manually read the slide and reclassified the cellavision dm96 results . in addition , the selection of peripheral blood smears for this study is not random as slides only with abnormalities were selected . the percentage of abnormal smears is low in routine hematopathology practice and a random sample would evaluate very low numbers of abnormal smears . additionally , the testing of normal blood samples has already been performed and the results have already shown the cellavision dm96 to be reliable and accurate . one interesting observation , corroborated by our study , was that rbc agglutination sensitivity has tested poorly in other cellavision dm96 validation studies . billard et al . , has previously shown decreased sensitivity in platelet aggregates / thrombocytic agglutinates and rbc agglutination . study , may indicate a possible limitation in sensitivity for rbc agglutination in the cellavision dm96 . this study shows that the cellavision dm96 has acceptable specificity , but lacks consistency for sensitivity . a future test featuring sensitivity of rbc agglutination , and other low scoring rbc morphologic abnormalities , combined with a larger number of samples may be warranted to confirm these results .\noutput:\n" }, { "from": "agent", "value": "background : red blood cell ( rbc ) analysis is a key feature in the evaluation of hematological disorders . the gold standard light microscopy technique has high sensitivity , but is a relativity time - consuming and labor intensive procedure . this study tested the sensitivity and specificity of gold standard light microscopy manual differential to the cellavision dm96 ( ccs ; cellavision , lund , sweden ) automated image analysis system , which takes digital images of samples at high magnification and compares these images with an artificial neural network based on a database of cells and preclassified according to rbc morphology.methods : in this study , 212 abnormal peripheral blood smears within the calgary laboratory services network of hospital laboratories were selected and assessed for 15 different rbc morphologic abnormalities by manual microscopy . the same samples were reassessed as a manual addition from the instrument screen using the cellavision dm96 system with 8 microscope high power fields ( 100 objective and a 22 mm ocular ) . the results of the investigation were then used to calculate the sensitivity and specificity of the cellavision dm96 system in reference to light microscopy.results : the sensitivity ranged from a low of 33 % ( rbc agglutination ) to a high of 100 % ( sickle cells , stomatocytes ) . the remainder of the rbc abnormalities tested somewhere between these two extremes . the specificity ranged from 84 % ( schistocytes ) to 99.5 % ( sickle cells , stomatocytes ) . conclusions : our results showed generally high specificities but variable sensitivities for rbc morphologic abnormalities ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: leprosy , a major source of morbidity in developing countries , is a chronic infectious disease caused by the obligate intracellular bacterium mycobacterium leprae . according to the system of classification of ridley and jopling ( 1966 ) , leprosy patients show two major manifestations of the disease , designated as lepromatous leprosy ( ll ) and tuberculoid leprosy ( tt ) . tt is observed in patients with good t - cell mediated ( th1 ) immunity and is characterized by granuloma formation and death of schwann cells ( scs ) leading to loss of myelin sheath and nerve destruction . patients with poor t - cell mediated immunity show the lepromatous - type leprosy ( ll ) . ll leads to massive bacterial load inside host cells specially scs and macrophages . the lesions of tt and ll types are named as t - lep and l - lep lesions , respectively , but damage of the nerves is observed in most of the cases of both types . lepromatous leprosy exhibits multiple lesions of the skin , eyes , nerves , and lymph nodes , which are characterized by tumor - like accumulations of foamy macrophages . the foamy macrophages are fully packed with lipid droplets ( lds ) and contain high numbers of lepra bacilli . foamy macrophages were described first by the pathologist rudolph virchow and despite these lipid - laden cells are a hallmark of lepromatous leprosy , only recently a few researchers started to elucidate the molecular biology of these cells . in the last ten years , it has become evident that m. tuberculosis induces the formation of foamy macrophages , a process which appears to be a key event in both sustaining persistent bacteria and release of infectious bacilli . moreover host lipids from lds are regarded as substantial nutrient source for mycobacteria during infection . middlebrook already demonstrated in the late 1940s that mycobacterial growth in vitro was enhanced by supplementation with oleic acid . wheeler et al . reported insufficient fatty acid synthase activity to support growth in m. leprae . this finding supported the hypothesis that m. leprae scavenges lipids from the host cell . over the last years , it has become evident that survival and persistence of m. tuberculosis is critically dependent on lipid body formation . furthermore , lipid body formation seems to be the prerequisite for transition of m. tuberculosis to the dormant state . this goes along with the important observation that sputum from tuberculosis patients contains lipid body - laden bacilli . for a great number of mycobacterial species , lipids from lipid bodies appear to be the primary carbon source for m. tuberculosis in vivo . for m. tuberculosis , several bacterial genes are upregulated during the dormant state and have been reported to be involved in lipid metabolism such as diacylglycerol acyltransferase ( tgs1 ) , lipase ( lipy ) , and isocitrate lyase ( icl ) . the obligate intracellular organism shows a moderate genome degradation and several genes are absent when compared with other mycobacterial species . due to the gene loss , m. leprae is strongly dependent on thehost for basic metabolic functions . macrophages infected with m. leprae contain oxidized host lipids and it has been observed that m. leprae upregulates 13 host lipidmetabolism genes in t - leplesions and 26 in l - leplesions . the oxidized lipids inhibit innate immune responses and thus seem to be an important virulence factor for the organism . this paper highlights the importance of the lds as one of the most unique determinant for m. leprae persistence and virulence . the formation of lds in m. leprae infected cells has been compared to lds formation in macrophages infected with m. tuberculosis . thereafter , we will focus on the interplay between the lds of the host and the pathogen . m. leprae infects preferentially macrophages and scs . a typical feature of lepromatous leprosy is the survival and replication of m. leprae stored within the lds in the enlarged phagosome of histiocytes . due to strong immune response against m. leprae and arrested bacilli growth in t - lep lesions , the occurrence of foamy cells of m.leprae - infected macrophages / scs is a marker only in l - lep lesions . in l - lep lesions , the expression of lipoprotein and fatty acid metabolism , including lipases genes , was 4-fold greater than in t - lep lesions which supports the previous observation . the damage to nerves of the peripheral nervous system is caused by the infection of scs by m. leprae . in ll nerve biopsies , highly infected scs also contain lds and show a foamy appearance , such as virchow cells found in dermal lesions . neither the origin nor nature of the lipids has been elucidated yet . only recently , in vitro studies by mattos could show that m. leprae induces the formation of lds in human scs . moreover , the group found that lds are promptly recruited to bacterial phagosomes . in scs , lds recruiting by bacterial phagosomesdepends on cytoskeletal reorganization and pi3 k signaling but is independent of tlr2 bacterial sensing . important markers for the lipid accumulation in adipocytes or macrophages are lipid - droplet - associated proteins such as adipose differentiation - related protein adrp and perilipin , which play essential roles in lipid - droplet formation . after phagocytosis of live m. leprae , adrp expression is constantly upregulated in human monocytes . mycobacterium bovis bacillus calmette - gurin ( bcg ) and m. leprae are recognised by the toll - like receptors ( tlr ) tlr6 and tlr2 and induces the formation of foamy macrophages . for bcgit has been shown that surface molecule lipoarabinomannan ( lam ) binds to tlr2 . . m. leprae association to macrophages is mediated by binding of the bacteria to tlr2 and tlr6 . heterodimerization of tlr2 and tlr6 leads to downstream signalling and subsequent lds formation ( figure 1 ) . this suggests that both tlr2 and tlr6 can bind m. leprae alone , or / and the presence of other receptors , binding to m. leprae . the tlr2 or tlr6 knockout macrophages do not also completely abolish ld formation , but show only reduced lds formation . in contrast tlr6 , but not tlr2 , is essential for m. leprae - induced lds biogenesis in scs . members of the cd36 family have to be shown to be required for uptake of mycobacteria . macrophages infected with m. tuberculosis show an increased surface expression of the type 1 scavenger receptors cd36 and lox1 , which facilitate the uptake of oxidized host macromolecules including oxldl ( figure 1 ) . these findings are consistent with the observation that genes for adrp and cd36 are upregulated in l - lep lesions , accumulated with ld enriched macrophages . macrophages generate and release reactive oxygen species ( ros ) during activation of the respiratory burst upon infection with pathogenic bacteria . oxidative stress results not only in damage to cellular structures but also to oxidation of fatty acids , such as low density lipoproteins ( oxldl ) in granulomas . oxldl binding to lox - 1 also increases reactive oxygen species ( ros ) formation . the binding of oxldl to type 1 scavenger receptors cd36 and lox1 induces increased surface expression of both receptors , leading to uptake of oxldl . the increased rate of oxldl uptake results in the accumulation of oxidized lipids , which finally leads to the formation of foamy macrophages ( figure 1 ) . oxldl - laden lung macrophages show enhanced replication of intracellular m. tuberculosis compared to macrophages loaded with nonoxidized ldl . the presence of oxidized phospholipids in m. leprae infected macrophages downregulates the innate immune response and contributes to pathogenesis . moreover , scavenger receptor - deficient phagocytes are characterized by a reduced intracellular bacterial survival and a lower cytokine response . in 1863 , virchow described lipid - laden macrophages . the lipids in these foamy cells form droplets and surround also m. leprae within the phagososomes . this lipid layer or capsule forms a characteristic electron - transparent zone . in contrast to m. tuberculosis , lipid inclusions ( lipid bodies ) seem to be rather exceptional in m. leprae . the electron - transparent zone contains mycoserosoic acids of phthiocerol dimycocerosates as well as phenolic glycolipids . it has been postulated that many of these same molecules together with phosphatidylinositol mannosides and phospholipids are released from the cell wall after synthesis , forming the capsule - like region . the dominant lipid in the cell wall which gives m. leprae immunological specificity is phenolic glycolipid - 1 ( pgl - 1 ) . phenolic glycolipid 1 has been isolated in relatively high concentrations from purified bacteria and from m. leprae infected tissues . pgl - 1 is thought to be a major component of the capsule in m. leprae and constitutes an important interface between bacteria and host . it has been suggested that pgl - 1 is involved in the interaction of m. leprae with the laminin of scs , thus pgl - 1 might play a role in peripheral nerve - bacillus interactions . moreover , phenolic glycolipids seem to be involved in the stimulation of suppressor t - cells in lepromatous leprosy . demonstrated that m. tuberculosis inside foamy macrophages imports fatty acids derived from host tag and incorporates them intact into bacterial tag , which is accumulated in lipid bodies . recently , it was reported that also lds from m. leprae infected scs and macrophages accumulate mainly host - derived lipids , such as oxidized phospholipids . bodipy stains infected scs , indicating that lds contain neutral lipids , such as triacylglycerols ( tag ) . in m.leprae infected - cells , lds show high ability to fuse further to form giant lds . in most mammalian cells , dynein and extracellular signal - regulated kinase - 2 ( erk2 ) extracellular signal - regulated kinase - 1/2 is one of the most upregulated signals after m. leprae induced - scs demyelination and nerve injury . using nih 3t3 cells , andersson et al. demonstrated that erk2 is an essential signal in lds formation and also seem to be crucial for the phospholipase d1 - ( pld1 - ) mediated increases of lds . the erk2 mechanism is mediated by phosphorylation of dynein , which finally upregulates its association in adrp - containing lds . lipid droplets induction in all type of cells associates with lipid droplets protein adipophilin ( adfp ) . the classic model of lds postulates that lds formation take place in the outer leaflet of the endoplasmic reticulum ( er ) membrane ( the place of tag synthesis ) . in this formation , the function of afdp has been proposed in fatty acid absorption and transport . furthermore , the authors also pinpointed similarity in overall observations to one of the important metabolic disease atherosclerosis . similar observation in atherosclerosis showed that adfp is the most expressed ld - associated protein found in macrophages and that the accumulation of lds in lesional macrophages is associated with adfp aggregation . several reports have supported the inflammatory role of macrophages and scs , where lds induction by these cells associated with modulation in production of inflammatory mediators . moreover , increased lds formation accompanied by pge2 and transforming growth factor - ( tgf - 1 ) synthesis in bcg infected macrophage while strong pge2 was seen in foamy macrophages during m. tuberculosis infection . cytokines , chemokines , and growth factors seem to be correlated with lds formation by m. leprae . for instance , persson et al . found that il - 1 and tnf - inflate foamy macrophages formation . m. leprae infection significantly increased nf - b , tnf - , and il - 1 expression in nod1 - and nod2 - transfected macrophages cells . another example , il - 10 and il - 12 secretion correlated with bacilli - ld induction in l - lep lesions . schwann cells are able to produce several type of cytokines , including il - 1 , il - 6 , il - 8 , il - 10 , il - 12 , pge2 , tgf - , and tnf - . pge2 and il - 10 overexpression is associated with clog of il - 12 and no production in m. leprae - infected scs . in late infection state , m. leprae impede the expression of tnf signaling and induce expression of 9 - o - acetyl gd3 as smart strategy to avoid the cellular apoptosis and facilitate its persistence inside the favored cell niche . obviously , lipid biosynthesis and cytokine production as the whole immune response to m. leprae infection are well connected in scs . innate immune response in infected scs seems to be dependent on lds accumulation and tlr2 / tlr6 signaling . using a nonsteroidal anti - inflammatory drug and fatty acids synthesis inhibitors , both lds formation and innate immune responsescompletely abrogated , supporting the role of bacilli - lds induction and immune responses . another modulation observed is downregulation of th1 responses and bactericidal activity through overproduced pge2 where tlr2 and tlr6 heterodimerization plays important role . in general , m. leprae modified - tlrs function stimulates monocytes and macrophages in tt and ll disease type , but in l - lep lesions the adaptive response was debilitated more than what was seen in t - lep lesions . despite the strong evidences that lds induction is associated with modulation of cytokines , it is not known whether cytokines signaling functions within lds themselves . due to the genome reduction m. leprae is strongly dependent on catalytic activities provided by the host . macrophages infected with m. leprae contain oxidized host lipids and it has been observed that m. leprae upregulates 13 host lipidmetabolism genes in t - leplesions and 26 in l - leplesions . but still it is not clear what carbon source m. leprae uses under aerobic or anaerobic conditions . the genome contains genes for utilization of sugars , such as glycolysis , tricarboxylic acid cycle ( tca ) , and monophosphate shunt ( hmp ) pathways . the m. leprae genome contains all genes for a functional glyoxylate cycle , which would enable the organism to use acetyl - coa from the - oxidation of lipids . m. tuberculosis derives much of its energy from the degradation of host - derived lipids . neutral lipids are hydrolyzed by lipases or esterases , yielding fatty acids for energy generation and anabolism of membrane phospholipids . the genome of m. tuberculosis h37rv contains twenty genes designated as putative lipases ( lipa to w , except k and s ) . in the m. lepraegenome , only 2 lipase genes ( lipg , lipu ) were found , suggesting a gene loss in comparison to m. tuberculosis . but recently it has been found that in m. tuberculosis genome only six lip expressed - enzymes showed reasonable hydrolase activity for long - chain triacylglycerols ( lipy , lipc , lipl , lipx , lipk , and lipg ) . lipg and lipu from m. leprae are homologous with lipg and lipu from m. tuberculosis and show sequence identities of 72 % and 79 % , respectively . the lipases lipg and lipu from m. tuberculosis show very low and no activity with long - chain triacylglycerols as substrates . m. tuberculosis lipy is suspected to be a major functional lipase , which utilizes stored triacylglycerols ( tag ) during dormancy and reactivation of the pathogen . lipy shows only a weak similarity with m. leprae lipu ( 23 % identity ) . in summary , it appears that m. leprae uses different lipases for the hydrolysis of fatty acids than m. tuberculosis . all m. tuberculosis and their m. leprae homologs enzymes involved in lipid metabolism in lipid bodiesm . tuberculosis can grow on fatty acids as sole carbon source and it has been demonstrated that fatty acid oxidation is important for survival of the pathogen in the lungs of mice . fatty acids are oxidized via the - oxidation cycle and the glyoxylate shunt , to replenish tca cycle intermediated during growth . the - oxidation cycle consists of five biochemical reactions , where one molecule acetyl - coa of the fatty acid is split off per cycle . the genome of m. tuberculosis encodes around 100 genes , designated as fad genes ( fatty acid degradation ) with putative roles in the - oxidation of fatty acids . while e. coli has only one enzyme for each step of the - oxidation cycle , m. tuberculosis seems to have several backup enzymes for each reaction . however , there are three times more fadd acyl - coa synthases than there are fade acyl - coa dehydrogenases , whereas these are predicted in equal amounts in m. tuberculosis . the initial step of - oxidation is the formation of acyl - coa from free fatty acids and coenzyme a and is catalyzed by acyl - coa synthase . the acyl - coa synthase rv1683 is suspected to be essential for tag hydrolysis and growth . even though m. leprae genome contains less necessary - oxidation cycle genes than m. tuberculosis , transcripts analysis revealed active expression of acyl - coa metabolic enzymes including echa1 ( ml0120 , putative enoyl - coa hydratase ) , echa12 ( ml1241 , possible enoyl - coa hydratase ) , fada2 ( ml2564 , acetyl - coa - acetyltransferase ) , fadb2 ( ml2461 , 3 - hydroxyacyl - coa dehydrogenase ) , fadd19 ( ml0352 , acyl - coa synthase ) , fadd26 ( ml2358 , fatty acid - coa - ligase ) , fadd29 ( ml0132 , probable fatty - acid - coa synthetase ) , fadd28 ( ml0138 , possible fatty - acid - coa synthase ) , fade25 ( ml0737 , probable acyl - coa dehydrogenase ) , and fade5 ( ml2563 , acyl - coa dehydrogenase ) . combing observations from leprosy lesions , this gives strong evidence that host lipids provide the main carbon and energy sources for m. leprae during infection . together with malate synthase , isocitrate lyase ( icl ) is the key enzyme of the glyoxylate cycle that catalyzes the cleavage of isocitrate to glyoxylate and succinate . the m. leprae genome contains a gene , coding for an isocitrate lyase , acea . acea is upregulated in both m. leprae - infected nude mouse and human lesions . . the amino acid sequence of acea ( ml1985c ) shows 80 % identity with its homologue from m. tuberculosis icl2 ( rv1915 / 1916 ) . a second icl gene is not present in m. leprae , as observed in m. tuberculosis . this finding is of particular interest , because two m. tuberculosis isocitrate lyases , icl and icl2 , are jointly required for in vivo growth and virulence . so far the evidence indicates that m. leprae acea might play a slightly different role in both isocitrate lyases in m. tuberculosis . for persistent m. tuberculosis , tags seem to be the major carbon and energy source . biosynthesis of tag consists of the sequential esterification of the glycerol moiety with fatty acyl - residues by various acyltransferases . esterification occurs via sequential acylation of the sn - 1,2 and 3 positions of glycerol -3-phosphate , and removal of the phosphate group before the last acylation step . the terminal reaction is the esterification of diacylglycerol ( dag ) with acyl - coa by an diacylglycerol acyltransferase ( figure 2 ) . bacteria do not contain dgats but only bifunctional wax ester synthase / acyl - coa : diacylglycerol acyltransferases ( ws / dgat ) . ws / dgats mediate next to tag formation the synthesis of waxes by esterification of acyl - coa with alcohol . the genome of m. tuberculosis codes for 15 genes which contain the highly conserved putative active site motif of ws / dgats ( hhxxxdg ) . tgs , triacylglycerol synthases , but have only a weak sequence similarity to other ws / dgat sequences . all 15 expressed mycobacterial tgs proteins show diacylglycerol acyltransferase activity and tgs1 has the highest activity of all enzymes . tgs1 appears to be a major contributor to tag synthesis in m. tuberculosis so far . and moreover , two homologue proteins to tgs1 and tgs2 ( bcg3153c and bcg3794c ) and another poorly characterized acyltransferase ( bcg1489c ) were found to be exclusively associated to lipid bodies . bcg3794c , and bcg1489c reduces tag accumulation during hypoxia - induced nonreplicating state , revealing that the enzymes are involved in tag synthesis during latency and pathogenicity . ten of the 15 tgs genes in m. tuberculosis are located adjacent or proximal to 11 lip genes that are annotated as probable phospholipases or lipases - esterases carboxylesterases . some tgs genes may be cotranscribed with neighboring lip genes and may synthesize triacylglycerols from the released fatty acids from the host . lip gene products may be important for utilization of tags during dormancy and upon reactivation after dormancy . the tgs gene rv0221 is located near lipc ( rv0220 ) , lipw ( rv0217c ) , acyl - coa synthetase ( rv0214 ) , acyl - coa dehydrogenase ( rv0215c ) , and an integral membrane acyltransferase ( rv0228 ) . this clustering of genes of the fatty acid metabolism suggests that these genes may be cotranscribed and may release fatty acid from host tag , carry out the transport of fatty acids and finally catalyze the resynthesis of tags in the pathogen . rv0221 and lipc have to be shown to be catalytical active . the m. leprae genome shows only one predicted gene product which has a significant degree of identity to any tgs enzymes from m. tuberculosis . rv2484c is located next to a carboxylesterase lipq , ( rv2485c ) , a probable glycerol -3-phosphate acyltransferase , ( rv2482c ) , a lysophosphatidic acid acyltransferase - like protein ( rv2483c ) , and a probable enoyl - coa hydratase ( rv2486 ) . the gene cluster of lipid metabolism genes suggests a possible involvement of the gene products in the synthesis of tag . a few tgs genes ( rv3234c , rv3233c , rv2285 , and rv1425 ) are located proximally to lipoproteins , which may serve as donors or acceptors of fatty acids . ag85a , a mycoly transferase that is known to catalyze the formation of the cord factor was recently found to have additional dgat activity . although , mycoly transferase 85 complex genes ( a , b , and c ) transcripts were one of the major secreted group during mycobacterium infection of the mouse , ag85a is one of the most genes shown to be relatively highly expressed either in infected nude mouse or human skin lesions . the increased cholesterol level was also associated with a lower level of esterase activity in infected macrophages . recently showed by high - performance thin - layer chromatography that the amount of cholesterol increases in scs upon infection with m. leprae . pandey and sassetti found that m. tuberculosis can grow using cholesterol as a primary carbon source and that the mce4 transporter is required for cholesterol uptake . while the m. tuberculosis genome contains four homologous mce operons , mce1 - mce4 , which are thought to encode lipid transporters , m. leprae genome encodes only one operon ( mce1 ) . all m. leprae five mce genes were overexpressed during intracellular growth in mouse and human biopsies . this observation suggests that the intracellular bacilli population induces cholesterol uptake of the infected cell and subsequently uses the stored cholesterol as carbon and energy source . cholesterol accumulates at the site of mycobacterial entry in macrophages and promotes mycobacterial uptake . for m.tuberculosis and m. leprae it has been shown that cholesterol mediates the recruitment of taco from the plasma membrane to the phagosome . taco , also termed as coronin - 1a ( coro1a ) , is a coat protein that prevents phagosome - lysosome fusion and thus degradation of mycobacteria in lysosomes . the entering of mycobacteria at cholesterol - rich domains of the plasma membrane and their subsequent uptake in taco - coated phagosomes promotes intracellular survival . studying m. leprae metabolisms during infection is as complex as the choice of invasion mechanisms traffic and as their multifarious factors for entry are . in this scenario , several results support the view that m. leprae actively catabolizes fatty acids for energy and produces a wide array of secretory proteins . huge gaps remain in our knowledge of the structure and function of m. leprae lipid bodies , as the host metabolism required alterations to switch the organism to the utilization of lipids as alternate carbon sources . investigating the metabolic aspects of m. leprae especially lds formation is an important topic to learn more about metabolic pathways that could potentially be exploited for developing novel drugs against leprosy and tuberculosis .\noutput:\n" }, { "from": "agent", "value": "leprosy is a chronic infectious disease and is a major source of morbidity in developing countries . leprosy is caused by the obligate intracellular bacterium mycobacterium leprae , which infects as primary target schwann cells . lepromatous leprosy exhibits multiple lesions of the skin , eyes , nerves , and lymph nodes . the sites of infection are characterized by the presence of foamy macrophages , fully packed with lipid droplets ( lds ) , which are induced by m. leprae . in the last years , it has become evident that m. tuberculosis imports lipids from foamy macrophages and is dependent on fatty acids for growth in infected macrophages . m. leprae seems to have similar mechanisms for scavenging lipids from the host . but due to the inability to culture m. leprae on laboratory media , research progresses only slowly . however , in the last years , substantial progress has been made in the field of lipid metabolism in m. leprae . herein , we will present and summarize the lipid droplets formation and the metabolism of lipids during m. leprae infection ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: without considering major facial deformities typically associated with various syndromes , a small degree of craniofacial asymmetry is always present in all subjects with normal biometric parameters , although this asymmetry is rarely appreciable and is often unnoticed . diagnosis of asymmetry and of its localization could be essential for planning treatment and evaluating the results of orthognathodontics or maxillofacial surgery . asymmetry of the craniofacial complex can be evaluated only with appropriate radiological projections and cephalometric measurements on posteroanterior and submentovertex ( smv ) radiograms or by using three - dimensional ( 3d ) computed tomography ( ct ) imaging . furthermore , prior to combined orthodontic / orthognatic surgery , radiological images are recommended to evaluate if there were preexisting temporomandibular pathologies in the patients to identify or prevent temporomandibular disorders that could heavily influence the postsurgical function . altered anatomical condylar position and bone degeneration ( osteoarthrosis ) are often associated with the angle jaw discrepancies / malocclusion . those condylar alterations have to be detected and quantified to optimize the pretreatment diagnosis or post - treatment follow - up . although magnetic resonance represents the gold standard in tmd diagnosis , the smv radiogram gives at the same time an immediate localization and quantification of bone condylar asymmetries and the visualization of other facial and mandibular structures that could be involved in the craniofacial asymmetry . underlined the importance of the smv view in analyzing craniofacial asymmetries , in particular because other radiograms , such as lateral projections , can not detect asymmetries in the sagittal and coronal planes . the system of cephalometric coordinates to evaluate the symmetry of bone structures of splanchno - and neurocranium takes as its main reference the sagittal symmetry axis , whose identification has been examined by numerous authors over the last thirty years . cheney proposed a midsagittal plane passing through the nasion and the anterior nasal spine considering that this plane crosses the prosthion and the menton in subjects with a symmetrical face . conversely , in a cephalometric study in a posteroanterior cranial projection , sutton found that the anterior nasal spine , the prosthion and the menton are rarely aligned on the same line , confuting the validity of these points for tracing the symmetry axis . berger proposed examining asymmetries in the cranial basilar projection by tracing the midline passing through the vomer , the posterior portion of nasal septum and the crista galli process . marmary et al . identified the craniofacial midline as the line perpendicular to the midpoint between the right and the left spinosum foramina in the basilar view , as they believed it remained constant during cranial development . more recently , in a 3d ct study , katsumata et al . selected the midsagittal reference plane passing through points s , n and dent , whereas uysal and malkoc and janson et al . use the transporionic axis to trace , orthogonally , the midsagittal axis considering that the line connecting the midpoint of the external acoustic meatuses ( or mei ) is superimposable to the line connecting the tip of ear rods on smv cephalograms . although the key to evaluating asymmetries is defining the criteria to determine the cranial midline , the existence and utilization of different procedures to identify the ideal midline underlines that no clear , universally accepted , method currently exists for the evaluation of craniofacial asymmetries . furthermore , until now no study exists evaluating the comparison between the utilization of ear rods and spinosum foramina as starting points for drawing basicranium midline on smv radiograms . the aim of the study was to compare the validity and reliability of two different methods for localization of the cranial midline through a cephalometric analysis of asymmetries of the mandibular condyles in a representative adult population . the hypothesis that the spinosum foramina represent the most reliable starting points for tracing the coordinate system to identify transverse craniofacial asymmetries on smv radiograms , was tested . this retrospective cohort study was performed by analyzing the smv radiograms of 47 patients ( 26 females and 21 males ; age range : 2156 years ; mean age 2714.2 years ) , all italians and with italian parents , who were consecutively selected from orthodontic patients treated at the dental clinic of the university of trieste between 2003 and 2008 . all patients needed third molar extraction or mesiodens removal and subsequent planning of orthodontic treatment . patients met the following criteria : normal growth , normal development , no clinically apparent facial asymmetry , all teeth present ( or physiologic denture for age ) , no second or third class malocclusion , no functional mandibular deviation , no previous orthodontic treatment , no systemic pathologies or syndromes . furthermore , we analyzed the smv radiograms of 5 subjects ( range age : 425 years ; mean age 129.1 years ) , 3 of them still during the active growth phase , performed before and after orthodontic therapy , for a total of 10 radiograms . a written informed consensus was obtained by patients or their parents before treatment through a protocol approved by the university of trieste , italy . the principles outlined in the declaration of helsinkicranial radiographs in smv projection were obtained by the same operator ( m.m . ) with an axial tome ex ii unit ( axial tome corporation , san carlos , ca , usa ) . the choice of a single operator responded to the need to reduce inter - operator bias during the positioning of the patient and the insertion of the ear rods . radiograms were performed with the following technique : ear rods were positioned and each patient was asked to rotate the head posteriorly until the frankfurt plane became parallel to the film cassette . this position was fixed with the aid of the craniostat to allow for reproducibility in the assessment of cranial structure in the horizontal plane . the radiograms were then scanned using a powerlook 1000 scanner ( umax systems gmbh , willich , germany ) ( figure 1 ) . all cephalometric lines and angles were traced and measured with microsoft image pro plus 5.0 software ( media cybernetics inc . , bethesda , md , usa ) after appropriate calibration . the anatomic landmarks used in this study were extrapolated from the smv analysis developed by lew and tay and were : entire outline of the condylar head and identification of internal and external poles , tips of the ear rods and spinosum foramina ( figures 2 ( a ) and 3 ( a ) ) . a single operator ( f.c . ) performed a digital tracing of each radiogram for five times with the method described below . the resulting mean values of lengths and angles were calculated and considered for statistical analysis to reduce the measurement error . the first ( tracing 1 ) considers the craniostat ear rods as initial landmarks . the straight line connecting the tip of the left and right ear rods passes through the left and right midpoint ( or left and right mei lm and rm ) of the external acustic meatus ( transporionic axis , tpa ) ; the midline ( mp ) was established by tracing a perpendicular line crossing the midpoint of the tpa . the second analysis ( tracing 2 ) uses the spinosum foramina ( sf ) as main landmarks to identify the axis of symmetry . the outlines of the sf were identified on the radiograms , and the straight line passing through the centers of the left and right sf ( points spl and spr , resp . ) was traced ( transspinosum axis , tsa ) ; a second line that passes through the midpoint of the tsa was considered to be the cranial midline ( msp ) . the outlines of the mandibular condyles were traced on each radiogram , and the medial and lateral poles were identified ( rcol , right condylion lateralis : most lateral aspect of right condyle ; rcom , condylion medialis : most medial aspect of right condyle ; lcol , left condylion lateralis : most lateral aspect of left condyle ; lcom , left condylion medialis : most medial aspect of left condyle ) . quantification of the condylar asymmetry was performed using eight parameters : left and right condylar width , left and right condylar angle ( the horizontal condylar angle is the angle formed by the straight line passing through the condylar poles and the straight line perpendicular to the midline ) , intracondylar hemidistance defined as the distance from lcom and rcom to mp ( tracing 1 ) or msp ( tracing 2 ) , extracondylar hemidistance defined as distance from lcol and rcol to mp ( tracing 1 ) or msp ( tracing 2 ) . the anatomic landmarks and reference planes used are shown in figures 2 ( a ) and 2 ( b ) and 3 ( a ) and 3 ( b ) . on each radiogram , the left / right symmetry ratio ( sr ) was calculated for tracing 1 and tracing 2 with this simple formula : ( 1 ) sr = left parameterright parameter . the left - side measurement was used as a reference . a sr 1 indicates that the left side is larger than the right side . all statistical analyses were performed with the spss software package ( statistical package for social sciences , windows 98 , version 10.0 , spss , chicago , ill ) using the student 's t - test for independent samples . table 1 summarizes the mean values obtained after measurement of the condylar parameters and the sr for tracing 1 and tracing 2 . furthermore , there was substantial equivalence of sr related to the horizontal condylar width and angulation calculated for tracing 1 and tracing 2 ( t - test ; p = ns ; c.i . srs were 1.060.11 and 0.990.08 , respectively , for the distances lcom and rcom to mp ( tracing 1 ) and msp ( tracing 2 ) and 1.040.09 and 0.980.07 , respectively , for the distances lcol and rcol to mp ( tracing 1 ) and to msp ( tracing 2 ) . statistical analysis did not reveal any significant difference in the comparison of the srs of the intracondylar and extracondylar hemidistance using the same tracing ( tracing 1 : t - test ; p 0.2 ns ; c.i .95 % ; tracing 2 : t - test ; p 0.9 ns ; c.i . conversely , the comparison between the srs obtained using the two different tracings and regarding the same parameter was statistically relevant ( intracondylar hemidistance sr for tracing 1 versus tracing 2 : t - test ; p 0.000 ; c.i . 95 % ; extracondylar hemidistance sr for tracing 1 versus tracing 2 : t - test ; p 0.000 ; c.i . table 3 reports the measurements of the distances between the ear rods and the spinosum foramina for the five control cases . an increment of the distance between the ear rods is appreciable in all three patients in the active growth phase whereas this measure becomes stable in the adult subjects . as reported by haraguchi et al . , nonpathologic facial asymmetry ( normal asymmetry ) , defined as the difference in size between the left and right hemifaces , is relatively common . asymmetry is often not easily appreciable clinically and could be considered a desirable condition of the craniofacial structures because we perceive it as esthetically pleasing . however during orthodontic planning , the identification and quantification of the asymmetry could be important in patients with clinically significant asymmetry or with pathologic conditions associated with asymmetry . in this context , the smv radiographic technique represents a useful method to examine the cranial base and to evaluate the rate of asymmetry of the anatomic structures in the axial plane . this kind of projection is more useful than panoramic and posterior / anterior radiography to determine the mediosagittal axis thanks to the excellent visualization of the cranial base structures . however , it should be remembered that radiological techniques , such as cephalometry , could be affected by image size distortion and that their quality and accuracy depend on many variables . although new tridimensional radiographic techniques have been recently introduced ( cone - beam computed tomography ) changing the potential in presurgical diagnosis and pretreatment planning , smv radiography remains a good choice in clinical practice for the diagnosis of uncomplicated malocclusions , thanks to the ease of execution , the low radiation dose , and the good spatial resolution . the analysis of asymmetries requires that all anatomic parameters have to be compared to a symmetry axis ( or midline ) that is established using stable anatomic references . williamson et al . underlined the importance of correct determination of landmarks and reliability of measurements to properly interpret the data and apply them to research or clinical practice . similarly , trpkova et al . remarked on the need to test the validity of reference lines in evaluating facial asymmetries . they studied how to assess the best sagittal midline from posteroanterior cephalograms and found that a different midline localization heavily interferes with the quantification of asymmetry . the technique is operator dependent , and the positioning of the patients has to be extremely precise . to avoid an altered localization of the midline , the patient 's head must be centrally positioned , and the correct skull rotation has to be accurately checked to eliminate the possible artefacts both of linear and angular measurements . summarizing , a diagnostic error in the craniofacial asymmetry due to poor identification of implicated structures could lead to an erroneous treatment . the sample comprised 26 females and 21 males considering that no gender - associated difference in craniofacial asymmetry has been reported in the adult population . two types of landmarks were used to trace the midline of the cranial base : the ear rods of the craniostat ( corresponding to the porion ) and the spinosum foramina . these landmarks are relevant in defining the sagittal , transverse , and angular position of the condyles , are commonly used in the published literature , and are easy recognizable on the smv radiographs . statistical analysis revealed the substantial equivalence and reliability of the two tracing methods for performing a cephalometric analysis in a representative population . this reliability results from the fact that the left / right discrepancy for tracing 1 and 2 is not statistically significant ( table 2 ) . furthermore , the extent of asymmetry falls within a physiological range for both tracings , since an anthropometric value of 2 - 3 mm for the left / right cranial discrepancy , with respect to a midsagittal symmetry axis , is considered as the normal limit . . underlined that there is no consensus concerning the right or left side prevalence in physiological asymmetries . our data indicate that some parameters may be more pronounced on the left or the right side , but that the side of prevalence of the same parameter can change if a different midline is established ( table 1 ) . this result underlines the importance of midline localization for asymmetry considerations in orthodontic and surgical diagnosis , independently to the choice of 2d or 3d imaging , and could explain why some authors identified a right prevalence , whereas others identified a left prevalence . comparing the sr of the intra and extracondylar hemidistances , the statistical analysis showed a lower sr for tracing 2 ( 0.990.08 versus 1.060.11 of tracing 1 for intracondylar hemidistance and 0.980.07 versus 1.040.09 of tracing 1 for extracondylar hemidistance ; table 2 ) . the first one is that the finding is casual considering that a certain grade of asymmetry is always present and that tmj internal derangements with bone modification ( condylar hipo / hiperplasy , osteoarthrosis , osteonecrosis , osteoarthritis ) could interest every subject independently to angle class . however , patients with a history of tmd have been excluded during the recruitment for the study reducing at the minimum this eventuality . the second possibility is that since the patients are class 1 patients , they are the least likely candidates to develop tmj anatomical and degenerative disorders and consequently the more symmetric subjects in the population . in light of this , the msp would be nearer than the mp to the ideal midsagittal axis , and this could explain why the sr is reduced for the tracing 2 . the sr calculated using the msp agrees with data obtained in a study on dry skulls performed by marmary et al . and demonstrates the high reliability of the spinosum foramina as references for midline localization . the smv images of the five control cases allowed us to verify the impact of successful therapy on the modification of the radiographic landmarks used to trace the symmetry axis . the distances between spinosum foramina and ear rods were identified on the radiograms to evaluate their changes over time . the repeatability of the cephalometric measurements before and after therapy was ensured by the same angle of incidence of the x - ray beam on the film thanks to the craniostat that maintains the position of the head unaltered . this projection allows also appreciation of the minimal variations in condylar dimensions and the relationship between mandibular condyles and basicranium . in the three growing subjects , the millimetric increase of the absolute values between ear rods , corresponding to the distance between the external acoustic meatuses , is clearly evidentthis change is the direct consequence of physiologic development : the advancing of the temporal bones and the new orientation of the glenoid cavities directly influence the position of the temporomandibular joint and acoustic meatus . in all five cases , spinosum foramina belong to the central area of the basicranium that reaches adult dimensions in an early age and preserves its morphology throughout life . specifically , sejrsen et al . found that the central area of the external cranial base reaches its final extension at the age of 4 - 5 years : this area is delimited by the magnus foramen , by the stylomastoid foramina and by the spinosum foramina . consequently , the growth of this area is very rapid until the age of 4 - 5 years and progressively decreases and eventually ceases after this age . for this reason , authors have suggested that the neurovascolar foramina can be used as references for the evaluation of the maxillomandibular complex . as found by moss and salentijn , after this age , the dimensional stability of some structural aspects of this median area , among which the passage and the localization of neurovascular foramina , is not influenced by orofacial growth or orthognathodontic therapy . conversely , major dimensional changes , both in the sagittal and transverse direction , take place during development in the contiguous anterior and lateral structures . this semilunar area includes also the glenoid cavities and the external acustic meatus , which are directly involved in the processes of bone remodelling during growth . it may also be hypothesized that masticatory function , facial trauma , and orthognathodontic therapy will influence the development of temporal bones but not the position of the neurovascular foramina . williamson et al . demonstrated that the spinosum foramina show the lowest identification error in the submentovertex projection , whereas greater difficulty was encountered in identifying the lateral poles of the mandibular condyles . the authors also underlined that the use of ear rods for the determination of a reference plane may be suspect because of the tridimensional asymmetry associated with the external auditory meatus . this asymmetry would provoke a head rotation during the positioning of the patient and a subsequent image distortion with a misinterpretation of the results . furthermore , the positioning of the ear rods in the acoustic external meatus could be influenced by the operator 's skill and precision . consequently , if the analysis of the condylar asymmetries is performed in growing subjects , utilization of anatomic references such as the neurovascular foramina seems to guarantee a lower error than nonfixed references . this hypothesis needs to be confirmed by a larger cases series to test its statistical significance and understand whether this margin of error is clinically relevant for the precise quantification of craniofacial asymmetries . one of the limitations of this retrospective analysis is that it lacks the comparison with 3d images although van vlijmen et al . recommended to avoid the comparison between 3d tracings and conventional cephalometry in longitudinal research if there are only 2d records in the past . submentovertex radiograms can provide assistance in diagnosing condylar asymmetries and planning the most appropriate treatment ; furthermore , the reliability of this examination allows assessment of the anatomic variations induced by the orthognathodontic or surgical therapy . a careful evaluation of physiologic condylar asymmetry is extremely important considering that if treatment on the craniomandibular complex does not respect this asymmetry , the risk of temporomandibular disorders can increase . the extent of the asymmetry can be quantified by using as a reference the midline , which should be as much as possible superimposable to the ideal midsagittal axis and not change during cranial development . the results of this study validate our hypothesis indicating that the midline traced using the spinosum foramina as references more closely approximates the ideal midsagittal axis and represents the most reliable line to trace the coordinate system for identifying craniofacial asymmetry during cranial development on submentovertex radiograms .\noutput:\n" }, { "from": "agent", "value": "the purpose of this research was to compare the reliability of two different methods for cranial midline localization through cephalometric analysis of mandibular condyle asymmetries . a retrospective cohort study was performed analyzing consecutively the smv radiograms of 47 patients undergoing oral surgery before orthodontic treatment at the dental school , university of trieste ( italy ) from 2003 to 2008 . two different cephalometric analyses were used to identify the basicranium midline ( tracing 1 : initial landmarks = craniostat ear rods ; tracing 2 : initial landmarks = spinosum foramina ) , and the left / right symmetry ratio ( sr ) for four parameters ( condylar length , condylar angle , intra - condylar hemidistance , extra - condylar hemidistance ) was calculated . the main result showed that no significant statistical difference between the srs of the intra - condylar and extra - condylar hemidistance obtained with the same tracing was found ( t - test ; p = ns ; c.i . 95 % ) . conversely , the difference between the srs obtained with the two different tracings was statistically significant ( t - test ; p < 0.000 ; c.i . 95 % ) . in conclusion , if the analysis of condylar asymmetries is performed in growing subjects , utilization of anatomic references such as the neurovascular foramina seems to guarantee a lower error compared to non - fixed references such as ear rods ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: alveolar capillary dysplasia ( acd ) is a fatal developmental anomaly resulting in misalignment of the pulmonary veins ( mpv ) and abnormal intrapulmonary shunting 1 . most patients with acd have multiple associated anomalies , predominantly of the gastrointestinal tract , but cardiovascular , urogenital , and musculoskeletal system involvement has also been described 2 . infants with acd generally become critically unwell in the first few days of life with pulmonary hypertension , but presentation in later life has also been reported 3 , 4 , 5 . currently availablehowever , a few studies have suggested some therapeutic benefits of pulmonary vasodilators with a single case report of a longterm survivor 6 . the precise etiology of acd remains unclear , but recent literature suggests that foxf1 gene mutations are present in some cases 7 , 8 . in this report , we describe the clinical outcomes of three infants that illustrate the extensive clinical spectrum and pathophysiology of this disorder . all three infants succumbed to respiratory failure and in two , a pathogenic heterozygous foxf1 gene mutation was detected . we compare our cases to reports in the literature , especially in atypical cases and provide a comprehensive update on this condition . a female infant , the second child of a healthy nonconsanguineous caucasian couple with a previous term healthy infant , was born to a mother with a history of depression and mild temporal lobe epilepsy who was treated with escitalopram in early pregnancy . prenatal ultrasound scans at 19 weeks showed a fetal rightsided abdominopelvic cystic mass , initially thought to be ovarian in origin and which increased in size on sequential scans . the infant was born by a spontaneous vaginal delivery at 38 weeks gestation with a birthweight of 3340 g. her apgar score at 5 min was 9 . the infant was admitted to the nursery for further management and investigation of the intraabdominal lesion and at admission , the infant 's pulse oximetry ( spo2 ) readings were consistently 95 % . an abdominal xray showed a gas filled bowel loop in the right abdomen with a paucity of distal bowel gas and normal lung fields . at 12 h of age , therapy was quickly escalated to highfrequency ventilation , inhaled nitric oxide up to 20 ppm and inotropic support , including milrinone . preductal spo2 remained persistently below 90 % after intubation , and there was no response to exogenous surfactant . she continued to deteriorate with profound hypoxemia , hypercapnia , metabolic acidosis , and hypotension . extracorporeal membrane oxygenation ( ecmo ) was considered and discussed with the parents , but in view of the critical situation , a palliative care plan was instituted and the infant died at 47 h of age 9 . at autopsy , the alveolar septa were thickened with several thin walled capillaries that were not opposed to the epithelium . a duodenal volvulus and an aganglionic distal colon with the transition zone placed about 20 cm from the anorectal junction were also present . sequence analysis of a dna sample identified a novel heterozygous foxf1 nonsense mutation in exon 1 ( c. 668c a ) ; p.ser223ter 7 . dilated capillaries are not in contact with the alveolar epithelium . a , arteries ; v , veins ; b , bronchioles ; she was delivered by elective cesarean section at 38 weeks with a birthweight of 3470 g and 5 min apgar score of 9 . the first postnatal abdominal xray was suggestive of duodenal atresia , and an imperforate anus was noted on clinical examination . cardiorespiratory status was normal , and initial spo2 readings were consistently 95 % . on day 2 , she was electively intubated and placed on mechanical ventilation in preparation for abdominal surgery . she was extubated the next day and continued for 15 days without respiratory difficulties . on day 15 , a second laparotomy was performed for a duodenoplasty and bishopkerr jejunostomy as the infant had persistent feeding difficulties secondary to a dysfunctional and dilated duodenum . she was then extubated uneventfully again to room air on day 17 . on day 22 , she developed a urinary tract infection ( uti ) from e. coli and required supplemental oxygen by high flow nasal cannula until day 30 . on day 41 , she became profoundly unwell with suspected necrotising enterocolitis . high flow nasal oxygen ( fio20 .3 ) was recommenced with empiric antibiotics ( meropenem and vancomycin ) but respiratory deterioration continued and she required mechanical ventilation on day 43 . highfrequency ventilation and nitric oxide were commenced for pulmonary hypertension ( confirmed on 2dechocardiography , which also showed a small secundum atrial septal defect ) . hypoxemia remained persistent , and the infant passed away on day 48 despite intensive care . at autopsy , abnormally sited and patchilydistributed pulmonary veins were seen . however , some pulmonary veins were also appropriately positioned within the interalveolar septa . cytomegalovirus ( cmv ) infection without an inflammatory response in the lungs was diagnosed by identification of viral inclusions and confirmation on immunohistochemical staining and molecular testing . ( a ) lung tissue histology abnormally located veins adjacent to arteries and bronchioles . a , arteries ; v , veins ; b , bronchioles . ( b ) immunohistochemically dual stained for cd31 ( brown , endothelial marker ) and cytokeratin ( red ; epithelial cell marker ) demonstrating variability in arrangement and size of alveolar capillaries . this male infant was the first child of a healthy nonconsanguineous caucasian couple , who had previously had six miscarriages . amnioreductions were performed twice for maternal comfort . preterm labor and rupture of membranes occurred at 34 weeks gestation . she proceeded to cesarean section in view of a nonreassuring fetal trace and clinical chorioamnionitis at 36 weeks gestation . the infant had a small omphalocele and a birthweight of 2985 g. his apgar score at 5 min was 9 . the cord blood gas was normal , and there was meconium staining of the amniotic fluid . from birth , he required supplemental oxygen to keep spo290 % . he remained persistently hypoxemic despite mechanical ventilation , 100 % oxygen , exogenous surfactant , inhaled nitric oxide ( pulmonary hypertension was confirmed on echocardiography with a structurally normal heart ) , highfrequency ventilation , and inotropic support . in view of the critical situation , the infant died at 45 h of age . at autopsy , lung microscopy showed generalized acd ( figure 3 ) and mpv . duodenal atresia with a mesenteric band causing malrotation of ascending and midtransverse colon was also noted . the ileum , cecum , and appendix were located within the omphalocele which showed autolytic changes but were otherwise unremarkable . dilated capillaries are not in contact with the alveolar epithelium . a , arteries ; v , veins ; b , bronchiolesa female infant , the second child of a healthy nonconsanguineous caucasian couple with a previous term healthy infant , was born to a mother with a history of depression and mild temporal lobe epilepsy who was treated with escitalopram in early pregnancy . prenatal ultrasound scans at 19 weeks showed a fetal rightsided abdominopelvic cystic mass , initially thought to be ovarian in origin and which increased in size on sequential scans . the infant was born by a spontaneous vaginal delivery at 38 weeks gestation with a birthweight of 3340 g. her apgar score at 5 min was 9 . the infant was admitted to the nursery for further management and investigation of the intraabdominal lesion and at admission , the infant 's pulse oximetry ( spo2 ) readings were consistently 95 % . an abdominal xray showed a gas filled bowel loop in the right abdomen with a paucity of distal bowel gas and normal lung fields . at 12 h of age , therapy was quickly escalated to highfrequency ventilation , inhaled nitric oxide up to 20 ppm and inotropic support , including milrinone . preductal spo2 remained persistently below 90 % after intubation , and there was no response to exogenous surfactant . she continued to deteriorate with profound hypoxemia , hypercapnia , metabolic acidosis , and hypotension . extracorporeal membrane oxygenation ( ecmo ) was considered and discussed with the parents , but in view of the critical situation , a palliative care plan was instituted and the infant died at 47 h of age 9 . at autopsy , the alveolar septa were thickened with several thin walled capillaries that were not opposed to the epithelium . a duodenal volvulus and an aganglionic distal colon with the transition zone placed about 20 cm from the anorectal junction were also present . sequence analysis of a dna sample identified a novel heterozygous foxf1 nonsense mutation in exon 1 ( c. 668c a ) ; p.ser223ter 7 . dilated capillaries are not in contact with the alveolar epithelium . a , arteries ; v , veins ; b , bronchioles ; she was delivered by elective cesarean section at 38 weeks with a birthweight of 3470 g and 5 min apgar score of 9 . the first postnatal abdominal xray was suggestive of duodenal atresia , and an imperforate anus was noted on clinical examination . cardiorespiratory status was normal , and initial spo2 readings were consistently 95 % . on day 2 , she was electively intubated and placed on mechanical ventilation in preparation for abdominal surgery . she was extubated the next day and continued for 15 days without respiratory difficulties . on day 15 , a second laparotomy was performed for a duodenoplasty and bishopkerr jejunostomy as the infant had persistent feeding difficulties secondary to a dysfunctional and dilated duodenum . she was then extubated uneventfully again to room air on day 17 . on day 22 , she developed a urinary tract infection ( uti ) from e. coli and required supplemental oxygen by high flow nasal cannula until day 30 . on day 41 , she became profoundly unwell with suspected necrotising enterocolitis . high flow nasal oxygen ( fio20 .3 ) was recommenced with empiric antibiotics ( meropenem and vancomycin ) but respiratory deterioration continued and she required mechanical ventilation on day 43 . highfrequency ventilation and nitric oxide were commenced for pulmonary hypertension ( confirmed on 2dechocardiography , which also showed a small secundum atrial septal defect ) . hypoxemia remained persistent , and the infant passed away on day 48 despite intensive care . at autopsy , lung microscopy revealed patchy acd with mpv ( figure 2 ) . abnormally sited and patchilydistributed pulmonary veins were seen . however , some pulmonary veins were also appropriately positioned within the interalveolar septa . cytomegalovirus ( cmv ) infection without an inflammatory response in the lungs was diagnosed by identification of viral inclusions and confirmation on immunohistochemical staining and molecular testing . ( a ) lung tissue histology abnormally located veins adjacent to arteries and bronchioles . ( b ) immunohistochemically dual stained for cd31 ( brown , endothelial marker ) and cytokeratin ( red ; epithelial cell marker ) demonstrating variability in arrangement and size of alveolar capillaries . this male infant was the first child of a healthy nonconsanguineous caucasian couple , who had previously had six miscarriages . amnioreductions were performed twice for maternal comfort . preterm labor and rupture of membranes occurred at 34 weeks gestation . she proceeded to cesarean section in view of a nonreassuring fetal trace and clinical chorioamnionitis at 36 weeks gestation . the infant had a small omphalocele and a birthweight of 2985 g. his apgar score at 5 min was 9 . the cord blood gas was normal , and there was meconium staining of the amniotic fluid . from birthhe remained persistently hypoxemic despite mechanical ventilation , 100 % oxygen , exogenous surfactant , inhaled nitric oxide ( pulmonary hypertension was confirmed on echocardiography with a structurally normal heart ) , highfrequency ventilation , and inotropic support . in view of the critical situation , the infant died at 45 h of age . at autopsy , lung microscopy showed generalized acd ( figure 3 ) and mpv . duodenal atresia with a mesenteric band causing malrotation of ascending and midtransverse colon was also noted . the ileum , cecum , and appendix were located within the omphalocele which showed autolytic changes but were otherwise unremarkable . dilated capillaries are not in contact with the alveolar epithelium . a , arteries ; v , veins ; b , bronchioles . the exact incidence of the disease is unclear as post mortems or lung biopsies are not routinely performed in deceased infants . in confirmed cases of acd , affected infantsmost patients present within 24 h of life with respiratory distress and hypoxemia but as illustrated by case two and other patients , presentation may be delayed and can be as late as 7 months of age if pulmonary involvement is patchy 5 ( table 1 ) . review of literature on acd with relevant gastrointestinal malformation ( intestinal malrotation , hscr ) and fox gene mutation only cases of acd and mpv confirmed on lung histology are included with longterm survivors are in bold . acd , alveolar capillary dysplasia ; mpv , misaligned pulmonary veins ; hscr , hirschsprung 's disease . most infants with acd die from hypoxemic respiratory failure within the first 2 weeks of life . there are eight cases in which longterm survival beyond the neonatal period have been described and one infant survived for 36 months 4 , 5 , 6 , 10 , 11 , 12 , 13 , 14 . in this case series , two infants with generalized lung involvement presented within the first 2 days of life and died the day after . in the infant with patchy lung involvement from our cases , respiratory symptoms arose at 3 weeks of age and death occurred much later , at 3 months of age . the pathophysiology of acd is not fully defined , and the mechanism to explain its delayed presentation is far more unclear .15 suggest that variations in disease severity and timing of presentation correspond to alterations in capillary density and contact with the alveolar epithelium or to better lobular development and patchy involvement 4 , 16 , 17 . case 3 in this series would support this proposition , where a later clinical presentation was accompanied histologically by alveolar capillaries appropriately juxtaposed in many areas to the alveolar epithelium . histological findings have only been characterized from symptomatic cases , and the evolution of acd in asymptomatic patients has not been ascertained in humans . these triggers may initiate constriction of hypertrophied pulmonary arteries leading to pulmonary hypertensive crises 16 and may include various infections , such as viral upper respiratory tract infections or as in case 2 , a urine tract infection . currently , histopathology is the gold standard for the diagnosis , but lung tissue may also be difficult to obtain antemortem if there is no surgical expertise or if the infant is very unwell . typical histological findings include evidence of misaligned pulmonary veins ( anomalous distended pulmonary veins within the bronchovascular bundles instead of the interlobular septa ) representing the intrapulmonary shunts , paucity of capillaries proximal to the alveolar epithelium , medial thickening of small pulmonary arteries ( reflecting pulmonary hypertension ) , and immature alveolar development 15 . an index of suspicion of acd should be entertained if there are extrapulmonary anomalies in an infant with deteriorating respiratory status as these have been noted in up to 80 % of infants with acd 18 . gastrointestinal malformations , such as hirschsprung disease and omphalocele , are rare but a recognized association with acd ( table 1 ) . these associations suggest that the molecular pathophysiological factors underlying acd may be affected by a common genetic pathway , for example , an embryonic mesenchymal migration defect 19 . mutations of the foxf1 gene causing acd were first described in 20097 and have been detected in up to 5570 % of acd cases 8 , 20 ( table 1 ) . the foxf1 gene is located at chromosome 16q24 .1 , and the gene consists of two exons , a dna binding forkhead boxdomain ( dbd ) , and the celltypespecific activation domain coded by exon 1 and the general activation domain coded by exon 2 . most ( 90 % ) cases are sporadic and are a result of de novo foxf1 mutations . rare familial recurrences are described on the basis of a maternal mutation on the paternal imprinted allele , which is not expressed . therefore , females may be carriers of a foxf1 mutation on their paternal allele and have no clinical features . this is a very important group to identify as the recurrence risk is high ( 50 % ) . in contrast , recurrence risk in de novo cases is ~ 1 % based on the possibility of gonadal mosaicism in one of the parents . foxf1 is involved in mesenchymal epithelial interactions during development of the gastrointestinal tract and lungs as it is expressed in splanchnic mesenchyme closely opposed to endoderm 20 . it was proposed that foxf1 point mutations were associated with bowel malrotation ( as in one of our cases ) , while foxf1 microdeletions appear to be linked with hypoplastic left heart syndrome and gastrointestinal atresias caused by involvement of adjacent genes foxc2 and foxl17 . cases with mutations in upstream regulators of foxf1 are also reported , showing variable lung involvement and severity of disease 21 , 22 . in our patients ( case 1 and 2 ) , a foxf1 nonsense mutation at exon 1 ( c. 668c a ) ;p . ser223ter and exon 1 ( c. 260g t ) ; p.gly87val were found , which has not been previously reported , adding further to the mutation and phenotypic spectrum of foxf1related disorders . the availability of faster turnaround times for gene testing may allow a genetic diagnosis to support timely clinical decision making . the clinical presentation of acd is similar to any infant presenting with pulmonary hypertension , but the response to therapy is often minimal or transient 23 , 24 . lung recruitment strategies , such a highfrequency ventilation or surfactant , are often the first step in clinical practice in view of severe hypoxemia . there are reports of transient improvement with pulmonary vasodilators , but this is usually futile . other reports have demonstrated a similar pattern of response to inhaled or intravenous prostacyclin including epoprostenol at doses up to 120 ng / kg / h 5 . extracorporeal membrane oxygenation ( ecmo ) may temporize death 24 , but lung transplantation is currently the only theoretically curative option but no successful cases have so far been reported and no data on longterm neurodevelopmental outcome and life expectancy are available . there are emerging data of longer survival of some patients with less severe disease which could help clinicians triage patients for potential lung transplantation . a single longterm survivor is reported in literature who recovered from his pulmonary hypertension crisis by a combination therapy of inhaled no , epoprostenol , milrinone , and oral pulmonary vasodilators . the mild phenotype of this case can be explained by unique lung ct and histopathological findings 6 ( table 1 ) . in any infant with severe hypoxemic respiratory failure , a broad differential diagnosis , especially of treatable conditions , these include severe sepsis , surfactant protein deficiency , congenital infections , and other congenital lung malformations that may be amenable to surgery . infection screens including blood cultures for bacterial and fungal infections and blood tests ( pcr ) for herpes simplex , toxoplasma , and cytomegalovirus virus dna must also be performed and were negative in all three of our cases . in conclusion , the combination of an infant presenting with escalating and intractable respiratory failure and a possible nonpulmonary , gastrointestinal malformation , should alert clinicians to the possibility of acd after exclusion of other treatable conditions . a lung biopsy is the current gold standard of diagnosis for this disease , but genetic analysis ( chromosome microarray looking for 16q24 .1 deletion and foxf1 sequencing and microdeletion screening ) may offer rapid confirmation and counseling for future pregnancies . jlo : supervised dr goel , revised manuscript , and approved final manuscript to be published . kl : assisted dr goel with data interpretation and approved final manuscript to be published . aws : assisted dr goel with data acquisition and interpretation and approved final manuscript to be published . dm : assisted dr goel with data acquisition and interpretation and approved final manuscript to be published . ajg : performed the autopsy on two of the presented cases . established the diagnosis of acd / mpv in these cases . revised manuscript and approved final manuscript to be published . cl : performed the autopsy on one of the presented cases and established the diagnosis of acd / mpv , supervised dr goel , revised manuscript , and approved final manuscript to be published .\noutput:\n" }, { "from": "agent", "value": "key clinical messagealveolar capillary dysplasia ( acd ) is a rare condition with variable presentation and clinical course . clinicians should consider this diagnosis in neonates presenting with nonlethal congenital gastrointestinal malformation , a period of wellbeing after birth then unremitting hypoxemia and refractory pulmonary hypertension . lung biopsy and foxf1 gene testing may help in diagnosis ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 49 - year - old woman was admitted to our clinic with progressive lower back pain for 2 years . examination of the nervous system revealed paresthesia in the sacral dermatomes . no weakness or sensory loss in the lower extremities was recorded . magnetic resonance imaging ( mri ) of the lumbar spine revealed a tumor in the conus medullaris region with nerve compression . the lesion located intradurally and was measured 4 cm 2.5 cm 2.5 cm ( figure 1 ) . after t12l1 laminectomy under microscopic visualization , a midline durotomy was performed and a well - defined , encapsulated , round lesion was found in the conus medullaris region ( figure 2 ) . a , the sagittal t1 - weighted mr image shows an intradural , isointense lesion of the conus medullaris . b , on the axial t1 - weighted mr images , this lesion was heterogeneously enhanced with contrast . a , observing under a microscope , the tumor shows cellular and hipocellular areas ( he 100 ) . b , plumped spindle - shaped cells with palisading nuclei can be seen ( he 100 ) . schwannoma is a benign tumor of the peripheral nervous system that arises from schwann cells and can occur in any body location where peripheral or cranial nerves are present . schwannomas account for approxima - tely 0.3 % of primary intraspinal neoplasms . the lumbar region is the most common location for spinal schwannomas . tumors arising in the cauda equina or around the conus medullaris can become larger than other spinal tumors because of the relative mobility of the roots and the wide diameter of the spinal canal . they may be well circumscribed , intradural or extradural , or combined intra - extradurally . schwannomas , together with meningiomas , are the most common intradural tumors . generally , they occur between the fourth and sixth decades of life , and women and men are equally affected by this disease . schwannoma can occasionally display degenerative changes like cyst formation , calcification , hemorrhage , and hyalinization . the differential diagnoses of such a large cyst include a cystic schwannoma , cystic neurofibroma , ependymoma , epidermoid cyst , arachnoid cyst , cystic lymphangioma , cysticteratoma , and cystic meningioma , , . however , widening of the neural foramen , erosion of the pedicle , increased interpedicular distance , and scalloping of the adjacent vertebral body may be seen by imaging examinations . schwannomas generally have low - to - intermediate signal intensity on t1 - weighted images . on t2 - weighted images , they may be heterogeneous with focal areas of hyperintensity and hypointensity , corresponding to cyst formation , hemorrhage , dense cellularity , and collagen deposition , , . schwannoma in its classic form consists of spindle - shaped cells with pale , eosinophilic cytoplasm arranged in two characteristic patterns : antoni a ( compact , hypercellular , well - organized spindle cells in a palisading pattern ) and antoni b ( hypocellular , loose - textured pleomorphic cells with predominantly myxoid cytoplasm ) . in addition , schwannomas show diffuse immunoreactivity for s - 100 protein , . the treatment of schwannomas of the conus medullaris is similar to other spinal schwannomas and consists of radical surgical excision of the tumor and decompression of the spinal nerves , . although schwannomas originate from nerve tissue , only 50 % of cases have a direct connection with a nerve . hence , complete excision without sacrificing nerve roots is feasible in most of the confined non - invasive cases . in our case , a laminectomy and total excision of the tumor were performed . using the microscope with the aid of intraoperative monitoring ( ssep ) , we completely removed the tumor that was attached to the spinal nerves in the conus medullaris . intradural schwannoma of the conus medullaris region is a rare , benign and slow growing tumor . complete resection of schwannoma of the conus medullaris is advised to avoid recurrence if the tumor has no dense adhesion to neural tissue .\noutput:\n" }, { "from": "agent", "value": "intradural schwannoma of the conus medullaris is a rare form of spinal neoplasm , which commonly occurs in the lumbar region . conus medullaris level is unusual for schwannomas . a 49 - year - old woman presented with chronic sciatica , mild bladder dysfunction , and paresthesia in the buttocks . magnetic resonance imaging of the spine showed a mass lesion in the conus medullaris region with nerve compression . the tumor was completely resected and diagnosed histologically as schwannoma . the patient recovered after surgery . clinical and radiologic features of this rare tumor are reviewed and are accompanied by literature findings ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: metabolic syndrome ( mets ) also known as insulin resistance syndrome is characterized as a combination of cardiometabolic risk determinants including insulin resistance , glucose intolerance , dyslipidemia , nonalcoholic fatty liver disease , and hypertension and is associated with a significantly increased probability of type 2 diabetes development . the liver is partially susceptible to ectopic fat accumulation , one of the most important causal components of mets , and nonalcoholic fatty liver disease ( nafld ) is now considered to be the hepatic manifestation of mets . the conventional explanation of hepatic triglyceride accumulation is that obesity and insulin resistance result in an increased release of ffas from adipocytes . increased adipocyte mass and increased hydrolysis of triglycerides through enhanced activity of a hormone - sensitive lipase contributes to elevated plasma levels of ffas . up to date no specific regulation of ffa transport into hepatocytes has been described and hence it is supposed that the rate of hepatic ffa uptake is gun - regulated and therefore directly proportional to plasma ffa concentrations . nevertheless detailed studies performed by kalopissis and her coworkers showed that in fat - fed rats the cellular uptake of c - oleate by hepatocytes in vitro is decreased despite significant tag accumulation in the liver . qualitatively this phenomenon was observed on different metabolic backgrounds ( wistar , zucker lean , zucker obese ) and differs only in the extent of its manifestation . these observations indicate that the regulation of liver triacylglycerol content is not merely a function of plasma ffa delivery alone but that other intrahepatic mechanisms ( i.e. , regulation of intracellular tag breakdown , partitioning of the ffa between oxidation and esterification , de novo fatty acid synthesis , regulation of tag secretion ) determine steatosis development . without any doubt dietary factorsare one of the significant contributors to the nafld phenotype and dietary recommendations are a significant tool in current trends in health promotion . from this point of viewa detailed understanding of the impact of different diets on the network of metabolic pathways involved in liver tag metabolism is essentially necessary . special attention should be given to the interaction of dietary composition with particular genetic / metabolic background . hereditary hypertriglyceridemic ( hhtg ) rats that were the subject of our study display a majority of the mets symptoms including hypertriglyceridemia , impaired glucose tolerance , hyperinsulinemia , insulin resistance , and increased blood pressure ( see supplementary material s1 available at doi : 10.1155 / 2012 / 757205 ) . this phenotype is manifested even without nutritional stimuli but high sucrose feeding aggravates these symptoms further . the aim of the present study was to determine the effect of two different diets ( high - sucrose and high - fat ) on the main metabolic pathways potentially contributing to the development of steatosis specifically on genetic background that is particularly prone to the onset of diabetes symptoms . we focused on following metabolic processes : ( 1 ) mechanisms regulating intracellular tag degradation in the liver specifically on the activities of liver lysosomal ( lipa ; ec3 .1.1.13 ) and heparin - releasable ( hl ; ec 3.1.1.3 ) lipases ; ( 2 ) partitioning of the released ffa between oxidation and secretion as tag ; ( 3 ) on the ffa de novo synthesis . male hereditary hypertriglyceridemic rats ( hhtg ) were kept in a temperature - controlled room at a 12:12 - h light - dark cycle , the dark phase from 6 pm till 6 am animals had free access to drinking water and diet unless stated otherwise . the strain of hhtg rats was originally selected from wistar strain rats in our laboratory . all experiments were performed in agreement with the animal protection law of the czech republic 311/1997 which is in compliance with european community council recommendations for the use of laboratory animals 86 / 609 / ecc and were approved by the ethical committee of the institute for clinical and experimental medicine .2813 g ) , all animals were fed either a high sucrose diet ( hs : 70 cal % as sucrose ; 20 cal % as protein , 10 cal % as carbohydrate ) , a high - fat diet ( hf : 70 cal % as saturated fat , 20 cal % as protein , 10 cal % as carbohydrate ) or a standard laboratory chow diet ( sd ) for 4 weeks . fed had free access to the diet until termination and the groups designed as fasted were food deprived for the last 24 hours . the fasted or fed rats were euthanized between 910 am and their liver slices ( approx . the tissues were incubated for 2 hours in a krebs - ringer bicarbonate buffer supplemented with 5 mmol / l unlabelled cold glucose , d - [ u - c - ] glucose ( specific activity 20 ci / mmol ) and 2 % bovine serum albumin , gaseous phase 95 % o2 and 5 % co2 . all the incubations were carried out at 37c in sealed vials using a shaking water bath . the estimation of the c - glucose incorporation into total lipid content was carried out as described previously . briefly , liver slices were removed from incubation medium , rinsed in physiological solution , and immediately put into ch3cl . the pieces of tissue were dissolved using a teflon pestle homogeniser , methanol was added ( ch3cl : methanol 2 : 1 ) and lipids were extracted at 4c overnight according to folch et al . . next day the residual tissue was removed and the clear extract was taken for further analysis . an aliquot was evaporated , reconstituted in scintillation liquid and its radioactivity was measured by scintillation counting . to determine the site ( glycerol versus acyl moiety ) of glucose incorporated into neutral lipids , an aliquot of clear extract was evaporated and saponified in ethanolic 15 % potassium hydroxide at 70c . after cooling to room temperature the released fatty acids were extracted repeatedly into petroleum ether . the pooled petroleum ether fractions were evaporated , reconstituted in scintillation liquid and the radioactivity was measured by scintillation counting . the amount of radioactivity incorporated into the glycerol residue was calculated as the difference of total activity incorporated into neutral lipids and the petroleum ether fraction of the same aliquot . the labelling of cytoplasmic tag in vivo was performed as described by francone et al . . the rats received an intravenous injection of 20 ci c - palmitic acid complexed to 4 % albumin under light ether anaesthesia . the animals were euthanised 90 min later and the preparation of liver slices was carried out as described above . for determination of c - palmitic acid oxidation to co2 , the experiment was carried out in glass vials with central wells . the vials were capped with rubber stoppers and the reaction was terminated by addition of 0.5 ml of 0.5 m h2so4 whereas strips of filter paper soaked with hyamine hydroxide were added to the central wells for collection of co2 . tca ( tricarboxylic acid cycle ) intermediate content was measured in the incubated liver slices after homogenisation by ultraturax ( ika worke , staufen , germany ) in 150 mm nacl . the homogenate was extracted into petroleum ether and radioactivity remaining in the water fraction was counted by scintillation counting . according to kawamura and kishimoto this fraction represents mostly tca cycle intermediates ( 80 % ) and a minor part are amino acids derived from ffa via the tca cycle ( 20 % ) . the c - palmitic acid incorporation into secreted tag was determined in a chlorophorm extract of the incubation medium . the conversion of c - palmitic acid into secreted water - soluble oxidation products ( i.e. , predominantly ketone bodies ) was assessed according to the radioactivity remaining in the aqueous fraction of the incubation medium following the chlorophorm extraction .0.5 g of liver was homogenised in 2.5 ml of homogenisation buffer ( 0.25 m sucrose ; 0.001 m edta ph = 7.4 ; heparin 7 iu / ml ) on a teflon pestle homogeniser . the homogenate was passed through a nylon mesh , centrifuged briefly in order to remove crude impurities ( 800 g , 5 min , 4c ) and kept on ice until lipase assay was performed ( maxthe subcellular fractions were obtained by centrifugation at 10000 g for 15 min . the reaction medium for acid or alkaline lipase assay was prepared identically except for the buffer used . h triolein in toluen was added to 88 mg ( 100 m ) of cold triolein and the solvent was evaporated under a nitrogen stream .3 % ffa free bsa was dissolved in 4 ml 0.1 m buffer ( acetate buffer ph = 4.5 for lysosomal lipase or glycine buffer ph = 9.5 for hepatic lipase ) with 150 mm nacl and 0.05 % triton x-100 . the whole mixture was emulsified on a hielsler sonicator up200s , amplitude 1 on an ice / water bath 3 min continuously .40 l of the homogenate or subcellular fractions were incubated for 60 min at 30c with the 160 l of reaction medium in a shaking water bath . after termination of the reaction , the released fatty acids were extracted according to belfrage and vaughan and counted for radioactivity . this approach takes advantage of the coordinated changes in the intracellular localisation of lysosomal lipase and its intracellular substrate . the liver homogenate and subcellular fractions were prepared as described above under iso - osmotic conditions that prevent lysosome disruption .20 % homogenate was mixed 1 : 1 with 0.2 m acetate buffer ph = 4.5 and incubated for 60 min at 30c in a shaking water bath . the reaction mixture was extracted into chloroform - methanol and phases were separated by 1 m nacl . an aliquot of the chlorophorm phase was evaporated and 100 l of krebs - ringer phosphate buffer ( ph = 7.6 ) containing 6 % ffa - free bsa was added . ffa concentration in final krf / bsa solution was measured using commercially available kit . in order to check the efficiency of ffa solubilisationthe emptied tubes were washed with fresh krb + 6 % bsa and then 100 l of chlorophorm was added . briefly , rats were starved for 24 hrs and then given 1 ml of 10 % triton wr - 1339 in 0.9 % nacl or 0.9 % nacl alone intravenously via the tail vein under the light ether anaesthesia . triton wr - 1339 is an alkaryl polyether anionic detergent that blocks the removal of intravascular d 1.006 g / ml lipoproteins . the animals were sacrificed 90 min after receiving either triton or 0.9 % nacl by exsanguination via aortic puncture . it has been demonstrated that the concentration of triglyceride in plasma is linear up to 3 hrs after the intravenous injection of wr 1339 hence the time point 90 min after application lies within the linear range . triglyceride entry ( secretion ) rate into the plasma was calculated from the following formula : tag entry rate ( mol .100 g b. wt . . hr ) = [ ( t90 t0 ) / 1.5 ] v ( w / 100 ) , where t0 is plasma tag concentration ( mol / ml ) before triton administration , t90 is plasma tag concentration ( mol / ml ) at the end of the study , v is plasma volume ( ml ) and w is body weight . lipids were extracted from 1 g of fresh tissue homogenised in 1 ml of h2o . 0.2 ml of the homogenate was extracted in 15 ml of 2 : 1 chloroform : methanol for 24 hours . the organic and aqueous phases were separated by adding of 6 ml kh2po4 and centrifugation at 3000 rpm for 20 min .1 ml of the organic phase was completely dried , resuspended in 100 l of isopropylalcohol and 10 l were used for the analyses . the triglyceride concentration in this aliquotwas determined using a commercially available kit ( pliva - lachema diagnostics , czech republic ) . nonesterified fatty acids , insulin , triglyceride and glucose serum content and - hydroxybutyrare were determined using commercially available kits ( ffa : ffa half microtest , roche diagnostics , gmbh germany ; triglycerides : pliva - lachema diagnostics , czech republic ; glucose : pliva - lachema diagnostics , czech republic ; insulin : mercodia , sweden ; - hydroxybutyrate : ranbut , randox , uk ) . c - palmitic acid and h - trioleinwere purchased from amersham , d - [ u - c - ] glucose was purchased from uvvvr , prague . ffa free bovine serum albumin ( fraction v ) was purchased from serva , palmitic acid and triolein from fluka , all other chemicals were purchased from sigma czech republic . statistical analyses were performed using anova and the tukey - kramer multiple comparisons test ( n = 57 ) . pearson 's correlation coefficients were calculated to assess possible relationships between lipase activities and liver triglyceride content and lipase activities and ketone bodies production . the weight of the animals on hs and hf diet ( hf hs ) rose rapidly during the first two weeks , then the rate of the weight gain significantly decreased . all tested diets were isocaloric and the more rapid increase in body weight in the hf and hs groups reflects the higher food intake during the first two weeks of diet administration ( see supplementary material s3 ) . in animals on standard dietthis parameter was even throughout the whole experiment ( figure 1 ) . during the last two weeks of diet administrationthe food intake and the rate of the weight gain in all three groups was comparable . both final body weight and the weight of epididymal fat pads was higher in hs and hf diet fed animals in comparison with the sd group ( hf hs sd ) ( table 1 ) . the fasting glycaemia and insulinemia were increased only in hf group . hs diet significantly increased both fasted and fed triglyceridemia compared to the standard diet while hf diets has slight hypolipidemic effect ( fed s - tag decreased by 30 % , p 0.05 ) . both diets significantly increased the ketogenesis in fasting ( hf hs ) but only the hf diet led to the increased production of ketone bodies in a fed state . the hepatic triacylglycerol content in fasting animals was increased by 105 % and by 280 % after hs and hf feeding , respectively . on standard diet , the liver triacylglycerol content was the same in the fed and fasted states but in the hs group liver tag content in fed state was significantly lower than in fasting . in contrast , in the hf group the trend was the opposite , hepatic triacylglycerol content being actually higher in fasted than fed animals ( table 2 ) . the liver of rats fed both hs and hf diets contained more triglyceride compared to the sd group . in order to assess the contribution of de novo ffa synthesis from glucose to the elevated tag content , we incubated liver slices prepared from the liver of rats fed each particular diet in the presence of c - labeled glucose without exogenous ffa and measured the incorporation of glucose into total lipids , into the glycerol part of tag molecules ( i.e. , glucose esterification ) and into the acyl moiety of tag molecule ( i.e. , ffa synthesis de novo ) . as shown in figure 2 , ffa de novo synthesis was significantly enhanced in the hs group ( fed fasted ) while being completely eradicated in the hf group . in order to estimate the accessibility of ffa derived from intracellular liver tag for further metabolic utilisation we prelabelled cytosolic tag by the injection c - palmitic acid in vivo and measured the radioactivity incorporation into tca intermediates , co2 and ketone bodies ( ffa oxidation ) and into tag secreted into medium ( vldl secretion ) in liver slices in vitro 90 min later . as reported by francone et al . , nearly 90 % of the radioactive label is found in cytosolic tag 90 min after the radioactivity administration into the venous blood , so we expect that under this experimental setting most of the ffa incorporated into oxidation products or vldl had to be released from intracellular tag by lipolysis . in sd fed animals , both oxidation and vldl production was lower in liver slices prepared from fed animals compared with those from the fasted ones . the administration of hsd resulted in a significant attenuation of tca intermediates and co2 production but the fasting ketogenesis was somewhat accentuated in this group ( p 0.05 ) compared to sd fed animals . the tag secretion was significantly higher in hs fed rats than in the two other groups and the prandial dependent regulation was eradicated . in liver slices from the hfd group , we did not find any effect of the diet on tca intermediates and co2 production but the ketone body productionin contrast , tag secretion into medium was significantly decreased ( p 0.001 ) . taken together , this data indicates that the diet type does not profoundly affect the total availability of ffa for metabolic utilisation but that it rather influences their partitioning between oxidation and vldl secretion ( table 3 ) . as demonstrated above , intracellular tag 's were degraded in vivo in the liver of both hs and hf administered animals . in order to analyse the effect of the diets on liver lipolysis in more detail , we directly measured the activity of two liver lipases on exogenous substrate . in liver homogenate , we were able to prove two distinct lipases with optimum ph 4.5 and 8 - 9 . the acid lipase can be identified as lysosomal ( ec 3.1.1.13 ) while the alkaline is termedthese two enzymes differ in their intracellular distribution and regulation and are affected differently by the administered diets . the effect of the diets on lipase activities in homogenate is shown in figures 3 ( a ) ( lysomal ) and 3 ( b ) ( hepatic ) . on standard diet , the activity of lysosomal lipase is higher in fasting and depressed postprandially , whereas the hepatic lipase activity did not differ between fed and fasted animals . both diets increased the activity of lysosomal lipase but by different amount . on the hs diet , the stimulatory effect of the hf diet on lysosomal lipase activity was significantly higher and was found both in the fasting and fed states . the regulation due to fasting was preserved in rats fed the hs diet but it was completely eradicated in the hf group . hs diet increased the activity of this enzyme both in fasting and postprandially while the hf diet led to significant decrease of its activity . centrifugation of liver homogenate for 10000 g allowed us to separate fractions containing dense lysosomes ( pellet ) and a fraction containing cytosol , total membranes and light lysosomes ( supernatant ) . on the standard diet , most of the lysosomal lipase activity ( 85 % ) was localised in the 10000 g pellet while most of the hepatic lipase activity ( fasting 70 % ; fed 77 % ) was found in the 10000 g supernatant . neither the hs nor hf diet influenced the subcellular distribution of hepatic lipase , approx .75 % of the activity was found in the 10000 g supernatant in all experimental settings . as far as the lysosomal lipase is concerned , the hf diet redistributed a significant portion of its activity into the 10000 g supernatant ( table 4 ) . this data indicate that lysosomal lipase is significantly affected by the hf diet both with regards to the total activity as well as the intracellular localisation . the activity of lysosomal lipase determined on endogenous substrate in vitro was positively correlated with hepatic triacylglycerol content . this correlation was stronger in the fed ( r = 0.97 ) than in the fasting state ( r = 0.65 ) ( figure 4 ) . we found no significant correlation between the hepatic triacylglycerols and hepatic lipase activity ( fed : ( r = 0.4 ; fasting : ( r = 0.35 ) ( data not shown ) . furthermore the lysosomal lipase is activity positively correlated with serum - hydroxybutyrate concentration both in fasting ( r = 0.81 ) and fed ( r = 0.62 ) states ( figure 5 ) . these positive correlations in the case of lysosomal lipase suggest that this enzyme is affected by the availability of the intracellular substrate and that ffa 's released by lysosomal lipase action are available at least for ketogenesis . this detergent effectively blocks the lipoprotein clearance from the blood due to its inhibitory effect on lpl and thus it seems that under such circumstances the accumulation of tag in plasma could be a valid measure of the rate of vldl secretion from the liver . as shown in table 5 , tag entry rate into the circulation is strongly accentuated in the hs group while being significantly diminished in animals administered with hf diet . the aim of the present study was to contribute to the understanding of the role of different metabolic pathways in the development of hepatic steatosis induced by two different dietary manipulations ( hs and hf diet ) in the model of the metabolic syndrome . the diet rich in simple carbohydrates or in fat rapidly promotes the tag accumulation in the liver . it has been suggested that the development of steatosis is associated with the attenuation of intracellular tag hydrolysis . in contrast to this hypothesis our data indicate that lipolysis , the first step in the intracellular tag utilisation , is not negatively affected by hs or hf diets . we showed that the important enzyme involved in the intracellular tag degradation is lysosomal lipase . furthermore we provided evidence that the mechanism underlying the dietary induced hepatic steatosis depends on the prevailing component of the diet . the hs diet induced steatosis is associated with a significant stimulation of ffa synthesis de novo , decreased ffa oxidation and with enhanced vldl output from the liver . in contrast hf diet associated steatosis is characteristic by downregulated ffa synthesis de novo , increased ffa oxidation and significantly impaired vldl output . in spite of decades devoted to the study of tag metabolism in the liver consensus is still not reached in identification of the exact contribution of particular lipases to the intracellular tag degradation . in our study , we focused on two lipases present in the liver - heparin - releasable hepatic lipase with ph optimum 8 - 9 and acid lysosomal lipase with ph optimum 4.5 . the activity of hepatic lipase in liver homogenate was increased by hs diet but depressed by hf feeding . hepatic lipase seems to be induced by chronic hyperinsulinemia which is associated with high sucrose as well . numerous studies indicate that the expression and activity of hepatic lipase is increased in an insulin resistant state , mostly accompanied by visceral obesity . nevertheless , most of the activities attributed to the hepatic lipase are oriented out of the hepatocyte , that is , facilitation of the interaction of ldl and remnant chylomicrons with an lrp receptor or participation in hdl metabolism . furthermore , we have previously reported that alkaline lipase is not able to degrade endogenous tag in the liver homogenate and the only lipolytic activity towards intracellular substrate was found in the acidic range . in perspective of these findings , lysosomal lipase , first described by vavnkov and mosinger , is localised in lysosomes and its activity is elevated in fasting under physiological conditions . in our experiments , this pattern of regulation was preserved only in hhtg rats on standard and hs diets but it was completely eradicated by hf feeding . both hf and hs diets had a stimulatory effect on the activity of lysosomal lipase but the effect of hf diet was significantly higher than the effect of the diet rich in sucrose . hf feeding led to the translocation of part of the lysosomal lipase activity to supernatant ( up to 25 % ) at the expense of the activity found in pellets . this observation is in accordance with the recently proposed mechanism of lysosome - dependent tag degradation in the hepatocytes . according to this hypothesis , lipid droplets are incorporated into the autophago ( lipo ) lysosomes by the process of autophagy , similarly to the autophagy of cytosolic proteins or damaged organelles . the translocation of lysosomal activity from the 10000 g pellet to supernatant may thus reflect the formation of less dense autophagolipolysosmes containing tag . we further found a strong positive correlation between acid lipase activity and tag content in the liver homogenate . taken together , these data indicate that tag degradation is actually enhanced in steatosis and that it is mediated by lysosomal lipase . in contrast to previously published hypotheses , our results based on direct measurements of acid lipase activity indicate that accumulation of intrahepatic lipids is not the consequence of the impaired mobilisation of intracellular triacylglycerol stores . despite this , we found positive correlation between the lysosomal lipase activity and oxidation of endogenous triglycerides ( ketogenesis ) even in the hf fed group which implies that the stored triglycerides are accessible at least for some metabolic pathways . as the capacity of hepatocytes to breakdown intracellular triglyceridesis actually raised in both diet groups another factor must explain the different effects of hs and hf diets on triacylglycerol accumulation in the liver and circulation . extensive literature concerning the effect of diet composition ( carbohydrate versus fat ) on liver tag metabolism is available . there is a fair consensusthat a diet rich in carbohydrates and low in fat resultsin elevation of serum tag levels , increased vldl production rate , elevation of tag amount per particle and attenuation of carbohydrate / fatty acid oxidation . numerous studies were performed in order to identify subject characteristics that may be useful in predicting sensitivity to carbohydrate feeding . characteristics such as sex , tag concentration when on hf diet , bmi , and insulin concentration have been variably shown to individually predict the effect of the diet and no single variable has a significant predictive value.in contrast , a highly significant effect of the type of carbohydrate has been demonstrated , the effect of monosacharides being much higher in comparison to polysaccharides , and this effect was similar in both hyper - and normotriglyceridemic subjects . previous studies performed in our laboratory showed that hhtg rats are significantly more sensitive to a hs diet but that the effects imposed by this diet on the tag metabolism are principally similar in hhtg and their normotriglyceridemic controls although they differ in their magnitude . the data concerning the effect of high fat dieton liver tag metabolism , particularly on vldl secretion , are more diverse . several detailed studies focused on this issue and performed on lean and obese zucker rats were published by kalopissis group in the 90 's . they demonstrated on primary hepatocytes that previous hf feeding ( 60 cal % as fat , lard ) decreases the uptake and utilization of exogenous fatty acids and profoundly influences the intracellular partitioning of ffa released from intracellular tag in favor of ffa oxidation at the expense of vldl secretion ( 4050 % decrease ) and lipogenesis ( 80 % inhibition ) . of note , qualitatively the effect of hfd on liver tag metabolism was the same both in lean and obese zucker rats , but the degree of the changes were more pronounced in the latter . in spite of the fact that the hf diet - induced inhibition of vldl secretion has been repeatedly observed the cause of this phenomenon has not been fully elucidated yet . the availability of glucose is severely lowered in hf diet compared to the standard and hs diets . one of the direct effects of glucose at the hepatic level is the increased secretion of vldl triacylglycerols . brown et al . in their study on primary hepatocytes showed that glucose mediated effects are numerous and involve enhanced transport of triacylglycerols out of the cells as vldl together with an increase in the net synthesis of apob - 48 in the intestine and apob - 100 in the liver . based on this data , we could speculate that the limiting condition determining the lipid accumulation in liver is the rate of lipoprotein output from the liver which depends on the availability of glucose . nevertheless , we found a slight increase in fasting serum glucose in hf fed rats which indicates the increased endogenous glucose production . whether this glucose is available for vldl productionstill remains an open question . in the presented study we focused on the mechanisms underlying the development of hepatic steatosis in a model that is particularly prone to the dietary manipulation . in conclusion , we provided evidence that in the hhtg rat model of metabolic syndrome hepatic steatosis ( both hs - or hf - induced ) is not associated with the impairment of intracellular tag lipolysis . on the contrary , the lysosomal tag breakdown was actually enhanced under these conditions . although the effect of both tested diets was qualitatively , but not quantitatively , the same tag accumulation in the liver the underlying mechanisms were different . high sucrose diet was associated with the depression of fatty acid oxidation in parallel with increased tag secretion and de novo ffa synthesis . in contrast in hf diet administered animals the intracellular tag - derived ffa were channelled predominantly to the oxidative utilisation , namely , ketogenesis , at the expense of a secretory pathway . this finding stresses the importance of understanding exact mechanisms responsible for particular cases in order to choose an efficient therapeutic approach .\noutput:\n" }, { "from": "agent", "value": "aims . to determine the effect of two different diets ( high - sucrose ( hs ) and high - fat ( hf ) ) on the main metabolic pathways potentially contributing to the development of steatosis : ( 1 ) activity of the liver lysosomal and heparin - releasable lipases ; ( 2 ) fatty acid ( ffa ) oxidation ; ( 3 ) ffa synthesis de novo ; ( 4 ) vldl output in vivo in a rat model of metabolic syndrome ( mets ) , hereditary hypertriglyceridemic ( hhtg ) rats fed hs or hf diets . results . both diets resulted in triacylglycerol ( tag ) accumulation in the liver ( hf > hs ) . the intracellular tag lipolysis by lysosomal lipase was increased in both groups and positively correlated with the liver tag content . diet type significantly affected partitioning of intracellular tag - derived fatty acids among ffa - utilizing metabolic pathways as hs feeding accentuated vldl secretion and downregulated ffa oxidation while the hf diet had an entirely opposite effect . ffa de novo synthesis from glucose was significantly enhanced in the hs group ( fed fasted ) while being completely eradicated in the hf group . conclusions . we found that in rats prone to the development of mets associated diseases dietary - induced steatosis is not simply a result of impaired tag degradation but that it depends on other mechanisms ( elevated ffa synthesis or attenuated vldl secretion ) that are specific according to diet composition ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: parkinson 's disease ( pd ) is the most frequent neurodegenerative disorder in europe , with a prevalence of 1/1 ,000 in the general population and 1.5 % in subjects more than 65 years of age . it originates in destruction of the dopaminergic nigrostriatal circuit ; and it is manifested in parkinson 's syndrome , which entails cognitive and psychic complications . in fact , depression is frequent in this disease , with an average prevalence of 40 % . many other neuropsychiatric subcortical manifestations have been described in the literature , but apathy is among the most frequent : current estimates of its prevalence in parkinson 's disease vary between 16.5 % and 42 % . apathy refers to a wide - ranging behavioural , emotional , and motivational constellation including reduced interest and participation in normal purposeful behaviour , lack of initiative with problems initiating or sustaining an activity to completion , lack of concern or indifference , and affective flattening . with that said , apathy syndrome may be partially secondary , with regard to dysfunction of a fronto - subcortico - striato - thalamo - cortical loop . furthermore , these circuits are in all likelihood the same as those involved in the motor and cognitive dysfunction typical of parkinson 's disease . in fact , apathy may be considered as a multicomposite entity consisting in dysfunction of associative and limbic loops and accompanied by emotional and motivational aspects . in most cases of apathy , the emotional and motivational dimension arises from intricate links between the generally unconscious mobilization of attentional resources and their purposeful utilization , in which the automatic attentional process assumes a major role . have underscored the basic role of the prefrontal cortex ( particularly the dorsolateral prefrontal cortex ) in attentional process . their studies were primarily based on analyses of patients with frontal lobe injury ( with chronic infarction in the dorsolateral prefrontal cortex ) in which subjects were made to view repetitive frequent ( for voluntary attention ) and infrequent ( for automatic attention ) background stimuli : they demonstrated a correlation between decrease of attentional level , prefrontal lesions , and increase of apathy level ( evaluated with marin apathy scale ) . another study showed a strong correlation between decrease of the electrophysiological attentional marker p300a ( novelty p3 ) and increase of apathy . the same correlation between p300a and apathy has been found in alzheimer 's disease and in cerebral trauma with selective lesion of prefrontal cortex , as illustrated in functional cerebral imaging studieswe nonetheless wish to hypothesise that , in parkinson 's disease , there exists a correlation between increase of apathy level and decrease of p300a amplitude , which constitutes an electrophysiological marker of automatic attention . twenty - five patients ( 13 women and 12 men ) , hospitalized in the department of neurology ( chu poitiers ) for evaluation of parkinson 's disease , were included with their agreement ; written informed consent for research purposes was obtained for each patient . the general characteristics of this population were age = 64.16.4 years ; duration of pd = 11.54.8 years ; daily dose of dopa therapy = 1567.8725.4 mg ; total updrs score during off period = 25.811.8 ; total updrs score during on period = 9.07.1 ; hoehn and yahr score = 2.50.4 . patients presented with the usual parkinson 's disease criteria . the severity of the disease was evaluated with the hoehn and yahr score , which maps out stages from i through v . the daily dose of dopa therapy was calculated by addition of a daily dose of levodopa and the dopaminergic agonists transcribed as dose - equivalent dopa . patients with dementia ( mmse 24 ) or with serious depression , melancholy , or depression with delirium ( according to the diagnostic and statistical manualcriteria ) were excluded from the study . each subject included in the study was evaluated with cognitive , motor , psychiatric , and subsequent electrophysiological tests during off ( without dopaminergic treatment ) and on ( with dopaminergic treatment ) periods . the study took into account the fluctuating characteristics of pd over the daytime . each period ( on or off ) was selected alternatively in order to have as many patients during the on period as during the off period ( 1 subject ) . only patients able to withstand the off period , or without important dyskinesia in the on period , were included in the study . patients were analyzed during the off period , before taking a levodopa test , patients stopped their treatments the previous evening , and the study began at 8:30 the following morning ( prior to the levodopa test ) . for each patient , the study took place over 3 days ( d0 , d1 , and d2 ) ; the order of tests was systematically the same for all patients . the cognitive assessment included 4 tests systematically taken in 30 minutes in the following order ( in both on and off periods ) : verbal fluency test , stroop test , wisconsin sorting card test , and fab ( frontal assessment battery ) test . in the verbal fluency test , patients were asked to name in one minute as many items as they could from one semantic category ( animals ) and then as many words as they could beginning with the letter m ( one minute ) ; category switching ( boys ' names and fruits ) was then assessed ( one minute ) . in an alternative form , the last one of these verbal fluency tests was used for evaluation of mental flexibility . the stroop test was used for evaluation of inhibitory control . with the wisconsin card sorting test ( wcst ) , we collected data ( number of series , number of mistakes , and perseveration percentage ) in order to evaluate mental flexibility . finally , the frontal assessment battery ( fab ) was used for the purposes of general evaluation of executive functions . after day 0 ( d0 ) assessment , we applied the updrs iii scale and then the hoehn and yahr score , for motor evaluation of pd . in order to assess apathy , we used the starkstein apathy scale . as a variant of the marin apathy scaleeach item was rated from 0 to 3 so as to calculate an apathy score ranging from 0 to 42 . cut - off score was 14 with 66 % sensitivity and 100 % specificity . in our study , only patients with score 14 were considered apathetic . for purposes of psychiatric evaluation , we used the dsm ( diagnostic and statistical manual ) criteria ( d0 ) and the had scale ( d1 and d2 ) . the had scale ( hospital anxiety and depression scale ) was also used during the on and off periods in order to quantify the depression and anxiety levels . we calculated a depression and anxiety score with cut - off 7 for each of two categories . each patient was subjected to the recording of long - latency auditory evoked potentials according to a previously described protocol , and according to the guidelines for event - related potentials ( erp ) , 140 tone bursts ( intensity : 80 db ; duration : 20 ms ; 0.9 ms rise - fall time ) were presented binaurally through earphones at a rate of 1 tone every 0.8 sec , including 100 lowfrequency sounds ( 1000 hz ) , 20 high target sounds ( 2000 hz ) , and 20 randomized unexpected novelty stimulations ( the word airplane in french , i.e. , avion ) . a disc electrode was affixed to the midline site cz and referred to linked mastoids ; responses to rare and frequent stimuli were averaged separately . the curves were numerically filtrated ( high - pass filter : 0.5 hz ; low - pass filter : 15 hz ) . the horizontal and vertical bipolar electrooculogram ( eog ) was recorded during the task to monitor artefacts . trials with artefacts were automatically excluded from the averages : if any data point ( beyond the first 2.5 ms of the sweep ) was greater than 96 % full scale , the entire sweep was rejected and was not added to the memory block . after this first run , all subjects were able to distinguish high - pitched from low - pitched tones and were then instructed to keep a mental record of the rare tones and to report their number at the end of the run ( active condition ) . the p300 wave ( target p3 ) was clearly identifiable only in the active condition in response to rare 2000 hz tones ; this condition was used in measurement of amplitude and latency of n200 and p300 potentials . the p300a ( novelty p3 ) was clearly identifiable in response to the randomized unexpected novelty stimulation ( word avion ) . latency values were calculated from the intersection of extrapolated lines from the ascending and descending slopes of each peak . latencies of n200 and p300 were determined for each subject , as well as the peak - to - peak amplitude of n200 - p300 . latency and maximum amplitude of p300a were identified in an interval ranging from 250 ms to 360 ms after stimulation ( on fz , cz , and pz electrodes ) . in addition , average p300a amplitude was calculated in an interval varying from 250 to 360 ms after stimulation and was evaluated in comparison with the basal line ( 60 ms before the stimulation ) . correlations between apathy score ( starkstein apathy scale ) and each feature ( electrophysiological , cognitive , psychiatric , and motor ) were carried out independently ( for data during on and off periods ) with correlation index ( nonparametric spearman 's test ) . the roles of dopaminergic innervation ( reflected by the percentage of improvement after updrs iii score ) or of nondopaminergic lesions ( reflected by the residual updrs iii score in on period ) on the different features ( electrophysiological , cognitive , psychiatric , and motor ) were determined with a matched nonparametric signed - rank wilcoxon test ( z ) with regard to averages during the on and off periods for each feature . differences for each feature ( electrophysiological , cognitive , psychiatric , and motor ) between apathetic and nonapathetic subjects ( a cut - off score was established at 14 ) were determined by using a nonparametric mann - whitney u test for quantitative data and a chi - square test ( corrected chi - square test and exact fisher 's test , according to the conditions of application ) for qualitative data . if a significant correlation between the apathy score and an electrophysiological data appeared , this electrophysiological variable is further dichotomized ( median as cut - off value ) for subsequent logistic regression to predict high or low value of electrophysiological data , apathy score , and other potential confounding factors . after univariate data screening , an ascending stepwise procedure for multivariate analysis was used with significant p values at 10 % level to include it into logistic regression . correlations between electrophysiological data and the other variables were calculated using the spearman nonparametric correlation coefficient . the risk was 5 % and the statistical tests were carried out in bilateral situations . the software we used for data capture and analysis was statview 5.0 ( from sas institute ) . the apathy score was correlated , during off periods , with a decrease of p300 amplitude in cz and pz locations and with average p300 amplitude in cz and fz locations ( see table 1 and figure 1 ) . during on periods , there was a significant decrease of the amplitude of p300a wave ( in fz ) in apathetic subjects ( see table 1 and figure 2 ) . during off periods , there was a tendency towards decrease of p300a amplitude in fz ( statistically insignificant : p = 0.0707 ) . the apathy score was positively correlated , on the one hand with alteration of mental flexibility ( wcst and verbal fluency test ) and on the other hand with severity of executive dysfunctions ( fab ) during on and off periods , whereas there was no correlation with disturbed inhibitory control ( explored by the stroop test ) ( table 1 ) . in the entire studied population ( 25 patients ) ,6 patients ( 24 % ) were depressive according to the dsm criteria , independently of on or off period . the apathy score was positively correlated with the depression score ( had depression ) , during on and off periods , whereas anxiety was not correlated with apathy ( table 1 ) . lastly , the apathy score was correlated with the treated motor score ( total updrs iii during on period ) and the axial updrs iii score . during the off period , the apathy score tended to be correlated with the axial updrs iii score ( statistically insignificant : p = 0.0594 ) ( table 1 ) . the dopaminergic treatment had no consequence on the latency of p300 and p300a amplitude ( in all localizations ) , but it brought about an electrophysiological modification by increasing n200 amplitude during the on period ( p = 0.045 ) . after administration of dopaminergic treatment , the apathy score was significantly lower ( p = 0.0394 ) , whereas there was no significant modification for the other cognitive data . there existed a dopaminergic effect on anxiety ( p = 0.0348 ) but not with regard to depression ( p = 0.3325 ) . lastly and logically , the motor score improved with dopa therapy ( p 0.0001 ) . during offperiods ( table 2 ) , no electrophysiological feature showed a detectable difference between apathetic and nonapathetic patients , but average p300a amplitude ( in fz ) tended to decrease in apathetic subjects ( statistically insignificant : p = 0.0592 ) . on the other hand , apathetic subjects during off period presented with alteration of mental flexibility ( verbal fluency and wcst ) and impairment of executive functions ( fab ) and a higher , more significant depression score ( had depression ) than in nonapathetic subjects . finally , the motor axial score ( axial updrs iii ) and patient age were higher in apathetic subjects ( during off period ) . during on period ( table 3 ) , apathetic patients in on showed a significant decrease of average p300a amplitude ( in fz ) ( figure 3 ) and an increase of n200 latency ( in cz ) . mental flexibility ( wcst ) was lower in apathetic patients during on . apathetic patients during on recorded higher significant depression ( had depression ) and anxiety scores ( had anxiety ) . no modification was observed for motor score or age during on period . following the correlation highlighted by spearman 's test between p300a amplitude ( in fz and on period ) and other variables , the logistic regression was applied only for four variables ( p 0.01 ) : age , verbal fluency ( letter m ) , fab , and apathy score ( starkstein ) . results indicated that apathy is the only variable correlated with the decrease of the amplitude of p300a ( in fz area and on period ) ( table 4 ) . to the best of our knowledge , this study is the first to explore characteristics of apathy in pd by analysing the role of a dysfunction in automatic attention and through use of a neurophysiological approach designed to test patients ' capacity of automatic reactivity to an unexpected sound . the first wave collected ( p300a ) is considered to be a reflection of the automatic attentional process . we have shown a correlation between the apathy score and the decrease of p300a amplitude ( only in fz localization ) and between apathy and treated motor score , severity of frontosubcortical cognitive alteration ( mental flexibility and executive functions ) , and depression . lastly , the dopaminergic treatment increased n200 amplitude ( in pz ) and lessened apathy . the decrease of p300a amplitude in pd is in agreement with other studies , one of which showed , in treated pd , a decrease of p300a amplitude with regard to frontal disturbances . our result nonetheless differs on account of its selectivity : it is observed only during on period ( but with a pronounced tendency during off period ) and it is correlated with the apathy score ( not explored in previous studies ) . the decrease of p300a amplitude has in fact been reported in other studies using a similar electrophysiological protocol , but with a solely visual modality . in patients with alzheimer 's disease , decreased p300a amplitude has been shown and was more pronounced in those with a higher apathy level . p300a wave abnormality was found to be maximal in the central area and interpreted as a consequence of a specific dysfunction of the automatic attentional process ( and not as a consequence of the cognitive disturbance ) . our results consequently suggest , in pd during on period ( and off period ) , the existence of a disturbance of automatic attention as one possible precursor of apathy . this result is in agreement with the hypothesis of marin : apathy could be the partial consequence of a deficit in mobilization of the appropriate attentional resources in a new or unusual situation . in this study , data obtained by linear regression analysis showed that , independently of other data , decreased p300a amplitude predicts severity of the apathy score , thereby confirming this hypothesis . if this hypothesis is admitted , how can we explain the lack of correlation between the apathy score and a modification of the p300a wave during the on period , whereas it is present during off period ? moreover , varied and at times contradictory results with regard to the effect of dopaminergic treatment on p300 and p300a waves have been reported : shortened or unmodified p300 latency with dopa therapy , lengthened p300 latency with dopaminergic agonists , or decrease of p300 amplitude with dopa therapy after acute levodopa and dopaminergic agonist treatment . the improved apathy score with dopaminergic treatment corroborates the results of starkstein et al . and of researchers exploring the influence of dopaminergic treatments on motivation . in a population of 30 nondepressive patients with pd ( without dementia ) , these authors have shown , in comparison with control subjects , that apathy or lessened motivation was more serious during the off period and less serious after the dopaminergic treatment . the clinical result is also coherent with experimental data suggesting a role for dopaminergic mesolimbic innervation in the regulation of the cerebral circuits involved in reward . in these circuits , secretion of dopamine strengthens the signalling of new stimuli for reward , and permits mobilization of attentional resources towards the latter . alternatively , in our work , the hypothesis of a different effect of dopaminergic treatments on attentional process can not be excluded : sensitivity of voluntary attention ( reflected by the p300 wave ) and insensitivity of automatic attention ( likewise reflected by the p300a wave ) for dopaminergic treatment . the results of our study indicate a correlation between the apathy score and severity of frontosubcortical dysfunction . indeed , apathetic patients present executive function disorders ( deterioration of fab ) such as disruption of mental flexibility ( verbal fluency and wcst ) and working memory ( verbal fluency ) . our findings confirm those of pluck and brown , who have shown in their study of apathy in 45 patients with pd a strong link between severity of apathy and disruption of executive functions ( wcst ) and verbal fluency . interestingly , another study using a visual modality of our neurophysiological protocol in patients with frontal lobe injury underscored a correlation between decrease of p300a amplitude and intensity of executive dysfunctions . the authors suggested that prefrontal dysfunction ( particularly dorsolateral prefrontal cortex ) contributed to the disruption of mobilization of attentional resources toward new stimuli . the prefrontal cortex assumes an important role in the appropriate direction of attentional resources toward new stimuli . in our patients , executivedysfunctions appear to contribute ( through a similar mechanism suggested by daffner et al . ) to the electrophysiological anomaly we have reported . the frontosubcortical dysfunction probably reflects the progression of nondopaminergic lesions , since it is insensitive to dopaminergic treatment and is correlated with the treated motor score ( reflected by updrs iii in on period ) and the axial motor score during the on period . illustrate one possible mechanism , by showing that apathetic parkinsonian subjects , in comparison with reference subjects , present an attentional disorder ( in situations where attention precedes action ) due to insufficient activation of connections between the prefrontal cortex and premotor cortical areas . andour data strongly suggest that while dopaminergic probably mesolimbic denervation contributes to apathy , nondopaminergic lesions ( bringing about a dysfunction of the frontosubcortical loops probably involving the dorsolateral prefrontal cortex ) likewise play a crucial role . if this is true , how do we explain the results with regard to noncorrelation with the stroop test ? in fact , similar results have been reported in studies concerning healthy or parkinsonian subjects . as is the case with ours , these results are compatible with the hypothesis according to which the stroop effect does not apply to perceptive mechanisms but rather to stimulation assessment and response elaboration . and , as we have found in this study , the stroop test requires an adequate attentional level but does not directly necessitate the presence of the loops involved in attentional process . lastly , imaging studies have reported a possible anatomical functional substrate for this hypothesis by showing a lack of activation during the stroop effectthis result is similar to the one reported by czernecki et al . who found , in a nondepressive parkinsonian population , using bdi depression scale , a correlation with depression . but it contrasts with the results given by pluck and brown who found no correlation between apathy and depression . furthermore , prevalence of 24 % of depression in our study may have reflected a bias . with that said , three arguments counteract this hypothesis : ( a ) prevalence of depression in our population is lower than the average of 40 % reported in the literature ; ( b ) in this work , the decrease of p300a amplitude ( in fz , during on period ) effectively predicts the severity of apathy score , independently from depression ( table 4 ) ; ( c ) finally , if modifications of p300a wave are reported in depression , they concern mainly a lengthening of latencies , and only melancholy is associated with a decrease of p300a amplitude . in fact , none of our patients present severe depression or melancholy . therefore , these different arguments confirm the postulate that it is possible to distinguish apathy from depression . the absence of a control group and the lack of event - related potential ( erp ) spatial resolution also represent methodological limits . on this subject , some studies have clearly shown modifications of p300a wave with age , but without any observed modification of amplitude . in our case , a control group would have facilitated confirmation that neurophysiological modifications are age independent . it may nonetheless be difficult to explain this result because , in pd , intensity of cognitive troubles is correlated with severity of treated motor score , duration of evolution of the disease , and age of the patient , but due to subject distribution , we are prudent when interpreting the data assembled in table 3 . finally , in our study , use of erp does not allow for topographical indication of the neuronal loops involved in apathy . this additional limit is inherent to erp , which presents the advantage of excellent temporal resolution and the drawback of spatial resolution so poor as to preclude precise topographical indication of the dysfunctions . in our exploration of apathy with an electrophysiological approach , it appears that apathy in pd is correlated with a decrease of p300a amplitude : it represents a reliable neurophysiological marker , independently from depression . our results confirm on the one hand the involvement of a dorsolateral prefrontal cortex dysfunction in the antecedents of apathy and on the other hand the beneficial effect on apathy of dopaminergic treatment . enhanced and more purposeful allocation and mobilization of attentional resources are likely to result . from a physiopathological aspect , our results allow us to put forward the following hypothesis : in pd , apathy is the consequence of dopaminergic denervation ( probably mesolimbic ) and nondopaminergic lesions ( linked to evolution of the disease and particularly affecting prefrontal subcorticodorsolateral circuits ) . unfortunately , the low spatial resolution inherent to erp does not allow for a sufficiently accurate approach to the topography of the neuronal pathways involved ; the success of such an approach will require an adroit combination of erp and functional imaging .\noutput:\n" }, { "from": "agent", "value": "in parkinson 's disease ( pd ) , apathy ( or loss of motivation ) is frequent . nevertheless , the contribution of attentional disorders to its genesis is still not clearly known . we want to determine the relation existing between apathy and attentional disorders by using p300a ( or novelty p3 ) as a marker of the attentional process . the study included 25 patients ( 13 women and 12 men ) with pd for whom we have determined the relationship between automatic attention ( represented by p300a ) and motor status , apathy , executive dysfunction , mental flexibility , inhibitory control , and depression / anxiety . we have found a correlation between the apathy score and amplitude of novelty p300 during the on period and also a correlation of the apathy score with a decrease in amplitude of p300 during the off period . in a linear regression model , changes in the p300a predicted the severity of apathy independently of any other variable . we concluded firstly that the reduction in amplitude of the p300a wave was a neurophysiological marker of apathy in pd and secondly that apathy led to both dopaminergic denervation ( mesolimbic ) and nondopaminergic ( dorsolateral prefrontal - subcortical ) dysfunction ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the giant magnetoresistive ( gmr ) sensor used in our experiment has a bottom spin valve structure of the type : si / ta ( 5 ) / seed layer / irmn ( 8 ) / cofe ( 2 ) / ru / ( 0.8 ) / cofe ( 2 ) / cu ( 2.3 ) / cofe ( 1.5 ) / ta ( 3 ) , all numbers in parenthesis are in nanometers . each chip contains an array of gmr sensors , which are connected to peripheral bonding pads by a 300 nm thick ta / au / ta lead . to protect the sensors and leads from corrosion , two passivation layers were deposited by ion beam sputtering : first , a thin passivation layer of sio2 ( 10 nm ) / si3n4 ( 20 nm ) / sio2 ( 10 nm ) was deposited above all sensors and leads , excluding only the bonding pad area ; then a thick passivation layer of sio2 ( 100 nm ) / si3n4 ( 150 nm ) / sio2 ( 100 nm ) was deposited on top of the reference sensors and leads , but excluding the active sensors and bonding pad area . the magnetoresistive ratio is approximately 12 % after patterning . the pinning direction of the spin valve is in - plane and perpendicular to the sensor strip . the easy axis of the free layer is set by the shape anisotropy to be parallel with the sensor strip . this configuration allows the gmr sensors to work at the most sensitive region of their mr transfer curves . due to the gmr effect , the resistance of the sensor changes with the orientation of the magnetization of the two magnetic layers , which are separated by a copper spacer layer : here r0 is the resistance under zero magnetic field , rmax is the maximum resistance change and is the angle between the magnetization of the two magnetic layers . in the bottom spin valve structure , the magnetization of the bottom magnetic layer ( pinned layer ) is pinned to a fixed direction , while the magnetic orientation of the top magnetic layer ( free layer ) can freely rotate with the external magnetic field . as a result , the stray field from magnetic labels can change the orientation of the free layer magnetization and therefore change the resistance of the sensor . each macs particle is a cluster of 10 nm fe2o3 nanoparticles held together by a matrix of dextran . due to the small size of the fe2o3 nanoparticles , the macs particle is superparamagnetic , with a hydrodynamic diameter of 46 nm , and contains 10 % magnetic material ( wt / wt ) . macs particles can be functionalized with specific affinity molecules corresponding to the analyte being studied . for epcam ( cea , vegf ) experiments , the macs particles are functionalized with anti - epcam ( cea , vegf ) antibodies ; for biotin - streptavidin experiments , the macs particles are functionalized with streptavidin . the sensor surface was first cleaned using acetone , methanol and isopropanol and subsequently exposed to oxygen plasma for three minutes . a 2 % ( w / v ) polyallylamine solution in milli - q waterthe chips were then rinsed with milli - q water and baked at 150c for 45 minutes . a 10 % ( w / v ) solution of edc and 10 % ( w / v ) solution of nhswere then added to the sensor surface at room temperature for 1 hour , after which the sensor was rinsed and dried . capture protein epcam ( 960 - ep - 050 from r & d systems ) , cea ( 4128 - cm - 050 from rd systems ) or vegf ( 293 - ve165 from r & d systems ) or capture antibody ( antibody to epcam ( ab20160 from abcam or 960 from r & d ) , cea ( 5910 from biospacific ) or vegf ( ab69479 from abcam ) was robotically deposited ( scienion sciflexarrayer from biodot ) over each sensor in 360 picoliter droplets 3 times ( total volume of 1 nanoliter ) . in order to monitor reproducibility , from 3 to 8 sensors , randomly distributed across the gmr sensor array , were incubated with the same capture protein . the control sensors were immobilized in a similar fashion with either bsa at 1 mg / ml or a non - complementary antibody ( typically anti - survivin antibody ( h00000332 - p01 from novus biologicals , llc ) at 500 g / ml . finally , the entire surface of the sensor array was blocked with 1 mg / ml of bsa in phosphate buffered saline for 30 minutes . after the sensor surface is functionalized with the appropriate capture protein , the bsa blocking buffer was washed away and a 50 l solution of the magnetically labeled detection antibody ( described above ) was added to the reaction well . the gmr sensor array was monitored in real - time as the magnetically labeled detection antibodies bound to the corresponding surface - immobilized proteins . the binding curves , unique to each protein , were then plotted and the binding constants could be determined . the giant magnetoresistive ( gmr ) sensor used in our experiment has a bottom spin valve structure of the type : si / ta ( 5 ) / seed layer / irmn ( 8 ) / cofe ( 2 ) / ru / ( 0.8 ) / cofe ( 2 ) / cu ( 2.3 ) / cofe ( 1.5 ) / ta ( 3 ) , all numbers in parenthesis are in nanometers . each chip contains an array of gmr sensors , which are connected to peripheral bonding pads by a 300 nm thick ta / au / ta lead . to protect the sensors and leads from corrosion , two passivation layers were deposited by ion beam sputtering : first , a thin passivation layer of sio2 ( 10 nm ) / si3n4 ( 20 nm ) / sio2 ( 10 nm ) was deposited above all sensors and leads , excluding only the bonding pad area ; then a thick passivation layer of sio2 ( 100 nm ) / si3n4 ( 150 nm ) / sio2 ( 100 nm ) was deposited on top of the reference sensors and leads , but excluding the active sensors and bonding pad area . the magnetoresistive ratio is approximately 12 % after patterning . the pinning direction of the spin valve is in - plane and perpendicular to the sensor strip . the easy axis of the free layer is set by the shape anisotropy to be parallel with the sensor strip . this configuration allows the gmr sensors to work at the most sensitive region of their mr transfer curves . due to the gmr effect , the resistance of the sensor changes with the orientation of the magnetization of the two magnetic layers , which are separated by a copper spacer layer : here r0 is the resistance under zero magnetic field , rmax is the maximum resistance change and is the angle between the magnetization of the two magnetic layers . in the bottom spin valve structure , the magnetization of the bottom magnetic layer ( pinned layer ) is pinned to a fixed direction , while the magnetic orientation of the top magnetic layer ( free layer ) can freely rotate with the external magnetic field . as a result , the stray field from magnetic labels can change the orientation of the free layer magnetization and therefore change the resistance of the sensor . each macs particle is a cluster of 10 nm fe2o3 nanoparticles held together by a matrix of dextran . due to the small size of the fe2o3 nanoparticles , the macs particle is superparamagnetic , with a hydrodynamic diameter of 46 nm , and contains 10 % magnetic material ( wt / wt ) . macs particles can be functionalized with specific affinity molecules corresponding to the analyte being studied . for epcam ( cea , vegf ) experiments , the macs particles are functionalized with anti - epcam ( cea , vegf ) antibodies ; for biotin - streptavidin experiments , the macs particles are functionalized with streptavidin . the sensor surface was first cleaned using acetone , methanol and isopropanol and subsequently exposed to oxygen plasma for three minutes . a 2 % ( w / v ) polyallylamine solution in milli - q waterthe chips were then rinsed with milli - q water and baked at 150c for 45 minutes . a 10 % ( w / v ) solution of edc and 10 % ( w / v ) solution of nhswere then added to the sensor surface at room temperature for 1 hour , after which the sensor was rinsed and dried . capture protein epcam ( 960 - ep - 050 from r & d systems ) , cea ( 4128 - cm - 050 from rd systems ) or vegf ( 293 - ve165 from r & d systems ) or capture antibody ( antibody to epcam ( ab20160 from abcam or 960 from r & d ) , cea ( 5910 from biospacific ) or vegf ( ab69479 from abcam ) was robotically deposited ( scienion sciflexarrayer from biodot ) over each sensor in 360 picoliter droplets 3 times ( total volume of 1 nanoliter ) . in order to monitor reproducibility , from 3 to 8 sensors , randomly distributed across the gmr sensor array , were incubated with the same capture protein . the control sensors were immobilized in a similar fashion with either bsa at 1 mg / ml or a non - complementary antibody ( typically anti - survivin antibody ( h00000332 - p01 from novus biologicals , llc ) at 500 g / ml . finally , the entire surface of the sensor array was blocked with 1 mg / ml of bsa in phosphate buffered saline for 30 minutes . after the sensor surface is functionalized with the appropriate capture protein , the gmr sensor array was placed in the test station . the bsa blocking buffer was washed away and a 50 l solution of the magnetically labeled detection antibody ( described above ) was added to the reaction well . the gmr sensor array was monitored in real - time as the magnetically labeled detection antibodies bound to the corresponding surface - immobilized proteins . the binding curves , unique to each protein , were then plotted and the binding constants could be determined . an assay is typically run for approximately 5 minutes .\noutput:\n" }, { "from": "agent", "value": "monitoring the kinetics of protein interactions on a high density sensor array is vital to drug development and proteomic analysis . label - free kinetic assays based on surface plasmon resonance are the current gold standard , but they have poor detection limits , suffer from non - specific binding , and are not amenable to high throughput analyses . here we show that magnetically responsive nanosensors that have been scaled to over 100,000 sensors / cm2 can be used to measure the binding kinetics of various proteins with high spatial and temporal resolution . we present an analytical model that describes the binding of magnetically labeled antibodies to proteins that are immobilized on the sensor surface . this model is able to quantify the kinetics of antibody - antigen binding at sensitivities as low as 20 zeptomoles of solute ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: hereditary haemorrhagic telangiectasia ( hht ) is an autosomal dominant inherited disease characterised by vascular malformations , ranging from small telangiectases in skin and mucosal membranes to large visceral arteriovenous malformations ( avms ) predominantly localised in the lungs , brain and liver . pulmonary arteriovenous malformations ( pavms ) are abnormally dilated vessels between pulmonary arteries and veins that cause a permanent extra - cardiac right - to - left shunt , which carries the risk of cerebral paradoxical embolisation of both thrombotic and septic origin . transcatheter embolisation of pavms can be safely performed , in order to prevent these potentially severe neurological complications , such as ischaemic stroke or cerebral abscess . currently , there are no data regarding the potential haemodynamic changes occurring directly after pavm embolisation . therefore , the present study investigated the direct haemodynamic effects of pavm embolisation , using non - invasive finger pressure measurements . between 2008 and 2010 , we included 29 patients who underwent transcatheter embolisation of pavms in the st . a pavm was defined as a direct communication between a pulmonary artery and a pulmonary vein , bypassing the pulmonary capillary filter , and was diagnosed using transthoracic contrast echocardiography ( ttce ) and subsequent chest computed tomography ( ct ) . before and after pavm embolisation , the right - to - left shunt fraction was measured using the 100 % oxygen method as previously described . pavms with a feeding artery diameter of 23 mm or greater were found suitable for embolisation therapy .1 a c ) was performed under local anaesthesia ( lidocaine 1 % ) . percutaneous access was derived through the right femoral vein and a six french sheath was inserted . the interventional radiologist selected the pavm closure device , based on the diameter and anatomy of the pavm . the most preferred closure device was the amplatzer vascular plug ( aga medical , golden valley , mn , usa ) ( fig . plugs with a diameter of 412 mm were used . if pavm closure with a plug was not possible , detachable coils ( boston scientific , natick , ma ) the embolic material was implanted under fluoroscopic guidance , with a maximum contrast volume of 300 ml ( xenetix ; iobitrol , guerbet , villepinte , france ) . within 24 h after embolisationc embolisation of pulmonary arteriovenous malformation in the left lower lobe with a amplatzer vascular plug . d amplatzer vascular plug a pulmonary angiogram of pulmonary arteriovenous malformation in the left lower lobe . c embolisation of pulmonary arteriovenous malformation in the left lower lobe with a amplatzer vascular plug . d amplatzer vascular plug during the transcatheter embolisation of pavms , arterial pressure was measured on a finger of the left hand using a finometer device ( fms , finapres medical systems , amsterdam , the netherlands ) . the finometer measures blood pressure by a combination of the volume clamp method of penaz and the physiocal criteria developed by wesseling . the hand was kept at heart level and a cuff was wrapped around the same arm for individual blood pressure calibration using the return - to - flow calibration . because of potential distortion of the measurements at the time of pavm closure , parameters were recorded after stabilisation of the finger pressure signal during a blanking period of 1 min immediately before and after placement of the first and the last plug . during the pavm embolisation , finger pressure measurements with the associated event marks were monitored and digitally stored . review of these data was performed using beatscope software . five minute averages of systolic ( sbp ) , diastolic ( dbp ) and mean blood pressure ( mbp ) , heart rate ( hr ) , stroke volume ( sv ) , cardiac output ( co ) , total peripheral resistance ( tpr ) and delta pressure / delta time ( dp / dt ) were calculated after an electronic calibration procedure . sv and co ( co is the product of sv and hr ) were calculated from the finger pressure wave using the modelflow methodology . the cardiac index ( ci ) return - to - flow calibration , using the arm cuff , was used for calibration of the blood pressure . both absolute values and absolute and relative changes ( delta absolute and delta percent ) are presented . differences within groups were analysed performing paired samples t - tests . a significance level of p 0.05 was considered significant . between 2008 and 2010 , we included 29 patients who underwent transcatheter embolisation of pavms in the st . a pavm was defined as a direct communication between a pulmonary artery and a pulmonary vein , bypassing the pulmonary capillary filter , and was diagnosed using transthoracic contrast echocardiography ( ttce ) and subsequent chest computed tomography ( ct ) . before and after pavm embolisation , the right - to - left shunt fraction was measured using the 100 % oxygen method as previously described . pavms with a feeding artery diameter of 23 mm or greater were found suitable for embolisation therapy . the procedure ( fig .1 a c ) was performed under local anaesthesia ( lidocaine 1 % ) . percutaneous access was derived through the right femoral vein and a six french sheath was inserted . the interventional radiologist selected the pavm closure device , based on the diameter and anatomy of the pavm . the most preferred closure device was the amplatzer vascular plug ( aga medical , golden valley , mn , usa ) ( fig . plugs with a diameter of 412 mm were used . if pavm closure with a plug was not possible , detachable coils ( boston scientific , natick , ma ) were used . the embolic material was implanted under fluoroscopic guidance , with a maximum contrast volume of 300 ml ( xenetix ; iobitrol , guerbet , villepinte , france ) . within 24 h after embolisationc embolisation of pulmonary arteriovenous malformation in the left lower lobe with a amplatzer vascular plug . d amplatzer vascular plug a pulmonary angiogram of pulmonary arteriovenous malformation in the left lower lobe . c embolisation of pulmonary arteriovenous malformation in the left lower lobe with a amplatzer vascular plug . during the transcatheter embolisation of pavms , arterial pressure was measured on a finger of the left hand using a finometer device ( fms , finapres medical systems , amsterdam , the netherlands ) . the finometer measures blood pressure by a combination of the volume clamp method of penaz and the physiocal criteria developed by wesseling . the hand was kept at heart level and a cuff was wrapped around the same arm for individual blood pressure calibration using the return - to - flow calibration . because of potential distortion of the measurements at the time of pavm closure , parameters were recorded after stabilisation of the finger pressure signal during a blanking period of 1 min immediately before and after placement of the first and the last plug . during the pavm embolisation , finger pressure measurements with the associated event marks were monitored and digitally stored . review of these data was performed using beatscope software . five minute averages of systolic ( sbp ) , diastolic ( dbp ) and mean blood pressure ( mbp ) , heart rate ( hr ) , stroke volume ( sv ) , cardiac output ( co ) , total peripheral resistance ( tpr ) and delta pressure / delta time ( dp / dt ) were calculated after an electronic calibration procedure . sv and co ( co is the product of sv and hr ) were calculated from the finger pressure wave using the modelflow methodology . the cardiac index ( ci ) return - to - flow calibration , using the arm cuff , was used for calibration of the blood pressure . both absolute values and absolute and relative changes ( delta absolute and delta percent ) are presented . the statistics were performed using spss version 17.0 for windows ( spss inc . , chicago , il , usa ) . differences within groups were analysed performing paired samples t - tests . a significance level of p 0.05 was considered significant . a total of 29 hht patients ( 62 % female , mean age 39.215.3 years ) were included , in which 72 pavms were embolised ( mean per patient 2.5 ) . an amplatzer plug was used in 54 cases and a detachable coil in the remaining 18 cases . the baseline characteristics are presented in tables 1 and 2 . table 1baseline characteristics of patientstotal29gendermale11 ( 37.9 ) female18 ( 62.1 ) age ( years ) 39.215.3 bmi ( kg / m ) 24.05.0 bsa ( m ) 1.90.2 hhtdefinite28 ( 96.6 ) type 119 ( 65.5 ) type 22 ( 6.9 ) type unknown8 ( 27.6 ) sao2 ( % ) before procedure95 .53.5 after procedure98 .42.3 shunt fraction ( % ) before procedure13 .68.3 after procedure4 .96.6 all characteristics are written in number of patients with percentage or mean with standard deviation bmi body mass index , bsa body surface area , kg kilogram , kg / m kilogram per square meter , hht hereditary haemorrhagic telangiectasia , sao 2 saturation level of oxygen in haemoglobin , p avm pulmonary arteriovenous malformationtable 2baseline characteristics of embolisation proceduretreated pavms1 pavm9 ( 31.0 ) 2 pavms9 ( 31.0 ) 3 pavms2 ( 6.9 ) 4 pavms8 ( 27.6 ) 4 pavms1 ( 3.4 ) closure deviceamplatzer plug54 ( 75.0 ) coil18 ( 25.0 ) plug diameter 4 ( mm ) 1 ( 1.9 ) 4 ( mm ) 13 ( 24.1 ) 6 ( mm ) 13 ( 24.1 ) 8 ( mm ) 9 ( 16.7 ) 10 ( mm ) 10 ( 18.5 ) 10 ( mm ) 6 ( 11.1 ) not known2 ( 3.7 ) all characteristics are written in number with percentage pavm pulmonary arteriovenous malformation , mm millimetre diameter coils are not know baseline characteristics of patients all characteristics are written in number of patients with percentage or mean with standard deviation bmi body mass index , bsa body surface area , kg kilogram , kg / m kilogram per square meter , hht hereditary haemorrhagic telangiectasia , sao 2 saturation level of oxygen in haemoglobin , p avm pulmonary arteriovenous malformation baseline characteristics of embolisation procedure all characteristics are written in number with percentage pavm pulmonary arteriovenous malformation , mm millimetre diameter coils are not know directly after pavm embolisation the sv and co decreased significantly : 6.413.0 ml ( range 45.9 to 17.9 ml ; 11.9 % , p = 0.01 ) and 0.40.8 l / min ( range 3.0 to 1.58 l / min ; 9.5 % , p = 0.01 ) . as expected , the ci decreased as well ( range 1.5 to 0.9 l / min / m ; 9.5 % , p = 0.01 ) . dbp and mbp increased significantly by 5.210.3 mmhg ( range 9.0 to 32.9 mmhg ; 5.9 % , p = 0.01 ) for dbp and 5.712.1 mmhg ( range 12.7 to 32.6 mmhg ; 4.1 % , p = 0.02 ) for mbp , respectively . there was no significant change in sbp ( 4.016.3 mmhg ( range 25.5 to 38.5 mmhg ; 1.7 % , p = 0.20 ) . the dp / dt did not change significantly : 2.1290.0 mmhg / s ( range 750.0 to 848.2 mmhg / s ; 0.2 % , p = 0.97 ) . there was a correlation between the delta dp / dt and the sbp ( pearson coefficient r = 0.73 , r = 0.53 , p 0.0001 ) . hr and tpr increased , but this appeared to be non - significant : 1.67.4 beats / min ( range 17.4 to 21.2 beats / min ; 1.8 % , p = 0.24 ) and 0.10.5 woods units ( range 1.62 to 1.39 woods units ; 5.8 % , p = 0.16 ) . these data are summarised in table 3 . table 3haemodynamic measurements before and after embolisation with absolute and relative changesbeforesdafter sddelta absolutedelta percentpsbp ( mmhg ) 144.925.3148.928.44.01.70.20 dpb ( mmhg ) 85.511.590.716.35.25.90.01 mbp ( mmhg ) 108.016.0113.719.95.74.10.02 hr ( beats / min ) 78.814.680.413.91.61.80.24 sv ( ml ) 70.920.964.519.36.411.90.01 co ( l / min ) 5.51.65.11.40.49.50.01 ci ( l / min / m ) 3.00.82.80.80.29.50.01 tpr ( woods units ) 1.40.51.50.50.15.80.16 dp / dt ( mmhg / s ) 1,233.7463.81,235.8481.72.10.20.97 sbp systolic blood pressure , dbp diastolic blood pressure , mbp mean blood pressure , hr heart rate , sv stroke volume , co cardiac output , ci cardiac index , tpr total peripheral resistance , dp / dt delta pressure / delta time , sd standard deviation , min minutes , ml millilitres , l / min litres per minute , mmhg millimetres of mercury , s second haemodynamic measurements before and after embolisation with absolute and relative changes sbp systolic blood pressure , dbp diastolic blood pressure , mbp mean blood pressure , hr heart rate , sv stroke volume , co cardiac output , ci cardiac index , tpr total peripheral resistance , dp / dt delta pressure / delta time , sd standard deviation , min minutes , ml millilitres , l / min litres per minute , mmhg millimetres of mercury , s seconda total of 29 hht patients ( 62 % female , mean age 39.215.3 years ) were included , in which 72 pavms were embolised ( mean per patient 2.5 ) . an amplatzer plug was used in 54 cases and a detachable coil in the remaining 18 cases . the baseline characteristics are presented in tables 1 and 2 . table 1baseline characteristics of patientstotal29gendermale11 ( 37.9 ) female18 ( 62.1 ) age ( years ) 39.215.3 bmi ( kg / m ) 24.05.0 bsa ( m ) 1.90.2 hhtdefinite28 ( 96.6 ) type 119 ( 65.5 ) type 22 ( 6.9 ) type unknown8 ( 27.6 ) sao2 ( % ) before procedure95 .53.5 after procedure98 .42.3 shunt fraction ( % ) before procedure13 .68.3 after procedure4 .96.6 all characteristics are written in number of patients with percentage or mean with standard deviation bmi body mass index , bsa body surface area , kg kilogram , kg / m kilogram per square meter , hht hereditary haemorrhagic telangiectasia , sao 2 saturation level of oxygen in haemoglobin , p avm pulmonary arteriovenous malformationtable 2baseline characteristics of embolisation proceduretreated pavms1 pavm9 ( 31.0 ) 2 pavms9 ( 31.0 ) 3 pavms2 ( 6.9 ) 4 pavms8 ( 27.6 ) 4 pavms1 ( 3.4 ) closure deviceamplatzer plug54 ( 75.0 ) coil18 ( 25.0 ) plug diameter 4 ( mm ) 1 ( 1.9 ) 4 ( mm ) 13 ( 24.1 ) 6 ( mm ) 13 ( 24.1 ) 8 ( mm ) 9 ( 16.7 ) 10 ( mm ) 10 ( 18.5 ) 10 ( mm ) 6 ( 11.1 ) not known2 ( 3.7 ) all characteristics are written in number with percentage pavm pulmonary arteriovenous malformation , mm millimetre diameter coils are not know baseline characteristics of patients all characteristics are written in number of patients with percentage or mean with standard deviation bmi body mass index , bsa body surface area , kg kilogram , kg / m kilogram per square meter , hht hereditary haemorrhagic telangiectasia , sao 2 saturation level of oxygen in haemoglobin , p avm pulmonary arteriovenous malformation baseline characteristics of embolisation procedure all characteristics are written in number with percentage pavm pulmonary arteriovenous malformation , mm millimetre diameter coils are not knowdirectly after pavm embolisation the sv and co decreased significantly : 6.413.0 ml ( range 45.9 to 17.9 ml ; 11.9 % , p = 0.01 ) and 0.40.8 l / min ( range 3.0 to 1.58 l / min ; 9.5 % , p = 0.01 ) . as expected , the ci decreased as well ( range 1.5 to 0.9 l / min / m ; 9.5 % , p = 0.01 ) . dbp and mbp increased significantly by 5.210.3 mmhg ( range 9.0 to 32.9 mmhg ; 5.9 % , p = 0.01 ) for dbp and 5.712.1 mmhg ( range 12.7 to 32.6 mmhg ; 4.1 % , p = 0.02 ) for mbp , respectively . there was no significant change in sbp ( 4.016.3 mmhg ( range 25.5 to 38.5 mmhg ; 1.7 % , p = 0.20 ) . the dp / dt did not change significantly : 2.1290.0 mmhg / s ( range 750.0 to 848.2 mmhg / s ; 0.2 % , p = 0.97 ) . there was a correlation between the delta dp / dt and the sbp ( pearson coefficient r = 0.73 , r = 0.53 , p 0.0001 ) . hr and tpr increased , but this appeared to be non - significant : 1.67.4 beats / min ( range 17.4 to 21.2 beats / min ; 1.8 % , p = 0.24 ) and 0.10.5 woods units ( range 1.62 to 1.39 woods units ; 5.8 % , p = 0.16 ) . these data are summarised in table 3 . table 3haemodynamic measurements before and after embolisation with absolute and relative changesbeforesdafter sddelta absolutedelta percentpsbp ( mmhg ) 144.925.3148.928.44.01.70.20 dpb ( mmhg ) 85.511.590.716.35.25.90.01 mbp ( mmhg ) 108.016.0113.719.95.74.10.02 hr ( beats / min ) 78.814.680.413.91.61.80.24 sv ( ml ) 70.920.964.519.36.411.90.01 co ( l / min ) 5.51.65.11.40.49.50.01 ci ( l / min / m ) 3.00.82.80.80.29.50.01 tpr ( woods units ) 1.40.51.50.50.15.80.16 dp / dt ( mmhg / s ) 1,233.7463.81,235.8481.72.10.20.97 sbp systolic blood pressure , dbp diastolic blood pressure , mbp mean blood pressure , hr heart rate , sv stroke volume , co cardiac output , ci cardiac index , tpr total peripheral resistance , dp / dt delta pressure / delta time , sd standard deviation , min minutes , ml millilitres , l / min litres per minute , mmhg millimetres of mercury , s second haemodynamic measurements before and after embolisation with absolute and relative changes sbp systolic blood pressure , dbp diastolic blood pressure , mbp mean blood pressure , hr heart rate , sv stroke volume , co cardiac output , ci cardiac index , tpr total peripheral resistance , dp / dt delta pressure / delta time , sd standard deviation , min minutes , ml millilitres , l / min litres per minute , mmhg millimetres of mercury , s secondto our knowledge , this is the first study describing the occurrence of significant haemodynamic changes directly after transcatheter embolisation of pavms . using the finometer and modelflow methodology , our study accurately recorded beat - to - beat non - invasive finger pressure measurements and thereby the immediate haemodynamic changes after pavm embolisation , amongst which a decrease in sv and co were most important . only one case report previously documented haemodynamic changes 4 months after pavm embolisation with a marked reduction in co of 5.1 l / min ( 41 % ) . this seems to be in line with the results in our current study in 29 hht patients who all underwent transcatheter embolisation of pavms . however , we found a less pronounced decrease in co , which can be explained by the smaller right - to - left shunts in our study population , with a mean shunt fraction before closure of 14 % versus 31 % described by andrivet et al . . it is possible that the co may further decrease over time as a result of additional thrombosis of the plug or coil in the pavm feeding artery . however , the long - term haemodynamic changes after pavm embolisation remain hard to predict , since new pavms may occur and existing pavms may grow , so this is still subject for larger studies in the future . the haemodynamic responses after pavm embolisation may differ between hht patients , which can be related to difference in number and size of pavms at baseline . in the present study , nine patients underwent embolisation of at least 4 pavms in one session , whereas less pavms were embolised in the remaining 20 patients . furthermore , a total of 16 pavms were treated with a large plug ( diameter 10 mm ) , whereas 14 pavms could be treated with smaller endovascular plugs ( diameter 4 mm ) . unfortunately , we could not find a significant association between plug size ( size of the pavm ) and the changes in haemodynamic parameters . furthermore , the haemodynamic response can be influenced by a different prevalence of underlying hepatic arteriovenous malformations ( havms ) in different hht subtypes . only one patient had a history of havms , which might be an underestimation , since screening for havms was only performed when clinically or biochemically suspected . clinically significant havms seemed to be absent in the present study , as a hyperdynamic circulation with an abnormal high ci at baseline was not documented in the present study ( mean ci within the normal range of 3.00.8 l / min / m ) . the amount of microscopic pavms under the detection limit of chest ct may further influence the shunt percentage and different haemodynamic responses in hht patients . due to the decrease in pulmonary right - to - left shunt from 14 to 5 % after pavm embolisation , a consequent decrease in preload and sv can be expected ( mean change 12 % in the current study ) . as there was no change in hr , the mbp increased by 4 % after pavm embolisation , which is probably due to the non - significant increase in tpr ( 6 % ) , as the mbp is a product of tpr and co. as blood pressure is inversely related to indoor temperature , the fall in ambient temperature during the procedure may have caused further vasoconstriction and thereby an increase in blood pressure . in a previous study about the association between brachial pulse dp / dt and other haemodynamic parameters in a chronic haemodialysis population , a pearson coefficient of r = 0.6 ( r = 0.36 , p 0.001 ) was reported for the correlation between the delta blood pressure and the delta dp / dt . this is in line with the results found in our study ( r = 0.73 , r = 0.53 , p 0.0001 ) and demonstrates that the dp / dt is responsible for more than 50 % of variance in the blood pressure . because of the significant increase in mbp and decrease in co , we also expected a significant increase in tpr . a possible explanation might be an increase in central venous pressure due to the embolisation . unfortunately , no measurements of the right atrium pressure were performed during the embolisation procedure . a potential clinical implication of our findings might be associated with the presence of pulmonary hypertension ( ph ) in hht . ph can occur both as gene - related pulmonary arterial hypertension and as a response to high output due to havms . as pavms are abnormally dilated vessels between pulmonary arteries and veins they provide low resistance pathways for the pulmonary blood flow and one may therefore expect an elevation in pulmonary artery pressure ( pap ) after transcatheter closure . it was suggested that this might be caused by other haemodynamic changes , for example recruitment of the pulmonary vasculature or a decrease in co , although this has been previously suggested in only one case report . we now present the first study that confirms the decrease in co after embolisation in a larger population of hht patients , which may indeed provide a potential explanation for the absent increase in pap after embolisation . furthermore , pavm - related hypoxaemia can induce pulmonary vasoconstriction with a concomitant increase in pulmonary vascular resistance ( pvr ) . in our studythere was indeed an increase in saturation after embolisation of pavms ( table 1 ) with probably an decrease in pulmonary vasoconstriction and pvr . first , our study is limited by its small sample , which may have influenced the results . second , the modelflow model does not seem to be accurate in measuring absolute values of sv , co and tpr . the differences between the uncalibrated model and invasive determinations ( measured with the thermodilution method ) in individual patients are usually small , but can be substantial and unreliable in some . however , the modelflow methodology is an accurate model to compare changes in haemodynamics within one patient and the british hypertension society has recommended the finometer for measurements in the clinical set - up as well as for research purposes . first , our study is limited by its small sample , which may have influenced the results . second , the modelflow model does not seem to be accurate in measuring absolute values of sv , co and tpr . the differences between the uncalibrated model and invasive determinations ( measured with the thermodilution method ) in individual patients are usually small , but can be substantial and unreliable in some . however , the modelflow methodology is an accurate model to compare changes in haemodynamics within one patient and the british hypertension society has recommended the finometer for measurements in the clinical set - up as well as for research purposes . the present study shows that significant haemodynamic changes occur directly after embolisation of pulmonary arteriovenous malformations , amongst which a decrease in stroke volume and cardiac output are most important . this may especially provide additional insights into the haemodynamic responses after pavm embolisation in hht patients prone to ph .\noutput:\n" }, { "from": "agent", "value": "backgroundtranscatheter embolisation is widely used to close pulmonary arteriovenous malformations ( pavms ) in patients with hereditary haemorrhagic telangiectasia ( hht ) . data on the direct cardiovascular haemodynamic changes induced by this treatment are scarce.objectiveswe investigated the direct haemodynamic effects of transcatheter embolisation of pavms , using non - invasive finger pressure measurements.methodsduring the procedure , blood pressure , heart rate ( hr ) , stroke volume ( sv ) , cardiac output ( co ) , total peripheral resistance ( tpr ) and delta pressure / delta time ( dp / dt ) were continuously monitored using a finometer . potential changes in these haemodynamic parameters were calculated from the pressure registrations using modelflow methodology . absolute and relative changes were calculated and compared using the paired sample t - test.resultsthe present study includes 29 hht patients ( mean age 39 15 years , 11 men ) who underwent transcatheter embolotherapy of pavms . the total number of embolisations was 72 ( mean per patient 2.5 ) . directly after pavm closure , sv and co decreased significantly by 11.9 % ( p = 0.01 ) and 9.5 % ( p = 0.01 ) respectively , without a significant change in hr ( 1.8 % ) . mean arterial blood pressure increased by 4.1 % ( p = 0.02 ) , while the tpr and dp / dt did not increase significantly ( 5.8 % and 0.2 % , respectively ) . conclusionssignificant haemodynamic changes occur directly after transcatheter embolisation of pavms , amongst which a decrease in stroke volume and cardiac output are most important ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: oct4 , nanog , and sox2 are three pluripotent transcription factors that are well known to contribute to the reprogramming of somatic cells into an esc - like state . the new article distinct lineage specification roles for nanog , oct4 , and sox2 in human embryonic stem cells , which was published in cell in april 2012 , changed our understanding of the mechanistic functions of oct4 , nanog , and sox2 in human escs ( hescs ) . in hescs , oct4 , nanog , and sox2 function as differentiation repressors , and the positive signals that initiate differentiation are mediated via alternative regulatory pathways . oct4 , nanog , and sox2 not only maintain the properties of self - renewal and pluripotency in escs but also prevent escs from dividing into the wrong cell type in advance . therefore , each of these transcription factors controls a specific cell fate instead of working as repressors of differentiation . oct4 controls both extraembryonic and epiblast - derived cell fates that are chosen in a bmp4 - dependent manner . moreover , key lif and bmp signaling pathways are integrated with the oct4 , nanog , and sox2 circuitries through smad1 and stat3 . csclcs express many proteins in common with early escs , especially oct4 , nanog , and sox2 . there is a wealth of evidence that the overexpression of these three genes occurs in human malignancies and are relevant to tumor transformation , tumorigenicity , tumor metastasis , and distant recurrence after chemoradiotherapy . oct4 , nanog , and sox2 together have been detected as co - up - regulated in many human cancers , including oral squamous cell carcinoma , prostate cancer , and breast cancer . oct4 alone , the most important pluripotent factor , has been shown to be up - regulated in additional cancers , including murine lewis lung carcinoma , human oral squamous cell carcinoma , bladder cancer , and seminoma cancer . nanog and sox2 have been observed to be up - regulated in cases of human somatic tumors . the expression levels of oct4 , nanog , and sox2 mrna transcripts , which are detected in tumor cells and csc niches , are usually higher than those of nontumor tissue or stem cell markers . they are also more frequently overexpressed in poorly differentiated tumors than in well differentiated tumors . in principle , the expression levels of the pluripotent transcription factors should decrease with the differentiation of the cell . however , the mechanistic functions of oct4 , nanog , and sox2 in csclcs are a little different from their functions in escs . although they both share the property of self - renewal , escs emphasize differentiation , whereas cscs emphasize proliferation . oct4 , nanog , and sox2 together maintain the repression of lineage - specific differentiation in hescs . however , in csclcs , the overexpression of oct4 , nanog , and sox2 modulates signaling pathways to inhibit apoptosis . there is evidence that heterogeneous oct4 , nanog , and sox2 are involved in signaling pathways related to cell fate determination , proliferation , and apoptosis in cancer cells . molecular mechanisms that regulate stem cell self - renewal in the early embryo may be re - activated during the dysregulated proliferation observed in tumorigenesis . oct4 is reported to maintain the survival of csclcs partly by inhibiting apoptosis through the oct4 / tcl1 / akt1 pathway . tcl1 is transcriptionally controlled by oct4 and enhances the kinase activity of akt1 , whose activation could promote cell proliferation . when oct4 is up - regulated , the oct4 / tcl1 / akt1 pathway is activated , which contributes to inhibiting tumor cell apoptosis . store - operated ca entry ( soce ) plays an important role in a variety of physiologic and pathophysiologic processes , including apoptosis . reduced soce is one of the factors that contribute to the anti - apoptotic milieu of prostate cancer . orail1 works as a gatekeeper to the plasma membrane , whereas stim1 senses the depletion of the endoplasmic reticulum ca store before interacting with orail1 to allow soce , . the up - regulation of sox2 reduces the expression of orail1 , thus reducing soce . nanog is a direct target of the lif - stat3 pathway , and it also maintains self - renewal of cscs through the igf1r signaling pathway . nanog overexpression enhances the expression of many csc - associated molecules , such as cd133 , abcg2 , aldh1a1 , and cd44 . the hedgehog ( hh ) and notch signaling pathways also take part in cell fate determination and regulate tumorigenicity . nanog overexpression was found to have a prominent effect on gynecologic tumorigenesis , whereas the dysregulation of oct4 and sox2 may vary in a context - dependent manner . different cancers involve different signaling pathways , but it seems that oct4 , nanog , and sox2 are nearly always up - regulated to activate or repress the previously discussed cancer - related pathways . the molecular weight of oct4 in bladder tumor cells is slightly higher than that in nt2 cells , possibly due to a differential posttranslational modification of oct4 . despite the dysregulation of oct4 , nanog , and sox2 in signaling pathways , the expression of their isoforms and pseudogenes may contribute to their different behaviors in escs and cscs . due to the high homology between oct4 , nanog , and sox2 , it may be possible that their isoforms , pseudogenes , or mutations function in the self - renewal process of cscs . the human oct4 gene can generate at least 3 transcripts ( oct4a , oct4b , and oct4b1 ) and 4 protein isoforms ( oct4a , oct4b - 190 , oct4b - 265 , and oct4b - 164 ) through alternative splicing and alternative translation initiation , . oct4a is highly expressed in hescs and regulates the self - renewal of pluripotent cells . oct4b is expressed at low levels in both pluripotent and nonpluripotent cells and lacks the stemness - promoting characteristics of oct4a . furthermore , oct4a is more abundant in hescs than in oct4b . additionally , oct4a is nuclear , whereas oct4b is cytoplasmic . in a recent study , oct4bwas shown to be expressed in 42 somatic tumor cell lines , whereas oct4a was not expressed in the tumor cell lines examined . in summary , oct4a possesses the unique function of maintaining self - renewal in escs . although oct4b is not sufficient to maintain stem cell self - renewal or an undifferentiated state , it would be of interest to determine whether oct4b can cooperate with oct4a to transform nontumorigenic cells . ( mrnas ) oct4a and oct4b encode proteins that share a pou dna - binding domain and c - terminal domain but differ in sequence at the n termini . thus , oct4a functions as a transcriptional activator , whereas oct4b does not function in this manner . among the 11 nanog pseudogenes , nanogp1 is transcribed in different leukemic cells , and it is hypothesized that the transcriptional activation of nanogp1 represents ananogp8 , a retrogene localized in the nuclei of transfected cells , is transcribed in 5 tumor cell lines , 2 teratocarcinoma cell lines , and 3 tumor tissues . nanog was also identified in selected tumor cell lines , and studies have shown that nanog can play a crucial role in maintaining the self - renewal of cscs through the igf1r signaling pathway . however , previous studies have shown compelling evidence that ( mrna ) nanog in cancer cells is derived predominantly from nanogp8 . nanogp8 is the dominant gene in cscs , whereas nanog is specifically expressed in escs , germ lineage cells , and neonatal human fibroblasts . one potential molecular mechanism is that both nanog and nanogp8 function as transcription factors in a cell type - specific manner . sox2 has no known isoforms to date , but sox2 gene mutations are associated with several human diseases , such as anopthalmia , optic nerve hypoplasia , and other ocular disorders . despite the critical role of oct4 , nanog , and sox2 ( including their isoforms ) in cscs , detailed knowledge of their expression patterns , functions , and precise regulatory mechanisms in csclcs and tumor growth are lacking . multiple assays , including marker analysis , loss - of - function assays , gain - of - function assays , and analyses of genetic and epigenetic signatures , together with simple approaches and methods used to detect and distinguish oct4 , nanog , and sox2 isoforms , must be refined and performed in the future to address these issues . they can serve as valuable markers of tumorigenesis and act as molecular switches that control the csc cell fate during cancer development . oct4 is a useful marker of germ cell metastasis in extragonadal tissues , and can also be regarded as a new potential molecular marker in bladder tumors . moreover , extensive loss - of - function analysis reveals that the rna interference - mediated nanog knockdown inhibits tumor development . sox2 can potentially be used as a pathologic marker to distinguish tumor from non - tumor in prostate tissues and to predict the prognosis of prostate cancer . sox2 overexpression induces a proximal phenotype in the distal airways / alveoli and promotes lung cancer . studies have shown that the expression of both oct4 and nanog can be important prognostic markers for oral cancer . the expression of nanog alone is a good survival prognosis marker in oral squamous cell carcinoma patients . importantly , there is significant associations between oct4 expression , nanog expression , cancer stage and patient survival . oct4 and sox2 are related to rectal cancer and are associated with distant recurrence after chemoradiotherapy . there is solid evidence that oct4 , nanog , and sox2 can contribute to cancer treatment . further work should focus on functional analysis to define the roles of these transcription factors in determining the csc phenotypes , revealing the precise regulatory mechanisms and identifying new components of the transcriptional regulatory networks that may be relevant to tumor transformation , tumorigenesis , and metastasis . tumors may be controlled by restricting the expression of oct4 , nanog , and sox2 or by disrupting the molecular pathways that are altered in cscs . eliminating cancer cells with the potential for self - renewal and tumor propagation should be the target of cancer drug development . it is also important to discriminate cscs from normal stem cells in cancer treatment , which will require the identification of drug targets unique to cscs . moreover , cscs are particularly resistant to conventional chemotherapy and radiotherapy compared with non - cscs . the genome - wide mapping of oct4 , nanog , and sox2 has revealed that these proteins co - target multiple downstream genes associated with many chromatin - associated activities and complexes , and these proteins form a regulatory network to control cell phenotypes . oct4 , nanog , and sox2 may fulfill the criteria for csc - specific agents because their expression levels are low or absent in normal stem cells ; they are also the genes responsible for maintaining the signature features of cscs , therefore , drugs targeting their activity are sure to have good efficacy . however , our understanding of the molecular structure and mechanism of these pluripotent transcription factors is still in its infancy . future studies of oct4 , nanog , and sox2 are needed to reveal the underlying mechanisms of tumorigenesis and to design individualized therapies for cancer patients .\noutput:\n" }, { "from": "agent", "value": "cancer stem cells ( cscs ) are thought to drive uncontrolled tumor growth , and the existence of cscs has recently been proven by direct experimental evidence , including tracing cell lineages within a growing tumor . however , cscs must be analyzed in additional cancer types . cancer stem cell - like cells ( csclcs ) are a good alternative system for the study of cscs , which hold great promise for clinical applications . oct4 , nanog , and sox2 are three basic transcription factors that are expressed in both csclcs and embryonic stem cells ( escs ) . these transcription factors play critical roles in maintaining the pluripotence and self - renewal characteristics of csclcs and escs . in this review , we discuss the aberrant expression , isoforms , and pseudogenes of oct4 , nanog , and sox2 in the csclc niche , which contribute to the major differences between csclcs and escs . we also highlight an anticancer therapy that involves killing specific cancer cells directly by repressing the expression of oct4 , nanog , or sox2 . importantly , oct4 , nanog , and sox2 provide great promise for clinical applications because reducing their expression or blocking the pathways in which they function may inhibit tumor growth and turn - off the cancer switch . in the future , a clear understanding of transcription factor regulation will be essential for elucidating the roles of oct4 , nanog , and sox2 in tumorigenesis , as well as exploring their use for diagnostic and therapeutic purposes ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: every anesthesiologist worth their salt is guilty of administering a wrong drug at least once in their career . most of the time the consequences have been harmless ( albeit not without feeling of guilt or remorse ) , but in some cases they have caused an undesired iatrogenic morbidity and / or mortality . the high duress milieu of an operation theatre ( ot ) , intensive care unit ( icu ) or emergency room ( er ) predisposes flawed actions . pediatric population in ot , icu , or er is at considerable hazard for medication blunders . once injected into the blood stream , oxford english dictionary defines error as something incorrectly done through ignorance or inadvertence ; a mistake , e.g. , in calculation , judgment , speech , writing , action , etc . kohn described it as a failure to complete a planned action as intended , or the use of an incorrect plan of action to achieve a given aim . a medication error can be defined as a failure in the treatment process that leads to , or has the potential to lead to , harm to the patient . failure here implies that the method used was beneath the usual realistic standards being practiced . whileincludes management of symptoms or their causes or investigation or prevention of disease or physiological changes . the aviation industry has adopted a definitive safety culture , whereas anesthesia professionals exhibit an attitudinal barrier to safety . both accidents and incidents in the aviation industryare reviewed and the risks are assessed , providing an opportunity for safety improvement and risk mitigation . accidents during periods of anesthesia are often not reported due to the fear of being blamed for carelessness , forgetfulness and sometimes character weakness . the institute for safe medication practices uses an index for categorizing medication errors written by the national coordinating council for medication error reporting and prevention . stelfox et al . have reported that medication errors are the seventh most common cause of death in the health care system . a canadian survey from 687 anesthesiologists ( 30 % response rate ) revealed that 85 % of the participants had experienced at least one drug error or near miss . although most errors ( 1,038 ) were of minor consequence ( 98 % ) , four deaths were reported . the most common incident involved the administration of muscle relaxants instead of a reversal agent . syringe swaps ( 70.4 % ) and the misidentification of the label ( 46.8 % ) were common contributing factors . most of the time , although the label color was an important secondary cue . about 84 % agreed that improved standards for drug labels would reduce the incidence of error . in norway , drug error was recorded in 63 cases ( 0.11 % ) in anesthesia - related information from all anesthetic cases for 36 months totaling 55,426 procedures . there were 28 syringe swaps , nine ampoule swaps , 15 instances where muscle relaxants were erroneously given , eightwrong drug cases and 18 instances where a wrong dose of the correct drug was administered . another study done in australia identified 144 incidents in which the wrong drug was nearly or actually administered to a patient . of these errors , the most common was actually giving the wrong drug from a correctly labeled syringe . interestingly , they found that communication failure was a significant factor in syringe incidents when two or more staff was involved . in a critical care related study by rothschild et al . , 120 adverse events were identified in 79 patients , including 66 ( 55 % ) non - preventable and 54 ( 45 % ) preventable adverse events . most serious medical errors occurred during the ordering or execution of treatments , especially in administering medications ( 61 % ) . of 5744 observations in 851 patients , calabrese et al . found 187 ( 3.3 % ) medication administration errors . therapeutic classes most commonly associated with those errors were vasoactive drugs 61 ( 32.6 % ) and sedative / analgesics 48 ( 25.7 % ) . we believe the key instigator of erroneous drug administration ( eda ) is the adaptation of the universal leur locking mechanism to intravenous drug delivery systems . all syringe ports on the fluid delivery system are able to interlock with any syringe nozzle by nature of the leur design . this inherently provides the opportunity for an adverse event to occur especially in a situation of high duress . the development of a fluid intake manifold used for multiple intravenous drug delivery featuring specially designed syringe ports , which can only interlock with a predispositioned syringe . an acronym which stands for vassopressors , emergency drugs , induction agents , reversal agents , opioids , and miscellaneous drugs . these seven categories encompass most of the intravenous drugs that are used frequently in anesthesia . the envisioned fluid delivery system , which we named veinrom , shall harbor one syringe port for each of the seven drug class categories that are most commonly used drugs in anesthesiology and critical care . veinrom is a unique drug delivery manifold and syringe assembly which has incorporated mechanical and electronic mechanisms that will make it very difficult to administer wrong drugs intravenously . these defense mechanisms are : veinrom manifold : the fluid intake manifold shall have seven differently designed syringe ports which feature a lock - and - key interaction between the port and designated syringe . through the improvised veinrom lock - and - key mechanism , it is impossible to incorrectly administer one category of drug into any one of the other six ports . incompatible syringes will not be able to enter the manifold ports , and thus the drug administrator will not be able to inject the drug [ figures 1 and 2 ] . figure 1ariel and lateral view of the dome shaped vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .210 a , b , and c are the port for miscellaneous drugs ( this will retain their universal port characteristics ) figure 2ariel and side view of the liner vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .111 - 112 is for connection to the intravenous lines veinrom syringes : preloaded syringes will further decrease the potential for human error when administering drugs instead of loading - labeling them perioperatively . the veinrom syringes shall have following features specific male ports : each syringe shall have uniquely designed tips that can only mate with their destined manifold ports [ figure 3 ] . figure 3vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies . . 504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors engraved labels : acting as a visual reinforcement to the user , each syringe shall display what category it belongs to by being boldly engraved on to the syringe body , obviating the need for colored sticker labeling [ figure 3 ] . color coded : syringe pistons and bodies for each drug class shall be color coded per american society for testing and materials standards . this feature promotes visual memory and obliterates the need to manually label the syringes.texture coded : each syringe class shall have a specific external texture embedded within the syringe body , producing tactile stimuli which generates neurogenic memory rendering identification of syringes easier [ figure 3 ] . scan able bar codes : each syringe shall have a barcode at its distal end that identifies drug class and lot number . before delivery , the drug administrator swipes the syringe in front of a barcode scanner which in turn enters the drug information and delivery time into patient specific electronic medical records [ figure 3 ] . inherent electronic data collection : veinrom shall incorporate a medical electrical system designed to identify and register the connection of a syringe to any port , thereby logging the port i d and time of delivery into the patient 's medical records . not only does this improve patient data logging practices , it implements practitioner accountability . veinrom manifold : the fluid intake manifold shall have seven differently designed syringe ports which feature a lock - and - key interaction between the port and designated syringe . through the improvised veinrom lock - and - key mechanism , it is impossible to incorrectly administer one category of drug into any one of the other six ports . incompatible syringes will not be able to enter the manifold ports , and thus the drug administrator will not be able to inject the drug [ figures 1 and 2 ] . figure 1ariel and lateral view of the dome shaped vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .210 a , b , and c are the port for miscellaneous drugs ( this will retain their universal port characteristics ) figure 2ariel and side view of the liner vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .111 - 112 is for connection to the intravenous lines ariel and lateral view of the dome shaped vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .210 a , b , and c are the port for miscellaneous drugs ( this will retain their universal port characteristics ) ariel and side view of the liner vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .111 - 112 is for connection to the intravenous lines veinrom syringes : preloaded syringes will further decrease the potential for human error when administering drugs instead of loading - labeling them perioperatively . the veinrom syringes shall have following features specific male ports : each syringe shall have uniquely designed tips that can only mate with their destined manifold ports [ figure 3 ] . figure 3vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors engraved labels : acting as a visual reinforcement to the user , each syringe shall display what category it belongs to by being boldly engraved on to the syringe body , obviating the need for colored sticker labeling [ figure 3 ] . color coded : syringe pistons and bodies for each drug class shall be color coded per american society for testing and materials standards . this feature promotes visual memory and obliterates the need to manually label the syringes.texture coded : each syringe class shall have a specific external texture embedded within the syringe body , producing tactile stimuli which generates neurogenic memory rendering identification of syringes easier [ figure 3 ] . scan able bar codes : each syringe shall have a barcode at its distal end that identifies drug class and lot number . before delivery , the drug administrator swipes the syringe in front of a barcode scanner which in turn enters the drug information and delivery time into patient specific electronic medical records [ figure 3 ] . inherent electronic data collection : veinrom shall incorporate a medical electrical system designed to identify and register the connection of a syringe to any port , thereby logging the port i d and time of delivery into the patient 's medical records . not only does this improve patient data logging practices , it implements practitioner accountability . specific male ports : each syringe shall have uniquely designed tips that can only mate with their destined manifold ports [ figure 3 ] . figure 3vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .503 , 603 are distinctive locking mechanisms for specified ports on the manifold . 504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .503 , 603 are distinctive locking mechanisms for specified ports on the manifold . 504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors engraved labels : acting as a visual reinforcement to the user , each syringe shall display what category it belongs to by being boldly engraved on to the syringe body , obviating the need for colored sticker labeling [ figure 3 ] . color coded : syringe pistons and bodies for each drug class shall be color coded per american society for testing and materials standards . texture coded : each syringe class shall have a specific external texture embedded within the syringe body , producing tactile stimuli which generates neurogenic memory rendering identification of syringes easier [ figure 3 ] . scan able bar codes : each syringe shall have a barcode at its distal end that identifies drug class and lot number . before delivery , the drug administrator swipes the syringe in front of a barcode scanner which in turn enters the drug information and delivery time into patient specific electronic medical records [ figure 3 ] . inherent electronic data collection : veinrom shall incorporate a medical electrical system designed to identify and register the connection of a syringe to any port , thereby logging the port i d and time of delivery into the patient 's medical records . we believe the key instigator of erroneous drug administration ( eda ) is the adaptation of the universal leur locking mechanism to intravenous drug delivery systems . all syringe ports on the fluid delivery system are able to interlock with any syringe nozzle by nature of the leur design . this inherently provides the opportunity for an adverse event to occur especially in a situation of high duress . the development of a fluid intake manifold used for multiple intravenous drug delivery featuring specially designed syringe ports , which can only interlock with a predispositioned syringe . an acronym which stands for vassopressors , emergency drugs , induction agents , reversal agents , opioids , and miscellaneous drugs . these seven categories encompass most of the intravenous drugs that are used frequently in anesthesia . the envisioned fluid delivery system , which we named veinrom , shall harbor one syringe port for each of the seven drug class categories that are most commonly used drugs in anesthesiology and critical care . veinrom is a unique drug delivery manifold and syringe assembly which has incorporated mechanical and electronic mechanisms that will make it very difficult to administer wrong drugs intravenously . these defense mechanisms are : veinrom manifold : the fluid intake manifold shall have seven differently designed syringe ports which feature a lock - and - key interaction between the port and designated syringe . through the improvised veinrom lock - and - key mechanism , it is impossible to incorrectly administer one category of drug into any one of the other six ports . incompatible syringes will not be able to enter the manifold ports , and thus the drug administrator will not be able to inject the drug [ figures 1 and 2 ] . figure 1ariel and lateral view of the dome shaped vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .210 a , b , and c are the port for miscellaneous drugs ( this will retain their universal port characteristics ) figure 2ariel and side view of the liner vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .111 - 112 is for connection to the intravenous lines veinrom syringes : preloaded syringes will further decrease the potential for human error when administering drugs instead of loading - labeling them perioperatively . the veinrom syringes shall have following features specific male ports : each syringe shall have uniquely designed tips that can only mate with their destined manifold ports [ figure 3 ] . figure 3vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .503 , 603 are distinctive locking mechanisms for specified ports on the manifold . 504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors engraved labels : acting as a visual reinforcement to the user , each syringe shall display what category it belongs to by being boldly engraved on to the syringe body , obviating the need for colored sticker labeling [ figure 3 ] . color coded : syringe pistons and bodies for each drug class shall be color coded per american society for testing and materials standards . this feature promotes visual memory and obliterates the need to manually label the syringes.texture coded : each syringe class shall have a specific external texture embedded within the syringe body , producing tactile stimuli which generates neurogenic memory rendering identification of syringes easier [ figure 3 ] . scan able bar codes : each syringe shall have a barcode at its distal end that identifies drug class and lot number . before delivery , the drug administrator swipes the syringe in front of a barcode scanner which in turn enters the drug information and delivery time into patient specific electronic medical records [ figure 3 ] . inherent electronic data collection : veinrom shall incorporate a medical electrical system designed to identify and register the connection of a syringe to any port , thereby logging the port i d and time of delivery into the patient 's medical records . not only does this improve patient data logging practices , it implements practitioner accountability . veinrom manifold : the fluid intake manifold shall have seven differently designed syringe ports which feature a lock - and - key interaction between the port and designated syringe . through the improvised veinrom lock - and - key mechanism , it is impossible to incorrectly administer one category of drug into any one of the other six ports . incompatible syringes will not be able to enter the manifold ports , and thus the drug administrator will not be able to inject the drug [ figures 1 and 2 ] . figure 1ariel and lateral view of the dome shaped vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .210 a , b , and c are the port for miscellaneous drugs ( this will retain their universal port characteristics ) figure 2ariel and side view of the liner vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .111 - 112 is for connection to the intravenous lines ariel and lateral view of the dome shaped vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .210 a , b , and c are the port for miscellaneous drugs ( this will retain their universal port characteristics ) ariel and side view of the liner vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous manifold .111 - 112 is for connection to the intravenous lines veinrom syringes : preloaded syringes will further decrease the potential for human error when administering drugs instead of loading - labeling them perioperatively . the veinrom syringes shall have following features specific male ports : each syringe shall have uniquely designed tips that can only mate with their destined manifold ports [ figure 3 ] . figure 3vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .503 , 603 are distinctive locking mechanisms for specified ports on the manifold . 504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors engraved labels : acting as a visual reinforcement to the user , each syringe shall display what category it belongs to by being boldly engraved on to the syringe body , obviating the need for colored sticker labeling [ figure 3 ] . color coded : syringe pistons and bodies for each drug class shall be color coded per american society for testing and materials standards . this feature promotes visual memory and obliterates the need to manually label the syringes.texture coded : each syringe class shall have a specific external texture embedded within the syringe body , producing tactile stimuli which generates neurogenic memory rendering identification of syringes easier [ figure 3 ] . scan able bar codes : each syringe shall have a barcode at its distal end that identifies drug class and lot number . before delivery , the drug administrator swipes the syringe in front of a barcode scanner which in turn enters the drug information and delivery time into patient specific electronic medical records [ figure 3 ] . inherent electronic data collection : veinrom shall incorporate a medical electrical system designed to identify and register the connection of a syringe to any port , thereby logging the port i d and time of delivery into the patient 's medical records . not only does this improve patient data logging practices , it implements practitioner accountability . specific male ports : each syringe shall have uniquely designed tips that can only mate with their destined manifold ports [ figure 3 ] . figure 3vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous syringes prototypes with its unique physiognomies .504 , 604 are the special texture , 506 and 606 are scan - able bar codes . each syringe will have american society for testing and materials specified colors engraved labels : acting as a visual reinforcement to the user , each syringe shall display what category it belongs to by being boldly engraved on to the syringe body , obviating the need for colored sticker labeling [ figure 3 ] . color coded : syringe pistons and bodies for each drug class shall be color coded per american society for testing and materials standards . texture coded : each syringe class shall have a specific external texture embedded within the syringe body , producing tactile stimuli which generates neurogenic memory rendering identification of syringes easier [ figure 3 ] . scan able bar codes : each syringe shall have a barcode at its distal end that identifies drug class and lot number . before delivery , the drug administrator swipes the syringe in front of a barcode scanner which in turn enters the drug information and delivery time into patient specific electronic medical records [ figure 3 ] . inherent electronic data collection : veinrom shall incorporate a medical electrical system designed to identify and register the connection of a syringe to any port , thereby logging the port i d and time of delivery into the patient 's medical records . as indicated previously , medical errors are prevalent within this field and current safety protocol has not been changed in over 60 years . not only will the implementation of a device like veinrom increase practitioner 's accountability , update patient records in real time and improve the overall health care system , it will most importantly save lives . it is an obligation for standards committee members and medical device manufacturers to implement safeguards that prevent human error . the institute of medicine estimates that at least 1.5 million americans are injured each year as a result of eda , costing the us healthcare field more than 3.5 billion usd annually . the global health care system is in the process of implementing improved standards and regulations that require syringes to be pre - filled by outside pharmacies rather than medical practitioners during the pre - operation period . to support this claim , transparency market research estimates that the global pre - filled syringe market will grow by a 13.3 % compound annual rate , reaching a market value of 4.98 billion usd by the year 2019 . these trends point to an estimated 3 billion usd in profit opportunity within the next 7 years . it is our moral and hippocratic duty to continue risk management processes that decrease the probability of iatrogenic morbidities . for a device such as veinrom , veinrom is the next step in making the art of anesthesia safer for all involved .\noutput:\n" }, { "from": "agent", "value": "erroneous intravenous drug administration has a high probability of causing substantial financial consequences along with patient morbidity or mortality . anesthesiologists and hospital administrators need to be cognizant of the problem . national and international anesthesiology bodies should be involved with the medical device manufacturing industry to alleviate this long standing enigma . we propose our concept vassopressors , emergency drugs , induction agents , reversal agents , opioids and miscellaneous ( veinrom ) as a conceivable solution to this paradox ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: this study was designed to assess the single role of ecg morphologic changes in patients after traumatic hemorrhagic events in the brain . lack of a control group ( patients with traumatic hemorrhagic brain events and no ecg changes ) made the analyses of the data for risk factors inappropriate , and the sensitivity and specificity of the tests inapplicable . the patients were not evenly distributed by gender and age , which led to analyzing a limited elderly group of patients . followed - up was not conducted for the secondary confirmation of existence of cardiologic pathology , in ami patients , and this could be the result of a transient stress cardiac pathology rather than true cardiac pathology , leading to an overestimation of ami cases . the authors of the present manuscript , amir masoudhashemian , kooroshahmadi , ali taherinia , mohamaddavoodsharifi , seyedbehzadjazayeri , soheilsaadat and vafarahimi - movaghar declare that they have no conflict of interest to state . the study protocol was designed in accordance with helsinki declaration of 1975 and update of 2000 , and was approved by the ethics committee of mashhad university of medical sciences .\noutput:\n" }, { "from": "agent", "value": "background : simultaneous electrocardiographic ( ecg ) changes are seen in hemorrhagic brain events even in the absence of associated myocardial infarction ( mi ) . this study was designed to assess the role of ecg changes to predict true mi in patients with hemorrhagic brain trauma . methods : data of 153 patients with traumatic brain injury and concomitant ecg changes were recorded . enzyme study was performed for the patients , and a cardiologist confirmed the diagnosis of mi . results : overall , 83 females and 70 males older than 50 years of age were enrolled in the study . the most common type of hemorrhagic brain event was subarachnoid hemorrhage , and the most common ecg change was an inverted t wave . mi was confirmed in 15 ( 9.8 % ) patients . patients with intracranial hemorrhage had significantly ( p = 0.023 ) higher rates of associated mi than other types of brain hemorrhages . st segment elevation was found to have a positive predictive value of 71.4 % in males and 25 % in females in terms of diagnosing a true mi associated with hemorrhagic brain events . conclusion : although simultaneous cardiac changes are seen after sympathetic over - activity in brain hemorrhages , regular ecg screening of elder patients with traumatic brain injury is suggested , particularly in patients with intracranial hemorrhages ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: it is a well known fact that a fearful person is a more problematic patient . despite of recent advances in dental technologies and treatment , fearful and anxious patients report experiences of pain , fear of specific procedures such as drilling , root canal treatment , extractions or injections . patient s anxiety has a negative effect on the performances of the dental practitioner and dental care may be hampered , giving rise to a constant source of occupational stress . treating anxious patients might take more time and they are often unsatisfied with their treatment . fearful and anxious patients often avoid or delay dental care and are three times more predisposed to postpone or cancel their appointments requiring 20 % more dental chair time . since many people delay or avoid dental care because of fear and expectation of pain , managing dental anxieties is recognized as an important issue in dental practice . the treatment of a patient s pain is one of the most challenging aspects of dental care that dentists face today . previous experiences , expectations , current emotional states are involved in the experience of pain . in the last years , the definition of pain has included the understanding that pain is influenced by our cognitions , our affective and somatic states . most dentists focus upon decreasing the somatic aspect of the perception of the pain and do not take in consideration the affective and cognitive elements . dental anxiety can be found worldwide and affects a significant number of people from all social backgrounds . it is a serious concern for both dentist and patient for provision of dental care . people feel comfortable with the familiar and feel discomfort or anxiety with a novel experience . the second factor is uncertainty which contributes to the increased general arousal of the patient . in generalthe information conveyed by parents or friends can lead to a heightened aroused and anxious state . this often takes the form of negative cognitions which encourage the growing of fear and anxiety . fear and anxiety increase when a patient feels loss or is out of control , so it is recommended to allow the patient to signal a temporary interruption of the dental procedure whendue to the occurrence of fear , pain and anxiety from many causes , in the dental offices , it is obvious that behavioral management is needed . they can be also controlled through pharmacology , psychology , cognitive behavioral psychotherapy or hypnosis . the dentist should be assertive in dealing with psychological aspects of the fearful and anxious patient . prior to dental treatment , identifying anxious patients can enable dentists to anticipate one s behavior and by using specific management techniques will help alleviate a patient s anxiety . the study conducted by saatchi et all revealed that only 20 % of dental practitioners regularly use a screening method in order to assess their patient s level of fear . the dentist can measure the levels of fear and anxiety through self report or by administrating a test . several scales have been developed of which two were used in the current study : the dental fear survey ( dfs ) and the modified dental anxiety scale ( mdas ) . for patients manifesting moderate amounts of anxiety , attention to basic aspects of good clinical care is sufficient . for patients exhibiting high levels of anxiety , a special treatment program conducted by a dental assistant is recommended . the effect of dental fear and anxiety on oral health has been reported by many studies . dental fear is associated with a lower frequency of dental visits , resulting in a worsening oral health status . in absence of proper dental treatments , oral diseasesa fearful or anxious patient has a poorer oral health status : decays , missing or less filled teeth which can produce negative effects on their social life . oral health has a significant impact on the quality of life and self esteem of a person . saatchi et al . indicated that an important factor in dental anxiety genesis is a previous traumatic experience . some researchers described a vicious cycle of dental fear where subjects with dental anxiety avoid dental care , contributing to a deterioration of their dental condition , awareness of their worsening condition leading to increased anxiety . dental anxiety has been identified as a barrier in receiving dental health care among people with hearing sensory impairment . a multidisciplinary approach using special behavior guidance strategies can be useful in preventing dental fear and promoting oral health in this particular group . in addition , they experience communication barriers so they are more often victims of emotional or physical abuse than hearing people . doctor - patient relationship is often viewed as the cornerstone of healthcare delivery . due to complex individual , interpersonal and systemic factors , people with disabilities encounter practical and social problems , poor social relationships beyond those experienced by non - disabled subjects . it is commonly accepted that individuals with physical disabilities may encounter difficulties in everyday life that reduce their activity levels . an individual s activity limitations are predictive of the level of psychological problems he may experience . the study performed by kvam in the united states related that the risk for clinically significant emotional distress was 2 to 4 times higher among persons with disabilities than among non - disabled . deaf people are known to be vulnerable to alienation and other negative outcomes including delays in cognitive processing , social maladaptation and psychological distress or disorder . the aim of our study was to assess factors associated with dental fear and anxiety among a sample of deaf patients . we evaluated prevalence of dental fear and anxiety and its relation to gender , educational level , previous dental experiences and frequency of visits was also researched and evaluated . a cross - sectional quantitative study was conducted among deaf patients , who were seeking dental checkups or dental treatment at the department of conservative odontology of the iuliu hatieganu university of medicine and pharmacy or at ortoelitte dental center in the city of cluj - napoca , romania . the inclusion criteria were : hearing impaired individuals , subject s reading and understanding abilities and agreement to participate in the study . eleven subjects from the study were excluded for not completing the survey form or for refusal to sign informed consent . the final sample consisted of 154 individuals . the response rate was 93.33 % , with a gender distribution of 66 male ( 42.86 % ) and 88 female respondents ( 57.14 % ) . most of them ( 92.20 % ) were born deaf or lost their hearing before the age of 4 , 3.24 % were aged 48 years , 2.59 % aged 918 , and 1.94 % was 19 years of age or above when they became deaf . etiology , specific levels of hearing or the use of hearing aids were not reported . most of them ( 95.45 % ) attended a school for deaf using sign language as a mean of communication ; the rest had attended local schools . the purpose of the study was explained to each patient and an informed consent was handed out to those who agreed to participate . additionally , all participants signed a statement attesting that the information provided will be maintained confidential . the first section contained questions concerning to obtain sociodemographic information such as name , age , gender , educational level , details of previous dental visits , duration since last visit ( choices were given within last 6 months , within the last 6 months to 1 year , 12 years ago , more than 2 years back ) , self perceived oral health status ( options were excellent , good , fair , bad ) , postponement of dental treatment due to dental anxiety , reasons for irregular attendance ( high cost , lack of time , not needing treatment , fear , communication difficulties ) and existence of post traumatic experiences . the second section was a romanian version of mdas , used to assess the level of anxiety . this scale included 5 multiple choice questions concerning patient s anxiety in the following situations : anticipating a visit to a dental office , waiting in the office , waiting in the dental chair for tooth drilling , scaling or for receiving an anesthetic injection . each question was scored from 1 ( not anxious at all ) to 5 ( extremely anxious ) . patients with scores ranging from 5 to 9 were not considered anxious , 10 to 18 moderately anxious while patient scores exceeding 19 were considered extremely anxious . it was pre - validated by a committee formed by a pediatric specialist , a dentist and a psychologist . this scale included 20 questions in three components : avoidance of dental care , physiologic reactions and fear provoked by different procedures . scoring 1 to 2 for a question expressed that the subject is nt fearful in a particular dental situation . there was no time limit for completing the survey in order to ensure that any difficulty with language was accommodated . the collected data was electronically introduced in a microsoft excel 2012 spreadsheet and then transferred to a statistical package for social sciences ( spss ) program , version 20.0 ( spss inc . , the significance of the observed associations and / or differences between variables was tested using student t test , anova and chi square statistic . a cross - sectional quantitative study was conducted among deaf patients , who were seeking dental checkups or dental treatment at the department of conservative odontology of the iuliu hatieganu university of medicine and pharmacy or at ortoelitte dental center in the city of cluj - napoca , romania . the inclusion criteria were : hearing impaired individuals , subject s reading and understanding abilities and agreement to participate in the study . eleven subjects from the study were excluded for not completing the survey form or for refusal to sign informed consent . the final sample consisted of 154 individuals . the response rate was 93.33 % , with a gender distribution of 66 male ( 42.86 % ) and 88 female respondents ( 57.14 % ) . most of them ( 92.20 % ) were born deaf or lost their hearing before the age of 4 , 3.24 % were aged 48 years , 2.59 % aged 918 , and 1.94 % was 19 years of age or above when they became deaf . etiology , specific levels of hearing or the use of hearing aids were not reported . most of them ( 95.45 % ) attended a school for deaf using sign language as a mean of communication ; the rest had attended local schools . the purpose of the study was explained to each patient and an informed consent was handed out to those who agreed to participate . additionally , all participants signed a statement attesting that the information provided will be maintained confidential . the first section contained questions concerning to obtain sociodemographic information such as name , age , gender , educational level , details of previous dental visits , duration since last visit ( choices were given within last 6 months , within the last 6 months to 1 year , 12 years ago , more than 2 years back ) , self perceived oral health status ( options were excellent , good , fair , bad ) , postponement of dental treatment due to dental anxiety , reasons for irregular attendance ( high cost , lack of time , not needing treatment , fear , communication difficulties ) and existence of post traumatic experiences . the second section was a romanian version of mdas , used to assess the level of anxiety . this scale included 5 multiple choice questions concerning patient s anxiety in the following situations : anticipating a visit to a dental office , waiting in the office , waiting in the dental chair for tooth drilling , scaling or for receiving an anesthetic injection . each question was scored from 1 ( not anxious at all ) to 5 ( extremely anxious ) . patients with scores ranging from 5 to 9 were not considered anxious , 10 to 18 moderately anxious while patient scores exceeding 19 were considered extremely anxious . it was pre - validated by a committee formed by a pediatric specialist , a dentist and a psychologist . this scale included 20 questions in three components : avoidance of dental care , physiologic reactions and fear provoked by different procedures . scoring 1 to 2 for a question expressed that the subject is nt fearful in a particular dental situation . there was no time limit for completing the survey in order to ensure that any difficulty with language was accommodated . the first section contained questions concerning to obtain sociodemographic information such as name , age , gender , educational level , details of previous dental visits , duration since last visit ( choices were given within last 6 months , within the last 6 months to 1 year , 12 years ago , more than 2 years back ) , self perceived oral health status ( options were excellent , good , fair , bad ) , postponement of dental treatment due to dental anxiety , reasons for irregular attendance ( high cost , lack of time , not needing treatment , fear , communication difficulties ) and existence of post traumatic experiences . the second section was a romanian version of mdas , used to assess the level of anxiety . this scale included 5 multiple choice questions concerning patient s anxiety in the following situations : anticipating a visit to a dental office , waiting in the office , waiting in the dental chair for tooth drilling , scaling or for receiving an anesthetic injection . each question was scored from 1 ( not anxious at all ) to 5 ( extremely anxious ) . patients with scores ranging from 5 to 9 were not considered anxious , 10 to 18 moderately anxious while patient scores exceeding 19 were considered extremely anxious . it was pre - validated by a committee formed by a pediatric specialist , a dentist and a psychologist . this scale included 20 questions in three components : avoidance of dental care , physiologic reactions and fear provoked by different procedures . scoring 1 to 2 for a question expressed that the subject is nt fearful in a particular dental situation . there was no time limit for completing the survey in order to ensure that any difficulty with language was accommodated . the collected data was electronically introduced in a microsoft excel 2012 spreadsheet and then transferred to a statistical package for social sciences ( spss ) program , version 20.0 ( spss inc . , the significance of the observed associations and / or differences between variables was tested using student t test , anova and chi square statistic . the majority of the respondents belonged to the 30 years of age group ( 81.16 % ) . prevalence of dental anxiety was at a value of 68.83 % as is shown in figure 1 . women demonstrated significantly higher mdas ( p 0.012 ) and dfs scores ( p 0.013 ) than men . mean total score for dental anxiety on mdas was 13.7 , 34.9 % of respondents were found to be less anxious ( 59 total score ) , 59.7 % moderately or extremely anxious ( 1018 total score ) , 5.3 % were found to suffer from dental phobia ( 19 total score ) as illustrated in figure 2 . evaluation of economic status revealed that participants with no income or who are financially dependent on another family member were more anxious than financially independent participants ( p 0.05 ) . the major reason given by 53.89 % of the subjects for not attending a dentist was cost , 22.07 % thought that treatment is not needed , 18.18 % of subjects delayed or avoided treatment because of fear while 6.49 % for lack of time as is shown in figure 3 . oral health was perceived as fair or bad by the majority of participants as presented in figure 4 and there was an inverse relationship between anxiety and frequency of dental treatment ( r = 0.119 p = 0.009 ) . it was seen that 42.86 % of the respondents were not anxious regarding their dental visit with 46.10 % reporting no anxiety while sitting in the waiting room of the dental office . most of the subjects ( 83.11 % ) felt anxious if tooth drilling or injection with local anesthetic were to occur , injection being the most feared dental procedure of all . dfs scores were ranged from 1867 , with a mean value of 286.29 with a statistically significant difference observed between males and females ( p 0.001 ) . independent t - test demonstrated that dfs scores ( 48.415.14 ) and mdas scores ( 17.34.2 ) in patients with previous traumatic experiences were significantly higher ( p 0.001 ) than in patients without a prior negative dental experience ( 36.617.8 ) . this study is one of few attempts to characterize dental fear and anxiety among deaf patients using a standardized scale . our findings suggest that there should be increased efforts to screen people with disabilities for dental anxiety . the delivery of health care services to individuals with hearing loss is poorly understood by the average physician . in addition limited research has been done on this subject to date . dental fear can act as a hindrance to dental care delivery and this psychological problem can turn into a health concern . managing dental fear and anxiety is recognized as an important issue in dental offices since many people delay or avoid dental procedures because of their fear , anxiety or expectation of pain . brief cognitive and behavioral approaches for dental anxiety are already established as effective treatment strategies . the dentist s office should provide a program antagonistic with novelty , uncertainty , negative expectations and cognitions or feelings of insecurity . medical assistants can implement programs that relax the patient , producing a positive expectation and a sense of security . a variety of distraction interventions can be used on a daily basis in medical offices in order to help patients to cope with unpleasant procedures ; these include watching television , listening to music , video games , and virtual reality ( vr ) goggles . forests , botanical gardens , snowy canyons are the most effective vr surroundings at reducing stress and creating positive experiences . also it is considered beneficial for a deaf patient to have the opportunity to visit the dental office in advance of the appointment so that he / she can familiarize with the dental care provider , office staff and smells . in our study , people who experienced previous traumatic dental episodes showed higher levels of dental anxiety , which was also observed in the findings conducted by do nascimento et al . . a history of urgent dental care may predispose people to be fearful of the dental practitioner . better knowledge of the antecedents of dental fear and anxiety are needed in order to design effective programs aimed to prevent dental fear and its oral health related consequences . evaluation of economic status showed that those with lower economic status ( with no income , who are financially dependent of another family member ) were more anxious than independent respondents . uneducated and unemployed people scored high on the anxiety scale while educated people cope better . lower or mediocre socioeconomic conditions lead to poor physical health and also psychological pathology such as depression or anxiety . shiboski reported that low income is a barrier to dental care and it may lead to a deteriorated state of oral health that may prompt such patients to seek oral health care only when experiencing acute pain . this can be explained by the fact that women are more able to express their feelings of fear . in addition , physiological conditions such as stress , social phobia and fear are more common in females . females usually admit their fears readily than men and have a lower tolerance to pain , thus exhibiting higher levels of neuroticism . other studies performed by kagen et all and el - housseiny showed no significant differences between gender and dental anxiety . even if people with hearing loss visited doctor s offices significantly more often than hearing people , they reported less satisfaction with health care services . only about 10.38 % of our participants claimed to visit dental offices regularly , while saatchi et al reported in general population 16.5 % or up to 5072 % in developed countries . similar observations were also seen in hearing people studies performed by el - housseiny et al . this is probably because some dentists use the threat of injection as a method of child discipline . the prevalence of dental anxiety in the present study was found to be 68.83 % while saatchi et all reported 58.8 % in hearing populations , suggesting that despite technological advances made in the field of modern dentistry , dental treatment related anxiety is still widespread . higher prevalence of dental anxiety among deaf people raises concern that its negative impact has the potential for serious health consequences . an important aspect of patient management in the dental chair is managing dental fear and anxiety . in order to reduce dental fearwhen a patient is known to be fearful and anxious , knowledge of the patient s cognition is a major first step in reducing fears and anxieties . behavioral management techniques are meant to reduce the need for excessive and unsafe use of medication . information coming from the dentist provides security for the dental procedures to come . modifying the atmosphere , taking time to ensure adequate anesthesia , being warm , providing treatment in short appointments rather than in a long visit , acting in a calm and confident manner are all essential management methods . touching the patient s hand orshoulder is a mean of establishing warmth , security and caring which is antagonistic to fear . it is recommended to refer the extremely anxious patient to a clinical psychologist who will consult the patient at the dental office during off hours . studies by sharath et all have shown that dental anxiety is not only a mental health concern but also a public health one . fear of dental procedures and delayed / cancelled dental visits contribute to severe oral symptoms . breaking the fear andproper use of management techniques can improve behavior , making things easier for patient and dental practitioner alike . limitations of our study include its cross sectional design , a limited population with lower economic status and educational level , convenience sampling , self assessment questionnaire , therefore studies on larger populations are needed in order to reveal dental fear and anxiety in modern society . it can be observed from our study that dental fear and anxiety are widespread among the deaf populations . our research highlighted the importance of using behavioral techniques in the field of dentistry in order to improve patient management strategies and policy making . dental anxiety was found to be higher in females while people who visit the dental practitioner regularly were less anxious . empowering deaf patients to actively address oral health care with their dentist can establish a positive framework , thus breaking the vicious cycle of dental fear and treatment avoidance . use of a standardized scale may enable dentists to detect the procedures that provoke fear and guide the patient s behavior accordingly using a cognitive approach . treating deaf patients is a challenge in need of close interdisciplinary collaboration between psychotherapist and dentist .\noutput:\n" }, { "from": "agent", "value": "background and aimdental fear and anxiety is a major barrier for dental care provision . identifying anxious patients can help dental professionals manage them appropriately . the study aimed at assessing dental fear and anxiety among a deaf population in cluj - napoca , romania and their associated and contributing factors.methodin this cross sectional study 165 deaf participants were invited to complete a questionnaire comprising three sections . the first section contained questions about social and economical status , the second comprised a romanian version of the modified dental anxiety scale ( mdas ) while part three was the dental fear survey ( dfs ) . data was introduced and analyzed with the statistical package for social sciences ( spss ) program , version 20.0 ( spss inc . , chicago , illinois , usa ) . resultsthirty four point nine percent ( 34.9 % ) of respondents were found to be insignificantly anxious , 59.7 % were moderately or extremely anxious with 5.3 % being identified with dental phobia based on the mdas scores . mean total score for dental anxiety on the mdas scale was 13.7 . patients suffering from a prior negative experience were found to be more anxious ( p < 0.05 ) . conclusionsdental fear and anxiety is widespread in the deaf communities . higher percentages were observed among women and people with a previous traumatic dental experience ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: an intrapancreatic accessory spleen may be misdiagnosed as a nonsecreting neuroendocrine tumor of the pancreas . an accurate diagnosis is crucial since such an accessory spleen does not require surgical treatment . a 67 - year - old woman in good general conditions with a family history positive for pancreatic cancer underwent a routine health check . physical examination was normal and laboratory tests revealed normal alpha fetoprotein and carcinoembryonic antigen but a slightly elevated tumor marker ca 19 - 9 ( 35 u / ml ; normal 27.0 u / ml ) . additional laboratory tests such as chromogranin a , neuron - specific enolase , 5 - hydroxyindoleacetic acid , pancreatic polypeptide and substance p were ordered and normal beside a slightly elevated pancreatic polypeptide level ( 437 pg / ml ; normal 210 pg / ml ) . the patient also underwent a ct scan investigation which showed a 181515 mm nodular lesion in the tail of the pancreas without any contrast enhancement ( fig . an additional octreotide scan was normal . because of the abnormal tumor markers ca 19 - 9 and pancreatic polypeptide , a neuroendocrine tumor was suspected , although the image appearances were not typical . due to this potentially malignant lesionintraoperatively , a dark red but soft tumor was found in the tail of the pancreas and the lesion was also confirmed by intraoperative sonography . postoperative histopathological examination revealed a completely intrapancreatic accessory spleen without any signs of a tumor ( fig . during the 5th week of gestation the spleen develops in the dorsal mesogastrium from mesenchymal cells that migrate between the leaves of the mesentery and coalesce . an accessory spleen may arise from isolated cells which rest separated from the main body of the spleen . in a large series of nonselected autopsy investigations an accessory spleenwas found in 1030 % . in 1,000 consecutive patients undergoing contrast - enhanced abdominal ctscan an accessory spleen was present in 16 % . in 80 % the accessory spleen is located at or near the splenic hilum . differential diagnosis of a solid pancreas tumor includes pancreatic adenocarcinoma , pancreatic neuroendocrine tumor , solid and papillary epithelial neoplasms and metastasis . pancreatic endocrine tumors are rare ( 10 % ) and often localized in the head of the pancreas . due to secretion of biologically active substances , 1553 % of these tumors become symptomatic , all others remain initially silent . however 50 % of these nonsecreting endocrine tumorsonly 11 cases of surgical resection of an intrapancreatic accessory spleen have been reported up to now . in most of these casesthe intrapancreatic accessory spleen was misdiagnosed as a pancreatic tumor and patients underwent unnecessary surgery . most intrapancreatic accessory spleens are roundish and have a characteristic homogenous contrast - enhanced appearance on ct scan with well - defined margins . however , definitive diagnosis based on imaging can be difficult because ct scan , mri and ultrasound images of such intrapancreatic spleens are quite similar to those of hypervascular pancreatic tumors , as islet cell tumors and acinar cell carcinoma . using contrast - enhanced ultrasound , ota and ono demonstrated in the hepatosplenic phase that contrast medium is trapped by hepatic and splenic tissue , which may allow to distinguish an intrapancreatic spleen from other lesions . somatostatin receptor scintigraphy ( octreotide scan ) has a high sensitivity in detection of gastrointestinal neuroendocrine tumors ( 7095 % ) . the presence of somatostatin receptors on the surface of lymphocytes within the splenic tissue , which also bind octreotide with a high affinity , may therefore mimic a neuroendocrine tumor . diagnosed in three of five patients an intrapancreatic accessory spleen based on the findings of standard gadolinium - enhanced mri . however , they were not able to exclude other diagnoses with this investigation , including pancreatic neuroendocrine tumors , pancreatic adenocarcinomas , solid and papillary epithelial neoplasms , and metastasis . the only possibility to differentiate an accessory spleen from a neuroendocrine tumor are nuclear scintigraphic investigations as 99 m tc - sulphur colloid or tc - tagged heat - damaged red blood cells scintigraphies . these are investigations which are noninvasive , sensitive and specific for detecting splenic tissue . in asymptomatic homogenous and well - circumscribed tumors in the pancreatic tail an accessory spleen has to be excluded before surgery . nuclear scintigraphies such as 99 m tc - sulphur colloid or tc - tagged heat - damaged red blood cells scintigraphies should be definitely routinely used in the preoperative evaluation of nonsecreting pancreatic lesions , particularly those which are located in the body and tail of the pancreas . these imaging modalities may provide the definitive diagnosis of an intrapancreatic spleen and therefore prevent patients from undergoing unnecessary major surgery .\noutput:\n" }, { "from": "agent", "value": "in a large series of nonselected autopsy investigations an accessory spleen was found in 1030 % . the second most common site is the pancreatic tail ( 17 % ) . we report a case of intrapancreatic accessory spleen misdiagnosed as a nonsecreting neuroendocrine tumor of the pancreas . nuclear scintigraphy may provide the definitive diagnosis of an intrapancreatic spleen and therefore prevent patients from unnecessary major surgery ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: for the study , we enrolled patients who attended the outpatient clinics at the all india institute of medical sciences , new delhi , and sheri - kashmir institute of medical sciences , srinagar , during 20112012 who had influenza - like illness ( ili ; defined as sudden onset or history of fever 38c , cough or sore throat and / or rhinorrhea ) ( 6 ) . we collected 510 nasopharyngeal samples from these patients each week and tested them for influenza viruses by type and subtype ( 9,10 ) . a confirmed case - patient was defined as a patient meeting the ili case definition who had positive results for influenza by reverse transcription pcr . sanger sequencing of the hemagglutinin and neuraminidase genes was completed , and consensus was used to construct a kimura 2 - parameter neighbor - joining tree ( technical appendix figure 1 ) . sequences from new delhi and srinagar were compared with those of vaccine strains and with published cognate sequences of corresponding genes ( technical appendix table 1 ) , including those from india ( 10 ) . surveillance for influenza viruses revealed that overall influenza positivity was 17.6 % ( 375 confirmed cases from 2,126 ili patients ) in srinagar and 9.46 % ( 239/2 ,526 ) in new delhi ( table ) . discrete winter time peaks were observed during january march ( epidemiologic weeks [ ew ] 112 ) in srinagar , whereas new delhi had peaks of influenza circulation during july 2011 and september 2012 ( ew 2636 ) ( figure 1 ) . influenza a was the predominant type in srinagar ( 275/375 ; 72.9 % ) , whereas influenza b dominated in new delhi ( 154/239 ; 64.4 % ) . circulation of influenza a ( h3n2 ) during the monsoon season of 2011 in new delhi was followed by predominance of h3n2 during winter 2012 in srinagar ( figure 1 ) . * percentages are of all influenza - positive test results in category . weekly trends and proportion of annual numbers of positive influenza cases , by epidemiologic week and influenza type , srinagar ( a ) and new delhi ( b ) , india , 20112012 . clear seasonal peaks are seen in january march ( weeks 116 ) for srinagar and in july and september ( weeks 2840 ) for new delhi . phylogenetic analysis of the hemagglutinin and neuraminidase genes from selected samples from new delhi and srinagar revealed no notable differences between circulating viruses ( technical appendix figure 1 ) . furthermore , circulating influenza strains were closely related to the selected influenza vaccine strains , a / california / 7/2009 ( h1n1 ) , a / perth / 16/2009 ( h3n2 ) , and b / brisbane / 60/2008 , which remained unchanged for 20112012 for the northern and southern hemisphere formulations ( technical appendix figure 2 ) . the 20122013 northern hemisphere formulation changed the h3n2 strain to a / victoria / 361/2011 and the influenza b strain to b / wisconsin / 1/2010 , but sequence information from 2013 circulating viruses from srinagar was not available to assess vaccine similarity . analysis of meteorologic factors ( i.e. , rainfall , temperature , relative humidity , vapor pressure , and dew point ) showed that the monthly proportion of influenza positivity correlated with decreased temperature and dew point in srinagar and with rainfall amount in new delhi ( data not shown ) . cumulative data over the 2 - year surveillance period revealed differences in seasonality by latitude ; influenza positivity peaked during december february in srinagar ( 34.09 n ) but in julyinfluenza seasonality indicates that new delhi would likely benefit from springtime vaccination ( may june ) , whereas vaccination in the fall ( october november ) would be better for srinagar ( figure 2 ) . we recently illustrated that india and most other tropical countries in asia exhibit influenza seasonality that coincides with the monsoon season , june october ( 11 ) . comparison of latitudes of srinagar and new delhi , india , and distribution of influenza virus infections , 20112012 . a ) locations of srinagar and new delhi ( black triangles ) , with vertical lines indicating 30n latitude and equator . b ) monthly distribution of cases of influenza virus infection in srinagar ( 34.0 n latitude ) . c ) monthly distribution of cases of influenza virus infection in new delhi ( 28.7 n latitude ) . arrows indicate proposed vaccination timing ; latitude of each city is shown . map created in epi - map in epi info 7 ( centers for disease control and prevention , atlanta , ga , usa ) . a city in the northernmost region of india , influenza positivity rates peaked in winter ( december march ) , whereas in new delhi , a city just 500 km south of srinagar , influenza peaked during the monsoon season ( july september ) . the winter peak in srinagar is similar to the timing of influenza circulation observed for most countries in europe and united states in the northern hemisphere ( 4,5 ) . by contrast , the data on influenza seasonality in new delhi corroborate findings which showed that many countries in tropical regions ( e.g. , brazil , india , vietnam ) experience high influenza transmission rates during the rainy season ( 6,1113 ) . overall , influenza a and b viruses co - circulated throughout the surveillance period in srinagar and new delhi ; however , the types and subtypes varied . peaks of influenza circulation in srinagar and new delhi show seasonal patterns that depend on factors such as temperature , rainfall , humidity , and latitude ( 2,3 ) . srinagar , at 30n latitude , has influenza seasonality that coincides with lower temperature and low dew points during winter , whereas new delhi , at 30n latitude , has a peak of influenza circulation that coincides with the rainy season . seasonal influenza activity coinciding with the humid , rainy season at lower latitudes has also been observed in large areas of central and south america and southern asia ( 11,13 ) . in contrast , cold , dry weather was predictive of influenza peaks at higher latitudes , as observed for srinagar . the latitude dependence of influenza circulation observed in this study is similar to such dependence observed in brazil and china ( 13,14 ) and collectively suggests that decisions on the timing of influenza vaccination should not be based only on the hemisphere a country is in but also on the types of seasonal patterns that exist within a country ( 15 ) . these latitudinal differences in influenza seasonality in india have implications for influenza vaccine timing and vaccine formulation . thus , the timing of vaccination has a direct effect on vaccine effectiveness . in the northernmost part of india , peak influenza circulation occurs during the winter months ; therefore , vaccination during october november using the northern hemisphere vaccine formulation may be appropriate . however , this practice would not be appropriate in the delhi metropolitan region , where influenza peaks in julyin addition , whereas our data points to an approximate latitude where temperate and tropical patterns for influenza peaks diverge , more robust data with multiple surveillance sites in tropical , subtropical , and temperate regions in india and china are needed to define the exact latitude points for influenza circulation patterns . additional surveillance data for multiple years and many cities around the latitude gradient are required to further corroborate these observations . furthermore , validation of vaccine formulation will require tracking of additional circulating influenza strains over several epidemic periods . in summarywe recommend that policy makers in india review circulation patterns closely before implementing influenza intervention plans . our data suggest that cities in india located north of 30n latitude can continue vaccination in the winter , but those south of 30n , including new delhi , should consider vaccination in may june ( 15 ) . collectively , these data should help decision makers , especially regulatory authorities , choose vaccines and vaccination schedules best suited for each region . accession numbers of isolates used for phylogenetic analysis , phylogenetic analysis of hemagglutinin and neuraminidase sequences of influenza virus strains from srinagar and new delhi , india , compared with published sequences and corresponding vaccine strains , and world health organization recommended vaccines by season and hemisphere , 20062014 .\noutput:\n" }, { "from": "agent", "value": "the seasonality of influenza in the tropics complicates vaccination timing . we investigated influenza seasonality in northern india and found influenza positivity peaked in srinagar ( 34.09 n ) in january march but peaked in new delhi ( 28.66 n ) in july september . srinagar should consider influenza vaccination in october november , but new delhi should vaccinate in may june ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: among the minor ophthalmological procedures , intravitreal injection of bevacizumab is probably one of the most widespread procedures .13 despite its lack of approval by the us food and drug administration ( fda ) for ophthalmological use ,4 data from the comparison of age - related macular degeneration treatments trials ( catt ) demonstrated that monthly and as - needed regimes of bevacizumab are equally as effective for controlling the exudative forms of age - related macular degeneration ( amd ) than the current fda - approved drug ( ranibizumab ) .2,3,57 this has somehow validated bevacizumab use and reinforced a common practice in the ophthalmological community since 2005 , when rosenfeld et al published the first pilot study using intravitreal doses of the drug , following a small uncontrolled , open label trial that used systemic doses of bevacizumab .811 bevacizumab ( avastin ; genentech , inc . , south san francisco , ca , usa ) , a full - length humanized monoclonal antibody against vascular endothelial growth factor - a ( vegf - a ) , has shown , repeatedly and consistently , its potential efficacy in controlling proliferative diseases and vascular leakages .13 nevertheless , its intravitreal use is not entirely free of adverse effects , most of which are more related to the administration procedure than to the drug per se .12 reports of sustained elevation of intraocular pressure and inflammation after the intravitreal use of bevacizumab have been increasing .4,1317 although the exact cause is yet to be determined , it is believed that the presence of particulate matter ( silicon droplets or protein aggregates ) due to a mishandling of the drug during storage or repackaging , as well as allergic reactions to the drug or a contaminant , might be involved .13,14,18 in the present series , we will describe the clinical characteristics and outcomes of ten consecutive cases of sterile endophthalmitis ( defined as the acute intraocular inflammation of the vitreous cavity after an intravitreal drug that either resolves without the need of intravitreal antibiotics and / or negative culture proven ) , in which the administered drug came from two different vials from the same batch . the study was approved by the internal review board of the asociacin para evitar la ceguera en mxico hospital , mexico city , mexico . all patients signed informed consent forms , in which the use of an off - label drug was explained , before any procedures were done . using strict sterile techniques , commercially availablebevacizumab ( 100 mg / 4 ml ) was divided into individual aliquots of 1.25 mg / 0.05 ml and stored for no more than 1 week at 4c . all intravitreal injections were carried out in an area of the operating room specially designated for intravitreal injections only . all personnel present at the moment of injection wore surgical scrubs and face masks . before the procedure , the attending physician washed their hands and wore sterile gloves , and an assistant cleaned the skin around the eye with a solution of povidone - iodine 10 % and instilled a single drop of povidone - iodine 5 % ( betadine ; alcon laboratories , inc . , fort worth , tx , usa ) in the cul - de - sac . all injections were done using a 27 - gauge needle at 3.54 mm from the limbus ( pars plana ) . a cotton swab was used for immediate local pressure of the injection site for a few seconds .12,19,20 topical antibiotic prophylaxis with ciprofloxacin hydrochloride 0.3 % ( ciloxan ; bausch & lomb incorporated , bridgewater , nj , usa ) was indicated in all cases for 5 days . at each post - injection visit , all patients had a complete ophthalmological examination , which included : best corrected visual acuity ( bcva ) examination ; slit - lamp biomicroscopy ; posterior fundus examination with indirect ophthalmoscope ; intraocular pressure assessment ; and screening for local and systemic adverse effects . vitreous and aqueous samples were obtained following a strict standard protocol from all patients with suspected endophthalmitis . we reviewed the cases of ten consecutive patients from a group of 46 patients who had intravitreal bevacizumab for a wide array of different pathologies , including choroidal neovascularization ( cnv ) secondary to amd , myopic cnv , diabetic macular edema , and macular edema secondary to vein occlusion . all patients were part of the intravitreal injection clinic of the hospital and were injected on the same day in november 2012 . the first two cases of mild anterior chamber inflammation occurred within days of the injection ( mean 3.51.95 days ) ; thereafter , all 46 patients were seen systematically , regardless of whether or not they had symptoms . the demographic and clinical presenting characteristics of the study group patients with suspected sterile endophthalmitis are summarized in tables 1 and 2 . all ten patients studied had variable degrees of conjunctival hyperemia , anterior chamber cells , and vitreous cells ; two of these presented hypopyon and severe vitreous cells . all patients reported mild - to - moderate ocular pain and slight decrease of baseline visual acuity . half of the group reported a final bcva better or equal to the baseline bcva on file , while the other half reported a slightly worse final bcva ( figure 1 ) . the visual acuity of patient number 6 was not available for analysis since he was being seen as a foreign patient and was lost to follow - up . although the majority of the patients did not need intraocular antibiotics or surgery for the resolution of the inflammatory process and all cultures were negative , the two patients who presented with hypopyon received intravitreal antibiotic ( moxifloxacin ) and steroid ( dexamethasone ) treatment at the moment of presentation due to our inability to rule out true endophthalmitis with the clinical presentation . nevertheless , the cultures from vitreous samples ( obtained before the intravitreal antibiotics administration ) were negative in both patients . reports from pathology indicated that one of the cultures from additional samples of aqueous humor of one of the patients showed positive staphylococcus aureus growth ; however , the result was considered as a possible contamination rather than a true infectious source of inflammation , given the lack of positive growth in other control samples taken . the rest of the patients were managed with topical antibiotics ( ocuflox [ ofloxacin 0.3 % ] ; allergan inc . , irvine , ca , usa ) , steroids ( prednefrin [ predonisolone 0.12 % ] ; allergan inc . ) , and cycloplegics ( mydryacil [ tropicamide ] ; alcon laboratories , inc . ) . furthermore , three of the patients presented a transitory rise of intraocular pressure , which was adequately controlled with a short course of topical glaucoma medication . one of the patients also had severe vitreous hemorrhage ( 3 + ) , which resolved without treatment . the inflammatory reaction yielded within the first week after diagnosis and vitreous cells cleared completely during the course of the first month . sixty percent of the patients had at least one injection of intravitreal bevacizumab before in one or both eyes . of this group , 40 % had at least one injection in the study eye before , and the rest in the contralateral eye . regarding the baseline pathology , four patients had cnv secondary to amd and three patients were diagnosed with macular edema secondary to central retinal vein occlusion . two more were diagnosed with ischemic retinal vascularization secondary to branch retinal vein occlusion and one had recurrent diabetic macular edema . a 63 - year - old caucasian female , whose previous medical history was unremarkable for the present illness , was seen during a follow - up visit at the retina clinic due to an active cnv secondary to amd in the left eye . the patient had been treated with monthly injections of intravitreal bevacizumab in the study eye on four previous occasions . during the follow - up consultation , the bcva was 20/50 ( right eye ) and count fingers at 1 foot ( left eye ) . fundus examination of the left eye presented a persistent subfoveal choroidal neovascularization , with hard drusen and intraretinal cystic fluid . fluorescein angiography showed active leakage , and spectral domain optical coherence tomography corroborated the diagnosis . the patient underwent a fifth dose of intravitreal bevacizumab using the technique and doses described previously . three days later , the patient was seen at the emergency room complaining of visual loss , mild pain , and conjunctival hyperemia ( 2 + ) . the biomicroscopy revealed fibrin in the anterior chamber , cells in aqueous and vitreous ( 3 + ) and microhypopyon . the patient was treated with topical steroids , antibiotics , timolol 0.5 % , and dorzolamide . one week later , the inflammation had yielded , the vision had improved to 20/300 , and the intraocular pressure had decreased to 16 mmhg . a 63 - year - old caucasian female , whose previous medical history was unremarkable for the present illness , was seen during a follow - up visit at the retina clinic due to an active cnv secondary to amd in the left eye . the patient had been treated with monthly injections of intravitreal bevacizumab in the study eye on four previous occasions . during the follow - up consultation , the bcva was 20/50 ( right eye ) and count fingers at 1 foot ( left eye ) . fundus examination of the left eye presented a persistent subfoveal choroidal neovascularization , with hard drusen and intraretinal cystic fluid . fluorescein angiography showed active leakage , and spectral domain optical coherence tomography corroborated the diagnosis . the patient underwent a fifth dose of intravitreal bevacizumab using the technique and doses described previously . three days later , the patient was seen at the emergency room complaining of visual loss , mild pain , and conjunctival hyperemia ( 2 + ) . the biomicroscopy revealed fibrin in the anterior chamber , cells in aqueous and vitreous ( 3 + ) and microhypopyon . the patient was treated with topical steroids , antibiotics , timolol 0.5 % , and dorzolamide . one week later , the inflammation had yielded , the vision had improved to 20/300 , and the intraocular pressure had decreased to 16 mmhg . the intravitreal administration of drugs has become the preferred route for the treatment of a wide array of ocular conditions . since the original description of the technique by rycroft in 1945,21 the recognition of the vitreous cavityas an excellent reservoir , where relatively high levels of drugs can be maintained for a long period ( typically higher concentrations than obtained by other administration routes ) without incurring undesirable reactions , has changed the approach and expanded the types of drugs that can be used in the treatment of such diseases .18,21 vegf is a glycoprotein that is secreted in the eye during ischemic conditions and which also has an important role in vascular permeability , tumor angiogenesis , and as an inflammatory molecule .2,3,22 bevacizumab is a 149 kda humanized full - length monoclonal igg antibody against vegf with a half - life of 9.8 days in human vitreous .13,16 the proven noninferiority of intravitreal bevacizumab relative to its fda - approved counterpart ( ranibizumab ) set a precedent for its off - label use .5,6 the safety of intravitreal injection depends not only on the surgical technique , but also on the characteristics of the administered drug ; infectious endophthalmitis is a rare but potentially blinding condition that requires prompt treatment with intravitreal antibiotics and surgery .23 certain intravitreal drugs can produce an acute and sterile intraocular inflammation that can mimic infectious endophthalmitis .4,18,24,25 an accurate differential between these two entities is crucial , as a delay in treatment of the former or unnecessary treatment of the latter can have major consequences .4 another important differential that needs to be ruled out is the possibility of toxic anterior segment syndrome .26 in this case , the distinction is easier , because patients with toxic anterior segment syndrome typically develop severe anterior chamber inflammation with hypopyon just 12 to 48 hours after anterior segment procedures , conversely to sterile endophthalmitis , in which the mild symptomatology and insidious onset develops 2 days to a few weeks after injection .26,27 in the past few years , there has been an increasing number of reports of high intraocular pressure and inflammation after intravitreal use of bevacizumab .13,28 the present case series describes the clinical presentation and outcomes of ten consecutive cases that occurred after intravitreal administration of bevacizumab from two different vials from the same batch . it is important to note that a total of 46 patients received drug from the same vials , at the same time , in the same place , and with the same technique . but only ten out of 46 patients showed manifestations of idiopathic inflammation and only three out of these ten had high intraocular pressure . although traumatic causes during injection were ruled out , the exact etiology of the hemorrhage is still uncertain and might be the result of the base pathology . the evolution and outcome in general was similar to the outcomes described in other case series , in which , after a mild episode of inflammation , the patients recovered vision without intravitreal antibiotics or surgery .12,25 our series seems to reinforce the notion that , although there is no clear relationship with age , sex , pathology , or number of previous intravitreal injections ; sterile endophthalmitis tends to occur in clusters to occur in clusters . interestingly , and conversely to the majority of case series published so far , our group showed slightly worse visual outcome than usual .17,18,25,29 the high variability among the baseline visual acuities prevents us from drawing any definite conclusion regarding this observation ; however , the small number of cases and a worse initial visual acuity than in previously reported series may be accountable for this observation . furthermore , although not mentioned previously , most of our patients had uncontrolled or poorly controlled concomitant systemic conditions , such as diabetes mellitus and high blood pressure , which led to poor response to treatment . this feature of our population might suggest that specific clinical conditions could be responsible for the development of sterile endophthalmitis and its evolution and treatment response , independently of the batch , contamination of aliquots , or injection technique . in our series , sterile endophthalmitis did not have any relation with previous history of surgery or inflammatory eye conditions as in other reports in the literature .4,12,14,17 the etiology of sterile endophthalmitis is poorly understood . risk factors that seem to be related are history of uveitis , pseudophakia , and past history of vitrectomy ; 4,2931 however , no definite association has been proven , and there are many possible explanations . for instance , the common practice of dividing individual aliquots commercially available vials of bevacizumab , as a cost - effective method ,23 may carry an increased risk of contamination with bacterial endotoxins .18,29 this situation may explain clusters of sterile endophthalmitis in patients treated with injections from the same batch . furthermore , bevacizumab normal formulation may contain traces of endotoxins at levels that are deemed safe for intravenous use , but which are still capable of inducing an inflammatory reaction intravitreally .18,29,32 another important factor is the possible existence of noninfectious particles in bevacizumab preparations .29 evidence published by liu et al13 and replicated by other groups31 ,33 has shown that physical mishandling and extreme freeze / thaw cycles may increase the levels of silicon oil microdroplets in the syringes containing repackaged bevacizumab .13 these particles are thought to be possibly responsible for increases in intraocular pressure seen after drug administration . temperature fluctuations have also been proposed as a factor that may increase immunogenic properties of bevacizumab .18 temperature oscillation outside the range recommended by the manufacturer ( 2c8c ) may promote protein degradation and induce novel antigenic epitopes not found in the original molecule , creating a specific immune reaction against bevacizumab .18 in addition , the relatively large molecule and extended half - life in the vitreous cavity theoretically increase this possibility .17 finally , it is possible that compensatory elevation of angiogenic and inflammatory factors , following vegf inhibition , may occur , promoting the clinical manifestations of sterile endophthalmitis .17,26,29 the relatively low risk of infectious endophthalmitis reported in the literature and small power of the studies to detect important adverse effects ( range 0.01 % 1.16 % , mean 0.0149 % 1 in every 1,949 injections ; catt : bevacizumab 0.014 % , ranibizumab : 0.07 % ) has precluded the elaboration of general guidelines aimed at preventing and decreasing the incidence .5,6,23,31,34 regarding sterile endophthalmitis , the exact incidence is unknown . the catt reported an incidence of pseudoendophthalmitis of one out of 599 patients ( 0.16 % ) with ranibizumab and none in a bevacizumab group .5,6 smaller underpowered studies have reported incidences ranging from 0.09 % to 1.1 % .5,6 according to the united states pharmacopeia , general chapter 797 , about pharmaceutical compounding of sterile preparations , the repackaging of multiple doses of bevacizumab is a medium - risk compounded sterile preparation , meaning that all personnel involved in aliquot preparation must wear sterile scrubs , work under a laminar airflow workbench , and do routine disinfection and air quality testing to maintain an international organization for standardization ( iso ) class 5 ( 3,520 particles / m ) environment .23 in the same way , several studies , recommendations , and guidelines have been published regarding the best injection techniques in order to minimize risk of complications after intravitreal administration of the drug .19,20,35,36 nevertheless , despite all these recommendations , cases continue to be reported worldwide . in summary , sterile endophthalmitis and transient elevation of intraocular pressure can occur after uneventful intravitreal injections of bevacizumab , regardless of the injection technique or aliquot preparation procedure . although there are several theories about the etiology of the intraocular inflammation , its causes are still unknown . in this case series , the majority of clinical characteristics were similar to those reported previously : presentation 2 days to 1 week after injection ; mild pain , with a slight decrease in visual acuity and various degrees of intraocular inflammation ; negative culture ; and recovery without intravitreal antibiotics or surgery . however , conversely to previous published data , 50 % of our group reported final bcva that was worse than the baseline bcva on file . the widespread acceptance of intravitreal bevacizumab as an accepted standard of care might explain why we are seeing these episodes more often . the general ophthalmologist as well as the retina specialist must be familiar with the clinical manifestations of these episodes in order to make good differentials , instigate proper treatment , and avoid long - term complications . nevertheless , the extremely low incidence of such events should not prevent the intravitreal use of bevacizumab in eyes that might benefit greatly from this type of therapy .\noutput:\n" }, { "from": "agent", "value": "backgroundsince the ophthalmological community adopted the use of intravitreal bevacizumab as an accepted off - label treatment for neovascular diseases , the amount of knowledge regarding its effects and properties has been increasing continually . in the last few years , there have been an increasing number of reports about sterile intraocular inflammation and intraocular pressure elevations after intravitreal bevacizumab . in the following case series , we describe the clinical presentation and outcomes of ten consecutive cases of patients developing mild - to - severe sterile intraocular inflammation after intravitreal bevacizumab and their management.methodsthis report presents a retrospective case series . we reviewed the medical records of ten consecutive patients from a group of 46 , in whom repackaged bevacizumab in individual aliquots from two vials from the same batch were used . all surgical procedures were performed using standard sterile techniques in the operating room . at each follow - up visit , patients underwent a complete ophthalmological examination including visual acuity assessment , intraocular pressure , biomicroscopy , and posterior fundus examination.resultsten patients presented sterile endophthalmitis with an onset time of 3.51.95 days . the clinical characteristics were mild pain , slight visual loss , conjunctival hyperemia , and various degrees of intraocular inflammation with microhypopyon . all cultures were negative . all patients were managed with topical steroids and antibiotics , except two , in whom , due to severe vitreous cells , intravitreal antibiotics were used . three patients showed a transient elevation of intraocular pressure . only 50 % of the patients regained a visual acuity equal or better to the baseline visual acuity on file.conclusionthe increasing number of intravitreal injections of bevacizumab applied every day , due to its widespread acceptance , might be one reason why the number of cases of sterile endophthalmitis is rising . fast recognition and accurate differential diagnosis is important to avoid unnecessary treatments and long - term complications . the low incidence of this event should not preclude the use of intravitreal injections in eyes that could benefit greatly from this therapy ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: ovarian stimulation with fsh , combined with gnrh agonist and triggered with hcg is a standard procedure in in vitro fertilization ( ivf ) and intra cytoplasmic sperm injection ( icsi ) ( albano et al . it has been demonstrated before that the triggering for final oocyte maturation by hcg can be replaced by gnrh agonist ( gonen et al . , 1990 ; griesinger et al . , 2007 ; humaidan et al . , 2009 ; humaidan , 2011 ; shapiro et al . , 2011 ; imbar et al . , in several randomized controlled trials it was demonstrated that the number of cumulus oocyte complexes ( cocs ) was certainly not lower and even higher in patients triggered by either gnrh agonist or hcg ( humaidan et al . , 2005 ) . however , if hcg is used for triggering final oocyte maturation , fsh and lh concentrations do not rise and oocyte maturation relies entirely on the lh activity of hcg ( kol and humaidan , 2010 ; kyrou et al . , this strategy will initiate a flare - up of both fsh and lh ( kol and humaidan , 2013 ) . however the mechanism of the additional fsh effect on the periovulatory hormonal changes requires further investigation ( griffin et al . , 2012 ; , 2012 ; kummer et al . , 2013 ; segal and casper , 1992 ) . in this study we aim to investigate the role of the gnrh agonist induced fsh surge on the number of metaphase ii ( mii ) oocytes . it could be expected that improved embryo quality would be obtained because of the mimicking of the natural mid cycle endocrinology . this phenomenon was investigated by comparing hcg triggering versus gnrh agonist combined with hcg triggering of final oocyte maturation in patients undergoing icsi in a prospective randomized controlled trial ( palermo et al . , 1992 ) . the choice for dual triggering in the second group was initiated by the negative effect on implantation by the induction of final oocyte maturation by gnrh agonist alone ( kol and humaidan , 2013 ) . the current randomized controlled trial was performed at the ivf centre of the hospital jan palfijn , gent between november 2011 and september 2013 . the inclusion criteria were tubal or male infertility , bmi 32 , age 38 years , absence of major endocrinologal pathology , first , second and third ivf cycle . exclusion was made for couples with azospermia and patients with female uterine abnormalities and major endocrinological disorders including pcos . patients willing to participate , and meeting the inclusion and exclusion criteria were , after signing the informed consent form , randomized in two groups . group a was assigned to the hcg triggering alone , whereas group b received the dual triggering . the randomization was performed by the study coordinator through a computer generated random number list . a statistician who was not involved in the recruitment orsince the primary endpoint was the number of metaphase ii ( mii ) oocytes , sample size calculation was performed in order to detect a difference in the mean number of mii oocytes between the two groups , one ( oocyte ) with a power of 80 % , tested by means of a t - test , and the two - sided at 5 % significance level and standard deviation estimated at two . according to this power calculation 120 patients were needed to be randomized in two groups : 59 patients were assigned to group a ( hcg triggering alone ) and 61 patients were assigned to group b ( dual triggering group ) . the study was registered at eudract in november 2011 , and also at clinicalstudies.gov in november 2011 . this second registration was reinstored in 2012 because of the replacement of the study coordinator . patient recruitment started in november 2011 and the last patient was randomized in september 2013 . ovarian stimulation was performed using a starting dose of 200 iu of recombinant fsh ( puregon , msd , brussels , belgium ) for all patients . suppression of endogenous lh was performed by using 0.25 mg gnrh antagonist ( orgalutran , msd , brussels , belgium ) from day six of fsh stimulation onwards . on day 7 of the stimulationan ultrasonic evaluation of the number and size of ovarian effect follicles was performed and the dose of recombinant fsh was adapted according to the individual reaction of the patient . triggering of final oocyte maturation was performed as soon as three follicles of = 17 mm diameter were present by either injecting 5000iu of hcg ( pregnyl , msd , brussels , belgium ) or a combination of 0.2 mg gnrh agonist triptorelin - acetate ( gonapeptyl , ferring , aalst , belgium ) plus 5000iu of hcg ( pregnyl , msd , brussels , belgium ) concomitantly ( kolibianakis et al . , 2004 ; kyrou et al . , 2011 ; polyzos et al . , serum oestradiol , progesterone , lh and fsh were measured at day two of the menstrual cycle before initiation of stimulation , on the day of triggering final oocyte maturation , on day one after triggering , on day two after triggering ( day of oocyte retrieval ) , on day five after triggering ( day of embryo replacement ) and on day eight after triggering . thirty - six hours after triggering oocyte retrieval was performed by ultrasound guided vaginal follicle aspiration ( hoff et al . , 1983 ; morley et al . , 2012 ) . the luteal phase support was started after egg retrieval by vaginal administration of 200 mg micronized progesterone three times daily ( utrogestan , besins , brussels , belgium ) ( germond et al . , 2002 ) . the number cocs was registered before being decumulated and the number of mii oocytes was analysed . icsi was applied to all mii oocytes ( palermo et al . , 1992 ) . in accordance with the belgian legislation , one or two embryos were replaced on day three after egg retrieval ( gordts et al . , 2005 ; ombelet et al . , supernumerary embryos of excellent quality were cryopreserved ( slow freezing protocol ) immediately after the fresh transfer ( day three after oocyte collection ) . embryos of excellent quality which met the following criteria : 7 or 8 - cell stage at day three after fertilization , less than 10 % fragmentation and homogenous blastomeres . according to the study protocol all embryo transfers were performed on day three after oocyte retrieval . thirteen days after embryo transfer hcg and progesterone were measured . in case of positive hcg the vaginal administration of 600 mg micronized progesterone was continued until 12 weeks of pregnancy . if hcg serum test was positive , an ultrasound confirmation of the pregnancy was performed 23 days after embryo transfer . at the end of the treatment cycle we recorded in each patient the number of mature oocytes ( mii ) , cumulus oocyte complexes , fertilized oocytes ( 2pn ) , excellent quality embryos and cryopreserved embryos . hormonal evolution over the treatment cyclecomparison of continuous variables was performed using t - test and for comparing distribution of categorical variables , a fisher exact was used . forall tests were performed two - sided at 5 % significance level . for statistical analysis of hormone profiles over timea mixed modelling approach was used , assessing the correlation between measurements within the same subject . analysis of the covariates age , body mass index ( bmi ) , basal fsh level , basal progesterone level , total dose of recombinant fsh administered during the stimulation , the number of days of stimulation as well as the cycle ranking did not demonstrate any differences between the groups compared , nor did the mean number of transferred embryos show any difference as shown in table i. the mean number of embryos transferred in both groups was similar . there was no statistical difference in the number of patients that received a single or double embryo transfer ( set or det ) . as shown in table ii , no significant differences were observed between the groups compared regarding the number of mii oocytes , the number of cocs , the number of fertilized oocytes ( 2pn ) and the number of cryopreserved embryos . the number of patients with surplus embryos for cryopreservation was 35.6 % ( 21/59 ) in group a and 54.1 % ( 33/61 ) in the group with dual triggering ( p = 0.04 ) . in the group with hcg triggering alone ( group a ) 47.5 % ( 28/59 ) of patients did have at least one embryo of excellent embryological morphology , as compared with 73.8 % ( 45/61 ) in the group with dual triggering ( group b ) ( p = 0.001 ) ( table ii ) . no significant difference was observed in the implantation rate between the two groups ( table iii ) . in groupa ( hcg ) the implantation rate was 34 % ( 28/82 ) whereas in group b ( hcg + agonist ) the implantation rate was 22 % ( 19/86 ) . finally 26 out of 59 ( 44.1 % ) patients became pregnant in the group with hcg triggering alone and 19 out of 61 ( 33.1 % ) in the group with the hcg combined with gnrh agonist triggering . to date 36 patients had frozen embryos transferred after thawing , 12 in group a and 24 in group b , leading to one ( 8.3 % ) and five ( 20.8 % ) pregnancies respectively . the combination of fresh embryo transfer with frozen / thawed embryo replacement brought the total pregnancy rate in group a to 27/59 ( 45.8 % ) whereas group b ( dual triggering ) achieved 24/61 pregnancies ( 39.3 % ) . in figure 1agraphical display of the evolution of the hormones following triggering of final oocyte maturation was made . there were no differences between the hcg and the gnrh agonist - hcg groups in terms of oestradiol ( e2 ) and progesterone following triggering of final oocyte maturation . however , the fsh curve showed a more distinct surge after administration of gnrh agonist in the group with combined triggering . the fsh levels remain at a higher level for a longer period after combined triggering . there is no lh surge in the group of hcg triggering whereas a clear and very explicit lh - peak can be observed in the group with combined triggering . no ohss was diagnosed in the study population , either in the group with hcg triggering , or in the dual triggering group . both groups in the current study were comparable regarding female age , bmi , basal fsh , basal progesterone , total dose of recombinant fsh needed and the number of days required for stimulation . so far it has been demonstrated that the administration of gnrh analogues for final maturation of oocytes after stimulation with recombinant fsh in combination with suppression of the lh surge by gnrh antagonists is a valuable alternative for classical hcg - triggering ( griesinger et al . , 2006 ; humaidan et al . , 2005 , 2009 ; humaidan , 2010 ; itskovitz et al . , 1991 ; kol et al . , 2011 ; however , simultaneous administration of 5000 iuhcg ( normal triggering dose ) and gnrh agonists for triggering the final maturation of the oocytes has only been studied in a limited number of studies ( schachter et al . the present randomized trial is a prospective study dealing with the specific research question as to whether there is a difference between triggering with hcg alone and triggering with the combination of gnrh analogues in collaboration with hcg in terms of number and quality of oocytes , embryological and clinical outcome and hormonal profiles . concerning the hormonal curvesit has been noted that there was no difference in the comparison of hormone evolution over time between both groups for both the oestradiol and progesterone levels in the luteal phase . however there was a significantly higher level of lh immediately after triggering in the combination group . also the induction of a distinct and significant additional fsh surge has been observed in all patients of the group in which dual triggering took place . as far as the primary endpoint is concerned , there was no significant difference in the number of mii oocytes , neither was there a difference in the number of cocs or in the number of 2pn oocytes . however , as could be expected from the literature ( lin et al . , 2013 ; schachter et al . ,2008 ) there was a significantly higher number of patients with at least one embryo of excellent quality in patients who were triggered by a combination of gnrh agonist and hcg . in the same group , there was also a significantly higher number of patients with frozen embryos and more embryos frozen per patient . in group ii ,132 embryos were frozen versus 91 in group i ( 2.2 versus 1.5 per patient ) . the pregnancy rate in the dual triggering group was lower than that obtained in the group triggered by hcg alone , despite the fact that the number of good quality embryos was significantly lower in the hcg - only triggered group . a possible explanation could be a negative effect on the endometrial receptivity , induced by the higher lh levels and the additional fsh surge . further research is required to analyse these effects . since the combination of hcg and gnrh agonist for triggering appears to have a beneficial effect on embryo morphology , there might be an opportunity for this strategy for final oocyte maturation i.e. especially in patients with repeated poor embryo morphology although a potentially negative effect of this dual triggering on implantation can not be excluded ( fanchin et al . , 2001 ) . therefore vitrification of all oocytes and embryos obtained and replacement of the frozen / thawed embryos in a natural or artificial cycle might be considered ( galindo et al . , 2009 ; griesinger et al . in case of an egg donation program in which all oocytes are vitrified for subsequent use , the combined triggering as used in the current study might be advantageous considering the increase in number of good quality embryos ( griesinger et al . , 2006 ) . however , it should be noted that such a strategy is only acceptable if there is no risk for ohss ( engmann et al . the higher incidence of good quality embryos after dual triggering , a similar on - going pregnancy rate was observed ; future randomized trials are still needed to assess the effect of the observed increase in embryo quality on pregnancy rate . ( 2010 ) concerning spontaneous lh surge and hcg triggering in natural cycles for the replacement of frozen / thawed embryos . in that study , the on - going pregnancy rates after spontaneous lh surge and after hcg triggering were analysed . surprisingly , when hcg was added to a spontaneous lh surge , the pregnancy rate was significantly decreased ( fatemi et al . , 2010 ) . although this study is dealing with a completely different patient population , it shows that hcg in combination with natural lh may have a negative effect on implantation . further research is needed to elaborate whether pregnancy rates are indeed lower after the combined triggering despite the improvement of embryo quality . this research question might be answered very soon when the outcome of the cryopreserved embryos is assessed , since the frozen / thawed cycles are not affected by the potential negative effect of the dual triggering on the endometrium . neither in the group with hcg triggering nor in the dual triggering group one case of ohss was diagnosed . this is remarkable , especially for the dual triggering group , since in most studies concerning gnrh triggering , only low dose hcg ( 1500 iu ) is added after oocyte retrieval in order to avoid ovarian hyperstimulation syndrome . ( humaidan et al . , 2010 ) . in our population 5000 iu hcg was used , but only at the time of triggering . in a randomized population of 120 patients there was no difference in the number of mature oocytes obtained between those patients that had induction of final oocyte maturation by the simultaneous administration of gnrh analogues and hcg , in comparison to the patients in the group that was triggered by the administration of hcg alone . in the group with dual triggering of final maturation of oocytes a significant increase of morphologically excellent embryos accompanied by a significant increase in the number of patients with cryopreserved supernumerary embryos\noutput:\n" }, { "from": "agent", "value": "a prospective randomized controlled trial comparing two groups of icsi ( intra - cytoplasmatic sperm injection ) patients with a different form of triggering the final oocyte maturation has been performed . all patients received an ovarian stimulation for in vitro fertilisation ( ivf ) using an antagonist protocol using recombinant - fsh ( rec - fsh ) and ganirelix . 120 patients were randomized into two groups with similar clinical parameters . the first group had triggering with hcg , whereas the second group received a combination of hcg + gnrh agonist ( gonadotropin releasing hormone ) . as the primary endpoint , the number of metaphase ii oocytes were analysed , the secondary endpoints were the number of cumulus oocyte complexes ( coc ) , the number of fertilized oocytes , embryo morphology , pregnancy rate and the number of cryopreserved embryos . the mean number of mii oocytes in the hcg triggered group was 9.2 compared with 10.3 in the hcg - gnrh agonist group . there was no statistically significant difference in the number of cocs or pregnancy rates . however , the number of patients who received at least one embryo of excellent quality was significantly higher ( p = 0.001 ) in the group with the combined triggering ( 45 out of 61 patients or 73.8 % ) versus the group with hcg triggering alone ( 28 out of 59 patients or 47.5 % ) . the number of cryopreserved embryos was also higher in this group ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: plyometric training ( pt ) consists of dynamic and rapid stretching of muscles ( eccentric action ) immediately followed by a concentric of shortening action of the same muscles and connective tissues ( 1 ) . this training focuses on learning to move from a muscle extension to a contraction in a rapid orexercises are of high - intensity , explosive muscular contractions combining strength and speed for acquisitions of benefits in power . pt involves hops and jumps used to capitalize on the stretch - shortening cycle of the muscle ( 1 ) . the stored elastic energy within the muscle is used to produce more force than can be provided by a concentric action alone . it is distinguished by a rapid deceleration of mass followed immediately by its rapid acceleration in the opposite vertical direction . for the lower limbs , pt entails exercise such as hopping , bounding or drop - jumping ( depth jumping ) from a raised box or platform and immediately jumping vertically after an amortization period of ground contact ( 2 ) . the pt programme typically includes sport - specific exercises including exercises for shoulder and muscles of arms ( 3,4 ) and has traditionally been used for sprinting , jumping , and sports with rapid changes in direction . the adaptability of pt has increased in popularity , thereby proven valuable for application to a range of sports as an effective tool in increasing lower body power ( 5 ) , as measured in several studies using adult subjects ( 6 ) . however , it has been reported that pt may also have negative aspects , particularly in its early phase . high intensity and repetition of eccentric contraction lead to a delayed onset of muscle soreness ( 7 ) . in addition , only athletes who have already achieved a high level of strength through standard resistance training should engage in plyometric drills ( 8 ) . it has been also shown that gains in jump performance following pt were due to change in mechanical properties of muscle - tendon complex more than to muscle activation ( 9 ) . taken altogether these data suggest that pt may constitute a high risk of injury of the youth growth plate ( 6,10 ) and may contraindicate them . additionally , vigorous movements that incorporate sprinting , jumping and throwing actions ( 11,12 ) in pt may be damaging for youth subjects or adult females , even if improvements in balance , coordination and agility and injury prevention after use throughout pre - season training are likely , although the suggestion is less well supported by experimental evidence . nevertheless , data demonstrating the use of pt for developing skill performance in soccer players ( 13 ) , particularly in youth and female players , are available , although there is currenlty little scientific information available regarding whether pt actually enhances skill performance in soccer players . the purpose of this review was to examine the effects of pt on soccer player in young and adult athletes of both genders . primarily used by martial artists , sprinters and high jumpers to improve the performances of athletes , pt has emerged in two forms that have evolved since 1980 . an original version defined as the shock method was created by the russian scientist yuri verkhoshansky , the second version is widely used in the united states ( ? ) . in the first formthis in turn led to a forced eccentric contraction , which was then immediately switched to a concentric contraction as the athlete jumped upward . the landing and take - off were executed in an extremely short period of time ( 0.10.2 sec ) . the shock method is the most effective method used by athletes to improve their speed , quickness , and power after development of a strong strength base . the second version of pyometrics widely used in the united states , relates to doing any form of jump regardless of execution time . this involves jumps that are lower in intensity and execution , while the time required for transitioning from eccentric to the concentric contraction is much greater .1 ) . the first phase is a rapid muscle lengthening movement known as the eccentric phase . the second involves a short resting period known as the amortization phase and , in the third phase , the athlete engages in an explosive muscle shortening movement , termed the concentric phase . the athlete repeats this three - part cycle as rapidly as possible , with the goal being to decrease the amount of time in between the eccentric and concentric movements . reductions of time in between eccentric and concentric movement induce the athlete to become faster and more powerful ( 14 ) as this primarily improves muscular , tendon and nerve functions ( 14 ) . the increase in physical power make athletes run faster , jump higher and hit harder and develop specific skills such as injury protections relative to specific practiced sport ( 15 ) . in addition , the forces involved and the quickness of execution induced the involvement of the central nervous system ( 16 ) . effects of a jump training program on landing mechanics and reduced extremity strength involved in jump sport were tested in female athletes who were compared prior to and after training with male athletes ( 17 ) . these data concurred with previous studies , which also reported a higher incidence of serious knee injury in female participants in jumping sports compared with male participants ( 1823 ) . accordingly , female athletes in jumping sports had significantly more minor and severe injuries , with 18 % of girl injuries being knee - related compared to 10 % boys in high school , and 89 % of surgeries performed on female basketball players were for knee injuries as well as a 4-fold higher incidence of serious knee ligament injuries in female versus male national championship level of volleyball games ( 18 ) . in professional basketball , a two - year study showed that the incidence of knee injuries in female players was 2.2-fold more than that in male players ( 22 ) . these findings suggested that although women were as well trained as their male counterparts , differences in knee injury frequency remained . by contrast , similar total injury rates of the patella and joints ( 24 ) reported for male and female collegiate athletes ( 24 ) or women and men ( 23 ) was attributed to differing levels of training ( 24 ) or sport practiced ( 23 ) and coaching , but not to anatomic or physiologic differences . although studies attributed injury rate differences to structural differences , such as increased joint laxity in women ( 22,24 ) , others refute this claim ( 23 ) . by contrast , authors of two studies argued that estrogen is directly involved in increased injury rates in female athletes ( 19 ) or differences in pelvic structure and lower extremity difference between men and women ( 22,24 ) . notably , jump training programs incorporating stretching , pt exercises and weightlifting have been advocated to increase performance and decrease injury risk in competitive athletes in jumping sports ( 25 ) . pt exercises are also clearly relevant in activities that demand high production and an important component in preparing for performance in a sport where jumping ability and large power output are not the major requirements . for example , in cross - country experienced male runners , in which the explosive strength training replaced 32 % of the conventional training volume ( 26 ) , improvement of their performances over 5 km was associated with the result of incorporating pt into their programmes . improvements were attributed to changes in running economy ( re ; a metric of efficiency commonly defined as submaximal oxygen consumption evaluated in milliliters per minutes per kilogram at a given velocity ( 27 ) that were reflected by reduced oxygen uptake at a fixed exercise intensity . accordingly , any improvement in the re referred to performance improvements because of the decreased oxygen consumption for a given distance , sparing of muscle glycogen , decrease in fatigue , and the ability to sustain higher velocity . this improved economy approach was achieved by means of change in tendon stiffness at the ankle joint caused by weight training ( 9 ) . improvements in the re related to pt exercises have been frequently demonstrated in recreational male and female runners to some extent but not all running speeds , without significant changes in the maximum volume of oxygen consume per unit time ( vo2 max ) ( 28 ) . similarly , in experienced male middle and long distance runners pt improved velocity by 5.7 and 4.1 % , respectively , after pt regimens of 6 and 9 weeks , respectively ( 29 ) . findings supporting the benefits of repeated and intense physical efforts in young subjects and adolescents , thereby improving motor skills and body composition in terms of reducing fat mass and enhanced bone health , particularly if sport practice began early , when subjects were pubescent , have been previously identified ( 3036 ) . these benefits enhance sports performance , and better prepare young athletes for the demands of practice and competition . however , age should be considered for both pre - pubescent and elderly because of hormonal changes , even if it can be concluded that strength training is a relatively safe and healthy practice for children and adolescents . despite earlier concerns regarding the safety and efficacy of youth strength training , children and adolescents should include fitness exercises in their training routine ( 3038 ) . fitness activities may be generated towards the strength , endurance , and flexibility requirements of the specific sport , but should not exclude other components of well - rounded general fitness . plyometrics are intense by nature with a lot of load on joints , tendon and muscles ( 11,12 ) and it is recommended that adding pt exercises to a routine ( 8 ) of an athlete be delayed until strength and flexibility have been built up with regular cardio , weight training and stretching ( 6,10 ) . therefore , plyometrics are not inherently dangerous , but the highly focused and intense movements used in repetition may increase the potential level of stress on joints and musculotendinous units . thus , safety precautions are strong prerequisites to this particular method of exercise . low - intensity variations of pt are frequently utilized in various stages of injury rehabilitation , indicating that the application of proper technique and appropriate safety precautions can make plyometrics safe and effective for many categories of people . authors have previously identified that , female athletes who participate in pivoting and jumping sports are 6-fold more likely to suffer non - contact anterior cruciate ligament injuries compared to male athletes ( 3941 ) . notably , after 8 weeks of pt training , there was alteration of lower limb kinematics and an increased eccentric hip torque and functional performance in young healthy recreational female athletes , compared to controls who carried out no physical training ( 42 ) . these data suggested the necessity to incorporate pt in preventive programs for anterior cruciate ligament injuries . effects of a jump training program on landing mechanics and reduced extremity strength involved in jump sport were tested in female athletes who were compared prior to and after training with male athletes ( 17 ) . these data concurred with previous studies , which also reported a higher incidence of serious knee injury in female participants in jumping sports compared with male participants ( 1823 ) . accordingly , female athletes in jumping sports had significantly more minor and severe injuries , with 18 % of girl injuries being knee - related compared to 10 % boys in high school , and 89 % of surgeries performed on female basketball players were for knee injuries as well as a 4-fold higher incidence of serious knee ligament injuries in female versus male national championship level of volleyball games ( 18 ) . in professional basketball , a two - year study showed that the incidence of knee injuries in female players was 2.2-fold more than that in male players ( 22 ) . these findings suggested that although women were as well trained as their male counterparts , differences in knee injury frequency remained . by contrast , similar total injury rates of the patella and joints ( 24 ) reported for male and female collegiate athletes ( 24 ) or women and men ( 23 ) was attributed to differing levels of training ( 24 ) or sport practiced ( 23 ) and coaching , but not to anatomic or physiologic differences . although studies attributed injury rate differences to structural differences , such as increased joint laxity in women ( 22,24 ) , others refute this claim ( 23 ) . by contrast , authors of two studies argued that estrogen is directly involved in increased injury rates in female athletes ( 19 ) or differences in pelvic structure and lower extremity difference between men and women ( 22,24 ) . notably , jump training programs incorporating stretching , pt exercises and weightlifting have been advocated to increase performance and decrease injury risk in competitive athletes in jumping sports ( 25 ) . pt exercises are also clearly relevant in activities that demand high production and an important component in preparing for performance in a sport where jumping ability and large power output are not the major requirements . for example , in cross - country experienced male runners , in which the explosive strength training replaced 32 % of the conventional training volume ( 26 ) , improvement of their performances over 5 km was associated with the result of incorporating pt into their programmes . improvements were attributed to changes in running economy ( re ; a metric of efficiency commonly defined as submaximal oxygen consumption evaluated in milliliters per minutes per kilogram at a given velocity ( 27 ) that were reflected by reduced oxygen uptake at a fixed exercise intensity . accordingly , any improvement in the re referred to performance improvements because of the decreased oxygen consumption for a given distance , sparing of muscle glycogen , decrease in fatigue , and the ability to sustain higher velocity . this improved economy approach was achieved by means of change in tendon stiffness at the ankle joint caused by weight training ( 9 ) . improvements in the re related to pt exercises have been frequently demonstrated in recreational male and female runners to some extent but not all running speeds , without significant changes in the maximum volume of oxygen consume per unit time ( vo2 max ) ( 28 ) . similarly , in experienced male middle and long distance runners pt improved velocity by 5.7 and 4.1 % , respectively , after pt regimens of 6 and 9 weeks , respectively ( 29 ) . findings supporting the benefits of repeated and intense physical efforts in young subjects and adolescents , thereby improving motor skills and body composition in terms of reducing fat mass and enhanced bone health , particularly if sport practice began early , when subjects were pubescent , have been previously identified ( 3036 ) . these benefits enhance sports performance , and better prepare young athletes for the demands of practice and competition . however , age should be considered for both pre - pubescent and elderly because of hormonal changes , even if it can be concluded that strength training is a relatively safe and healthy practice for children and adolescents . despite earlier concerns regarding the safety and efficacy of youth strength training , children and adolescents should include fitness exercises in their training routine ( 3038 ) . fitness activities may be generated towards the strength , endurance , and flexibility requirements of the specific sport , but should not exclude other components of well - rounded general fitness . plyometrics are intense by nature with a lot of load on joints , tendon and muscles ( 11,12 ) and it is recommended that adding pt exercises to a routine ( 8 ) of an athlete be delayed until strength and flexibility have been built up with regular cardio , weight training and stretching ( 6,10 ) . therefore , plyometrics are not inherently dangerous , but the highly focused and intense movements used in repetition may increase the potential level of stress on joints and musculotendinous units . . low - intensity variations of pt are frequently utilized in various stages of injury rehabilitation , indicating that the application of proper technique and appropriate safety precautions can make plyometrics safe and effective for many categories of people . authors have previously identified that , female athletes who participate in pivoting and jumping sports are 6-fold more likely to suffer non - contact anterior cruciate ligament injuries compared to male athletes ( 3941 ) . notably , after 8 weeks of pt training , there was alteration of lower limb kinematics and an increased eccentric hip torque and functional performance in young healthy recreational female athletes , compared to controls who carried out no physical training ( 42 ) . these data suggested the necessity to incorporate pt in preventive programs for anterior cruciate ligament injuries . effects of a jump training program on landing mechanics and reduced extremity strength involved in jump sport were tested in female athletes who were compared prior to and after training with male athletes ( 17 ) . these data concurred with previous studies , which also reported a higher incidence of serious knee injury in female participants in jumping sports compared with male participants ( 1823 ) . accordingly , female athletes in jumping sports had significantly more minor and severe injuries , with 18 % of girl injuries being knee - related compared to 10 % boys in high school , and 89 % of surgeries performed on female basketball players were for knee injuries as well as a 4-fold higher incidence of serious knee ligament injuries in female versus male national championship level of volleyball games ( 18 ) . in professional basketball , a two - year study showed that the incidence of knee injuries in female players was 2.2-fold more than that in male players ( 22 ) . these findings suggested that although women were as well trained as their male counterparts , differences in knee injury frequency remained . by contrast , similar total injury rates of the patella and joints ( 24 ) reported for male and female collegiate athletes ( 24 ) or women and men ( 23 ) was attributed to differing levels of training ( 24 ) or sport practiced ( 23 ) and coaching , but not to anatomic or physiologic differences . although studies attributed injury rate differences to structural differences , such as increased joint laxity in women ( 22,24 ) , others refute this claim ( 23 ) . by contrast , authors of two studies argued that estrogen is directly involved in increased injury rates in female athletes ( 19 ) or differences in pelvic structure and lower extremity difference between men and women ( 22,24 ) . notably , jump training programs incorporating stretching , pt exercises and weightlifting have been advocated to increase performance and decrease injury risk in competitive athletes in jumping sports ( 25 ) . pt exercises are also clearly relevant in activities that demand high production and an important component in preparing for performance in a sport where jumping ability and large power output are not the major requirements . for example , in cross - country experienced male runners , in which the explosive strength training replaced 32 % of the conventional training volume ( 26 ) , improvement of their performances over 5 km was associated with the result of incorporating pt into their programmes . improvements were attributed to changes in running economy ( re ; a metric of efficiency commonly defined as submaximal oxygen consumption evaluated in milliliters per minutes per kilogram at a given velocity ( 27 ) that were reflected by reduced oxygen uptake at a fixed exercise intensity . accordingly , any improvement in the re referred to performance improvements because of the decreased oxygen consumption for a given distance , sparing of muscle glycogen , decrease in fatigue , and the ability to sustain higher velocity . this improved economy approach was achieved by means of change in tendon stiffness at the ankle joint caused by weight training ( 9 ) . improvements in the re related to pt exercises have been frequently demonstrated in recreational male and female runners to some extent but not all running speeds , without significant changes in the maximum volume of oxygen consume per unit time ( vo2 max ) ( 28 ) . similarly , in experienced male middle and long distance runners pt improved velocity by 5.7 and 4.1 % , respectively , after pt regimens of 6 and 9 weeks , respectively ( 29 ) . findings supporting the benefits of repeated and intense physical efforts in young subjects and adolescents , thereby improving motor skills and body composition in terms of reducing fat mass and enhanced bone health , particularly if sport practice began early , when subjects were pubescent , have been previously identified ( 3036 ) . these benefits enhance sports performance , and better prepare young athletes for the demands of practice and competition . however , age should be considered for both pre - pubescent and elderly because of hormonal changes , even if it can be concluded that strength training is a relatively safe and healthy practice for children and adolescents . despite earlier concerns regarding the safety and efficacy of youth strength training , children and adolescents should include fitness exercises in their training routine ( 3038 ) . fitness activities may be generated towards the strength , endurance , and flexibility requirements of the specific sport , but should not exclude other components of well - rounded general fitness . plyometrics are intense by nature with a lot of load on joints , tendon and muscles ( 11,12 ) and it is recommended that adding pt exercises to a routine ( 8 ) of an athlete be delayed until strength and flexibility have been built up with regular cardio , weight training and stretching ( 6,10 ) . therefore , plyometrics are not inherently dangerous , but the highly focused and intense movements used in repetition may increase the potential level of stress on joints and musculotendinous units . thus , safety precautions are strong prerequisites to this particular method of exercise . low - intensity variations of pt are frequently utilized in various stages of injury rehabilitation , indicating that the application of proper technique and appropriate safety precautions can make plyometrics safe and effective for many categories of people . authors have previously identified that , female athletes who participate in pivoting and jumping sports are 6-fold more likely to suffer non - contact anterior cruciate ligament injuries compared to male athletes ( 3941 ) . notably , after 8 weeks of pt training , there was alteration of lower limb kinematics and an increased eccentric hip torque and functional performance in young healthy recreational female athletes , compared to controls who carried out no physical training ( 42 ) . these data suggested the necessity to incorporate pt in preventive programs for anterior cruciate ligament injuries . a successful performance is dependent on basic abilities , in particular , repeated explosive burst , strength , power , kicking , tackling , and their derivatives such as jumping , turning , sprinting , and changing pace ( 43 ) , all making important contributions to the performance of the soccer player . nevertheless , soccer relies primarily on aerobic metabolic for energy , and it has been suggested that up to 98 % of the total energy expenditure during 90 min of the game play is derived from aerobic metabolism ( 44 ) . aerobic endurance performance in soccer is governed by three interrelated mechanisms including , vo2 max , lactate threshold and re ( 45 ) . the average intensity is high , with a range of 7580 % of vo2 max , despite periods of recovery ( 46,47 ) . consequently , maximal oxygen consumption corresponds to the most important component of aerobic endurance performance in soccer ( 44 ) , and there is evidence that indicates maximal aerobic power correlates with soccer success ( 46,48 ) . accordingly , a plyometric agility training program may increase the percentage of vo2 peak in female soccer players ( 47 ) , increase several muscle powers and endurance measured after a 6 - week pt program in young soccer players ( 49 ) and improve and maintain the soccer kick for ball speed ( 50 ) , thereby confirming the place of pt in skill performance ( 51 ) and decisive determining of neuromechanical training responses in high - level soccer players ( 52 ) . in line with the abovementioned data , strength prior to pt interventionis also an important variable ( 53 ) to consider as men tend to be stronger than women ( 54 ) . additionally , in non - trained individuals , men gain in vertical jump performance compared to women after pt ( 54 ) while similar sprint ( 55 ) and endurance ( 56 ) performance adaptation are reported in men and women after pt . this difference suggests that pt - induced adaptation occurred in men and women independently of the initial performance prior to training ( 57 ) or basal differences in important performance - related hormonal markers ( 58 ) . however , in young ( ~ 21 years ) players with a similar training load and competitive background assigned to training women and men , and control men and women groups , no differences in performance improvement was observed between the pt groups ( 59 ) . the two pt groups improved more in all the performance tests compard to the controls group , suggesting that adaptation to pt does not differ between men and women . in addition , short - term ( 6 weeks ) pt intervention induced higher maximal - intensity exercise and endurance performance improvements compared to soccer training alone , and the improvements induced by pt were not affected by gender ( 60 ) . thus , male and female soccer players with similar competitive background and training load can undergo similar pt programs ( 60 ) . accordingly , pt induced significantly greater kicking distance in a group of adolescent females ( ~ 13 years ) after 14 weeks of training while no significant difference was seen in vertical jump height between the groups at pretest ( 61 ) . pt improved depth vertical jump performance , agility and isometric knee extensor strength ( 62 ) in young soccer players . due to the multifaceted nature of physical requirements in soccer , including strength , endurance , power and agility , soccer training must be able to fulfill the needs of improvement . taken altogether , the data demonstrated a strong ability of pt to transfer and improve specific cardiovascular and neuromuscular fitness . pt induces an increase in vo2 max , maximal strength , sprinting speed , solid kick , endurance , agility , particular soccer player skills and vertical jump ability ( 63 ) in male and female individuals at any age , whether in recreational or professional athletes . in addition , improvements include muscular and tendon strengthening , resulting in the abililty to avoid injuries ( 15 ) . thus , pt must be a part of soccer player training programs as is the case in many types of sports . safety consideration must be taken into account , including , evaluation of the athlete , ensuring facilities and equipment are safe , establishing sport - specific goals , determining program design variables , and teaching the athlete proper technique and properly promoting the program .\noutput:\n" }, { "from": "agent", "value": "plyometric training ( pt ) is a technique used to increase strength and explosiveness . it consists of physical exercises in which muscles exert maximum force at short intervals to increase dynamic performances . in such a training , muscles undergo a rapid elongation followed by an immediate shortening ( stretch - shortening contraction ) , utilizing the elastic energy stored during the stretching phase . there is consensus on the fact that when used , pt contributes to improvement in vertical jump performance , acceleration , leg strength , muscular power , increase of joint awareness and overall sport - specific skills . consequently , pt which was primarily used by martial artists , sprinters and high jumpers to improve performances has gained in popularity and has been used by athletes in all types of sports . however , although pt has been shown to increase performance variables in many sports , little scientific information is currently available to determine whether pt actually enhances skill performance in soccer players , considering that soccer is an extremely demanding sport . soccer players require dynamic muscular performance for fighting at all levels of training status , including rapid movements such as acceleration and deceleration of the body , change of direction , vertical and horizontal jumps , endurance , speed as well as power for kicking and tackling . in this review we discussed the effects of pt on soccer players by considering gender and age categories ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the hallmark feature of parkinson 's disease ( pd ) is degeneration of dopamine neurons in the substantia nigra pars compacta ( snc ) and a consequent striatal dopamine deficiency . current clinic treatments for pd mainly focus on alleviating the symptoms with l -3,4-dihydroxyphenylalanine , which increases the synthesis and release of dopamine ( da ) , particularly during early stages of the disease . as the disease progresses , however , pharmacological therapies can not arrest or reverse neurodegeneration of dopaminergic neurons , and the effectiveness of treatment progressively decreases . previous studies have focused on dopamine restoration in the neurotransmitter - depleted and denervated striatum by introducing essential enzymes for dopamine production , such as tyrosine hydroxylase ( th ) , aromatic l - amino acid decarboxylase ( aadc ) , and guanosine triphosphate ( gtp ) cyclohydrolase i ( gtpc - i ) . this strategy could potentially increase dopamine levels in the striatum and then improve symptoms in pd rat models . actually , the dopamine deficiency in pd leads to a cascade of functional changes in basal ganglia circuitry . the essential pathophysiological characteristic of the pd state is increased neuronal firing activity in the output nuclei of the basal ganglia ( globus pallidus pars interna ( gpi ) and substantia nigra pars reticulata ( snr ) ) leading to excessive inhibition of thalamocortical and brainstem motor systems . this was proposed to arise as a consequence of increased firing in basal ganglia output neurons resulting from reduced inhibition in the direct striatal pathway and increased excitation of subthalamic nucleus ( stn ) consequent to increased activity in striatopallidal gabaergic neurons in the indirect pathway . therefore , it has been proposed that the glutamatergic neurons of the stn can be induced to express gad and thereby change from an excitatory nucleus to a predominantly inhibitory system that releases gaba at its terminal region in the substantia nigra ( sn ) , leading to suppression of firing activity of these sn neurons . as previously reported , subthalamic gad gene therapy strategy results in neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype in a rat model . in that experiment , however , gad65 gene has been delivered to the stn in rats before 6 - ohda - induced degeneration of dopaminergic neurons . therefore , it is not known whether gad65 gene transfer could have restoration for the remnant dopaminergic neurons against neurodegeneration , improve pd symptoms , and may serve as a potential for treatment of pd . the present study uses an adeno - associated virus 2 ( avv2 ) delivery system to introduce hgad65 into the stn in a rat model of pd . fibroblasts are utilized as vector cells to transfer the th gene into the striatum of these rats . disease symptoms were measured , as well as the number of dopaminergic neurons in snc and the vta , and the concentration of glutamic acid and - aminobutyric acid ( gaba ) . in addition , the neurorestoration of the remnant dopaminergic neurons and potential improvements of symptoms were also monitored . the results demonstrate that the combination raav2 - hgad65 and fibroblasts ( th ) strategy provide no neurorestoration for remnant dopaminergic neurons in the snc and vta in this pd model , but it does alleviate some of the symptoms associated with pd . the sprague - dawley ( sd ) rats used in our experiments were from animal center of capital medical university . all methods conformed to the chinese national health and medical research council published code of practice for the use of animal research and was approved by the beijing animal ethics committee . human gad65 was cloned by reverse transcription polymerase chain reaction ( rt - pcr ) from the cerebral cortices of aborted human embryos ( 13 weeks of age ) . permission was obtained from the pregnant women , and this study was approved by the ethics committee of capital medical university ( beijing , china ) . the hgad65 gene was subcloned into the aav - 2 backbone , which contains a cmv enhancer promoter ( stratagene , usa ) . recombinant adeno - associated virus ( raav - hgad65 ) was then packaged and purified . the genomic viral titer was determined using real - time pcr with stocks at a final titer of 110 / ml . rat lungs ( sd , 1 day old ) were removed under aseptic conditions and rinsed in phosphate - buffered saline ( pbs ) solution ( ph 7.4 , 1 % penicillin and 0.5 % streptomycin ) for 5 minutes . pulmonary tissue was separated into 1 - 2 cm cubes and digested with 0.25 % trypsin for 15 minutes at 37c . pulmonary fibroblasts , obtained by centrifugation , were added to culture plates at 310 cells / ml with dulbecco 's modified essential medium ( dmen , containing 10 % fetal bovine serum ) . culture medium was replaced every two days , and cells were plated at 7080 % confluency . fibroblasts were plated at 310 cells / well into a 24 - well plate along with glass coverslips . after 24 hours , 2.010 of raav2 - hgad65 was added to each well in triplicate . after 48 hours , each well was washed with 200 l artificial csf ( 144 mm nacl , 4 mm kcl , 1 mm mgcl2 , 5 mm glucose , 1.5 mm cacl2 , and ph 7.4 ) . then , artificial csf was added to the 24 - well plates ( 100 l / well ) and incubated for 10 minutes prior to collection and analysis of gaba by hplc . subsequently , 4 % paraformaldehyde ( 4c ; sigma , usa ) was added to each well ( 300 l / well ) for 15 minutes , and glass coverslips were rinsed three times with pbs solution ( 1 % triton x-100 , ph 7.4 ) for 5 minutes each . the fibroblasts were plated at 310 cells / well onto a 24 - well plate and the glass slices were put into the 24 - well plate . twenty - four hours later , the fibroblasts were transfected by rad - th or rad vector ( reserved by our department ) based on the protocol of the transfect kit . after rinsed for 2 times by pbs ( ph = 7.2 ) , 2.010 rad - th particles in 200 l dmem ( contain 10 % fbs ) were added to the 24 - well plates , then the fibroblasts were continually cultured in incubator for 12 hours . fibroblasts were continuously cultured in incubator after the medium was changed by 10 % fbs dmem . artificial csf was applied to 24 - well plates ( 100 l / well ) and incubated for 10 minutes before being collected and analyzed . then 4 % paraformaldehyde ( 4c ) was added into each well ( 300 l / well ) for 15 minutes . the glass slices were rinsed for 5 minutes , 3 times , with pbs solution ( 1 % triton x-100 , ph 7.4 ) . then the slices were stored at 4c for immunohistochemistry to detect the efficiency of transfection . a total of 4 l 6 - hydroxydopamine ( 6 - ohda ) ( 0.3 % 6 - ohda , 0.2 % vitamin c , 0.9 % physiological saline ) was injected into the left snc and the medial forebrain bundle ( mfb ) of 190210 g of the male sd rats using the following stereotaxic coordinates : snc : 4.40.1 ap ( from bregma ) , + 1.1 ml , and 7.9 dv , with the incisor bar placed at 2.4 mm below the horizontal zero , mfb : 4.00.1 ap ( from bregma ) , + 0.8 ml , and 8.1 dv , with the incisor bar placed at + 3.4 mm above the horizontal zero . the perfusion rate was 0.8 l / min , and the needle was left in for an additional 15 minutes . all surgeries were performed under chloral hydrate ( 36 mg / kg , i.p . ) anesthesia . apomorphine - induced rotational behaviors were measured using automated rotameter bowls , with tethers attached to the skin of the nuchal region . apomorphine ( 0.1 mg / kg , i.p . ) was administered at 2 weeks after mfb and snc lesioned . rotational behavior was quantified every minute for 40 minutes after allowing the rats to habituate for 5 minutes . rats that exhibited at least seven full cycles per minute , contralateral to the 6 - ohda - lesioned side , were selected for subsequent experiments . rats were randomly administered combination ( raav2 - hgad65 ( intrastn injection ) and fibroblasts ( th ) ( intrastriatal injection ) ) ( n = 6 ) , raav2 - hgad65 ( intrastn injection , n = 6 ) , fibroblasts ( th ) ( intrastriatal injection , n = 6 ) , fibroblasts ( intrastriatal injection , n = 6 ) , raav2 vector ( intrastn injection , n = 6 ) , or pbs ( intrastn injection ) , respectively . raav2 - hgad65 ( 4 l , approximately 410 genomic particles ) plus 1 l 20 % mannitol was unilaterally injected into the stn of 305385 g of the male sd rats using the following stereotaxic coordinates : 3.80.1 ap ( from bregma ) , + 2.50.1 ml , and 7.30.1 dv , with the incisor bar placed at 2.4 mm below the horizontal zero . raav2 - hgad65 particles were injected at a rate of 0.3 l / min , and the needle was left in for an additional 15 minutes . all surgeries were performed under chloral hydrate ( 36 mg / kg , i.p . ) anesthesia . fibroblasts ( th ) ( fibroblasts transfected by rad - th , 10 l , about 110 cells ) were injected unilaterally into the striatum of 305385 g , male sd rats using the following stereotaxic coordinates : + 0.2 ap ( from bregma ) , + 3.00.1 ml , and 6.0 , 5.5 , 5.0 , and 4.0 dv ( 2.5 l / every point ) , with the incisor bar placed at 2.4 mm below the horizontal zero . fibroblasts were infused at the rate of 0.3 l / min , and the needle was left in for an additional 5 minutes at every point . all surgeries were performed under chloral hydrate ( 36 mg / kg , i.p . ) anesthesia . apomorphine - induced rotational behaviors were measured using automated rotameter bowls , with tethers attached to the skin of the nuchal region . apomorphine ( 0.1 mg / kg , i.p . ) was administered at 2 weeks after raav2 - hgad65 , or raav2 vector and pbs injections , every 2 weeks until the rats were sacrificed . rotational behavior was quantified each minute for 40 minutes , once the rats were habituated for 5 minutes . the total number of rotations per minute for a period of 40 minutes was used for analysis . at 4 , 8 , and 16weeks after the injection of the raav2 - hgad65 and / or fibroblasts ( th ) , the pd rats were deeply anaesthetized with chloral hydrate and perfused intracardially with 0.9 % saline , followed by 4 % paraformaldehyde ( 4c ) . the brain was removed and placed into 4 % paraformaldehyde solution for about 4 hours and then transferred into 30 % sucrose solution for 48 hours . serial , coronal , 40 m sections were cut at 20c using a freezing cryostat ( leica , germany ) through the pallidal , subthalamic , and nigral serial levels . sections were blocked with 10 % goat serum and 1 % triton x-100 and then incubated overnight with primary antibody diluted in pbs containing 10 % serum . the following primary antibodies were used : mouse anti - human monoclonal hgad65 ( 1 : 750 , sigma ) and mouse anti - rat monoclonal th ( 1 : 12000 , sigma ) . the secondary antibody was a biotinylated rabbit anti - mouse ( 1 : 500 , vector labs , usa ) , and positive reactions were detected using the vectastain elite abc and dab substrate kits ( vector labs , usa ) . at 4 , 8 , and 16 weeks after the injection of raav2 - hgad65 and / or fibroblasts ( th ) , the pd rats were sacrificed by deep anesthesia with chloral hydrate , followed by intracardial perfusion with 0.9 % saline . the striatum , snr , and gpi tissues were separated from the brains under an anatomical microscope . two - sided paired student 's t - test was used to compare the mean values of the other data . after construction of raav2 - hgad65 , rat fibroblasts were infected with raav2 - hgad65 and empty vector , which were confirmed by immunocytochemistry with antibodies specific to hgad65 ( figure 1 ) . the results of hplc showed that the concentration of the gaba in the supernatant reached 45.666.07 primary rat fibroblasts were cultured from rat lungs and were infected with rad - th and empty vector . expression was confirmed by immunocytochemistry with antibodies specific to th ( figure 2 ) , which indicated that approximately 85 % of the fibroblasts were th - positive . the untransfected fibroblasts were only showed in their morphologic shape ( figure 2 ) . da release was quantified by hplc . the concentration of the da in the artificial csf was about 51.348.28 it showed that the rotation rate significantly decreased ( p 0.01 ) in combination , fibroblasts ( th ) or raav2 - hgad65 groups ( 10.783.51 ) from 2 to 16 weeks after treatment compared with that of pretreatment ( figure 3 ) . from 4 to 16 weeks of after treatment , the rotation rates of raav2 - hgad65 , fibroblasts ( th ) groups , respectively , decreased ( p 0.05 ) compared with their control groups ( fibroblasts , raav2 vector and pbs ) . in addition , the effect of the combination group was better than that of fibroblasts ( th ) or raav2 - hgad65 groups but there was no significant difference between them ( p 0.05 ) . it also shows that the rotation rates of the combination group had decreased by more than 45 % from 4 to 16 weeks after treatment , and their effect continued for 3 months ( p 0.01 ) . the results demonstrated a greater loss of th - positive neurons in the snc and vta ( 90 % loss ) after 4 weeks , compared with the contralateral hemisphere in the all groups ( p 0.001 ) . and there was a decreasing tendency of the loss of th - positive neurons in stn and vta of all groups from 4 weeks to 16 weeks after treatment ( table 1 , figures 4 and 5 ) . at 4 weeks , the loss ratio of th - positive neurons ( snc and vta ) of the combination groups was 90.82 % and a little more than that of the fibroblasts ( th ) , or raav2 - hgad65 groups , but there was no significant difference between them ( p 0.05 ) . it also showed that the loss ratio of th - positive neurons of the combination was not significantly different compared with other groups at 16 weeks ( p 0.05 ) ( table 1 and figure 4 ) . to test the expression of rad - th in the striatum , we analyzed the da levels of the striatum by hplc from at 4 , 8 , and 16 weeks after treatment . the results showed that the da concentration in the striatum of the raav2 - hgad65 group was much lower than that of the rats of the fibroblasts ( th ) group or the combination group ( p 0.001 , table 2 ) . though the datum of the combination group rats was higher than that of the fibroblasts ( th ) group , there was no statistically significant difference between them ( p 0.05 , table 2 ) . the concentration of the da was almost the same as the control groups ( fibroblasts , raav2 vector , and pbs ) ( p 0.05 , table 2 ) . to evaluate raav - mediated gad65 gene transfer , snr and gpi tissues of the rats in all groups at 4 , 8 , and 16 weeks after treatmentthe results showed that gaba concentrations in gpi or snr tissues of the combination group were a little lower than those of fibroblasts - ( th - ) or raav2 - hgad65 - treated groups at 4 , 8 , and 16 weeks after treatment , respectively , but there was not a significant difference between them ( p 0.05 , figures 6 ( a ) and 6 ( b ) ) . the gaba concentrations in gpi or snr of the combination - , fibroblasts - ( th - ) , or raav2 - hgad65 - treated groups were all much lower than those of three control groups ( fibroblasts , raav2 vector , or pbs groups ) , respectively , at 4 , 8 , or 16 weeks after treatment ( p 0.01 ) . in addition , the results displayed that gaba gradually increase from 4 weeks to 16 weeks post - treatment of all groups . the tendency of glutamic acid concentrations was similar to the gaba performance ( figures 6 ( c ) and 6 ( d ) ) . the results of hgad65 immunohistochemistry showed that hgad65 - positive cells were observed in the injected side of the raav2 - hgad65 - treated rats and in the combination - treated rats at 4 , 8 , and 16 weeks after treatment ( figures 7 ( a ) , 7 ( c ) , and 7 ( d ) ) . however , hgad65 was not expressed in cells on the contralateral hemispheres of all groups , or in either ipsilateral hemispheres of the fibroblasts ( th ) group rats ( figure 7 ( b ) ) . the numbers of hgad65 - positive cells of raav2 - hgad65 group ( 703.245.3 , 674.521.5 , and 609.326.7 ) and combination group ( 721.466.7 , 667.232.9 , and 618.545.5 ) were decreased in the time course , but there was no significant difference between them ( p 0.05 ) ( table 3 , figures 7 ( a ) , 7 ( c ) , and 7 ( d ) ) . there was a correlation in time course between the number of hgad65 - positive neurons of stn and glutamic acid or gaba levels of the gpi and snr ( figures 6 and 7 , table 3 ) . it showed that the th - immunoreactive fibroblasts in the striatum were time - dependently reduced from 4 weeks to the 16 weeks after treatment . the th - immunoreactive fibroblasts could be seen in the area surrounding the injection site 4 weeks after the surgery ( figure 8 ( a ) ) . a few of the th - immunoreactive fibroblasts emigrated from the pin holes at 8 weeks after treatment ( figure 8 ( b ) ) , and the fibroblasts could be seen within the pin holes 16 weeks after treatment ( figure 8 ( c ) ) . in the striatum of control group rats ( fibroblasts treated ) , however , there was no th - positive cell around the pin track ( figure 8 ( d ) ) . gaba is the most widely distributed inhibitory neurotransmitter in the vertebrate brain . in addition , the brain contains two isoforms of gaba - synthesizing enzymes , gad65 and gad67 , which differ in molecular size , amino acid sequence , antigenicity , and cellular and subcellular localizations . gad65 functions were executed more as a neurotransmitter maker than does gad67 . in pd , dopaminergic neurons of snc are gradually degenerated for some reasons , leading to marked diminution of the dopamine concentration in the striatum , the primary projection region . the major inhibitory output nuclei of the basal ganglia , snr and gpi , as a result , are overexcited driven by a disinhibited and thereby overactive subthalamic nucleus . this further induces the canonical symptoms of pd , that is , trembling , dyskinesia , rigidity , and so forth . in the present studythe behavioral , immunohistochemical , and neurochemical analyses strongly support the hypothesis that in vivo gene delivery of hgad65 by aav2 ( intrastn - hgad65 ) improves motor symptoms in rat models . hgad65 gene expression , induced by aav2 , led to phenotypic changes in excitation neurons and inhibitory neurons , via enzymatic action from glutamic acid to gaba . these phenotypic changes resulted from inhibition of the neurons of the gpi and snr for the overactivation of subthalamic nucleus in the pd model rats . this method improved motor symptoms by inhibiting the efferent basal ganglial loop ( gpi and snr ) . the present results demonstrate that there is no significant protective function of the surviving dopaminergic neurons in the snc and vta from hgad65 gene expression in the stn . these results are not consistent with previous results , which could be due to the experimental stages . in the previous study , hgad65 gene was injected into the stn , followed by medial forebrain bundle lesion by 6 - ohda . in our study , however , mfb and snc 6 - ohda lesions were followed by hgad65 gene transfer . so it could be more similar to the disease progression in parkinson 's patients than in the previous study . in parkinson 's patients or pd model rats , as previously reported , once dopaminergic neuronal degeneration or necrosis is underway , the latency period could be longer than 10 years . the results here showed that hgad65 gene transfer did not effectively protect surviving dopaminergic neurons in the snc and vta . in addition , it also demonstrated that although the improvement effect of the combination method on the motor symptoms of the pd model rats did better than hgad65 gene transfer and th delivery alone , there is no significant protective function for surviving dopaminergic neurons in the snc and vta . in conclusion , the present study suggests that the methods of hgad65 gene injection into the stn and the combination of the hgad65 gene transfer and th gene therapy into the striatum can improve the phenotype shift of the pd model rats , independently of the protection of the da neurons from death .\noutput:\n" }, { "from": "agent", "value": "the aim of the present study is to detect a combination method to utilize gene therapy for the treatment of parkinson s disease ( pd ) . here , a pd rat model is used for the in vivo gene therapy of a recombinant adeno - associated virus ( aav2 ) containing a human glutamic acid decarboxylase 65 ( raav2 - hgad65 ) gene delivered to the subthalamic nucleus ( stn ) . this is combined with the ex vivo gene delivery of tyrosine hydroxylase ( th ) by fibroblasts injected into the striatum . after the treatment , the rotation behavior was improved with the greatest efficacy in the combination group . the results of immunohistochemistry showed that hgad65 gene delivery by aav2 successfully led to phenotypic changes of neurons in stn . and the levels of glutamic acid and gaba in the internal segment of the globus pallidus ( gpi ) and substantia nigra pars reticulata ( snr ) were obviously lower than the control groups . however , hgad65 gene transfer did not effectively protect surviving dopaminergic neurons in the snc and vta . this study suggests that subthalamic hgad65 gene therapy and combined with th gene therapy can alleviate symptoms of the pd model rats , independent of the protection the da neurons from death ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: preterm birth ( ptb ) , defined as delivery before completing 37 weeks gestation , is a growing global public health problem .1 ptb is the leading cause of mortality in children under 5 years of age ,1 and is a direct cause of at least 27 % of all neonatal deaths .2 of the live births reported in 2010 worldwide , 11.1 % , or 14.9 million , were estimated to be ptbs . in latin america , the estimates indicate that , of the total 10.2 million live births , 8.4 % were preterm .3 while the etiologies of ptb are not yet fully understood , a number of risk factors have been identified . the commonly recognized pathways leading to ptb include infection , inflammation , placental abruption , and maternal / fetal hypothalamic - pituitary - adrenal axis activation due to acute or chronic exposure to psychological stressors .4 maternal psychological stress ( hereafter referred to as stress ) , in the form of acute , chronic , pregnancy - related , or other life event - related stressors , is emerging as an important modifiable social determinant of ptb . investigators have discussed several mechanistically relevant theses concerning the role of stress as a determinant of ptb . for example , stress is known to upset the balance between neuroendocrine and immunological pathways , that may set into motion the events leading to spontaneous preterm labor5 ,6 and preterm premature rupture of membranes . antepartum stress has also been linked to behaviors including substance abuse ,7 mood and anxiety disorders ,8 and underutilization of prenatal care ,9 and these factors have been associated with ptb . research regarding the association between stress and ptb has yielded conflicting results , primarily attributed to varying measures of stress , study design , and underlying risk differences across populations studied and differences in timing and types of stressors . one study evaluating ptb risk in three different ethnic groups living in the us found that stress experienced during pregnancy was the one consistently identified risk factor for all three groups .10 investigators have studied specific types of events , such as experiencing a death , illness , or natural disaster , and found associations with risk of ptb .11,12 a danish study of life events , including physical illness or death of family or children , abuse , problems with partner , problems with the law , and financial stressors , found that it was the woman s overall assessment of stress caused by those life events that was associated with ptb and not the occurrence of specific events .13 studies in europe and south america have shown that the significance and strength of associations of stressful events with ptb varied based on the timing of exposure .1114 some investigators have found that pregnancy - related stress was a better predictor of ptb than general stress ,15 while another study that compiled a stress score based on life events and a general health questionnaire found no association , but suggested that evaluating specific types of life events could be important .16 an accumulating body of evidence has shown that the prevalence of ptb is increasing globally , and this prevalence is expected to increase primarily in low and middle income countries , such as peru .17 given the growing problem of ptb , it is important to explore how maternal stress , which can be defined using numerous measures , such as serious life events , chronic stress , anxiety , depression , or perceived stress ,2 contributes to the problem . this is of vital importance , especially since women living in poverty may be more prone to experiencing these events at a higher frequency and intensity , and they may also suffer higher rates of poor birth outcomes , such as low birth weight and short gestational age .18 to the best of our knowledge , no published work has evaluated the risk of ptb in relation to serious life events among low income peruvian women . a recent study of pregnancy outcomes in peru found that ptb occurred in 12.2 % of women ,19 reflecting the serious need to investigate ptb further . we hypothesized that serious life events experienced during pregnancy are associated with an increased ptb risk among low income women in lima , peru . detailed methods have been described previously .17 this case - control study was conducted among women who delivered live births from january 2009 through july 2010 at the hospital nacional dos de mayo , the instituto nacional materno perinatal de lima , and the hospital edgardo rebagliati martins in lima , peru . the study procedures and protocol were approved by the ethical review boards of the participating institutions . women with singleton pregnancies without any gross malformations who spontaneously delivered before completing 37 weeks of gestation were defined as cases . women from the same hospital , delivering immediately after a case patient and who delivered a singleton infant at term ( 37 weeks of gestation ) were defined as controls . there was no difference in sociodemographic and lifestyle characteristics between the groups of women with prior ptb , a risk factor for consequent ptb . spontaneous ptb cases at participating hospitals were identified by monitoring all deliveries at postpartum wards on a daily basis .17 a total of 515 eligible cases were identified and approached . of those , a total of 479 ( 93 % ) eligible cases agreed to participate in the study . a total of 546 eligible controls were identified and approached , and of those , 480 ( 88 % ) agreed to participate . written informed consent was sought and obtained prior to participation in the study . those who provided informed consent were asked to participate in a 45 - minute in - person interview using a spanish - language structured questionnaire . the questionnaire , administered by experienced and trained research personnel , collected data about maternal sociodemographic , behavioral , reproductive , and medical histories . trained obstetricians ( research fellows ) reviewed labor and delivery medical records as well as prenatal medical records using a standardized abstraction form to collect information about medical and reproductive histories , blood pressure values , any pregnancy complications experienced by the participant , and the condition of the newborn after delivery .17,20 we defined ptb in accordance with the guidelines set by the american college of obstetricians and gynecologists .21 the date of the last menstrual period was used to define gestational age and confirmed by an ultrasound examination before 20 weeks of gestation . ptb cases were categorized based on the three pathophysiological groups previously described , ie , spontaneous preterm labor and birth and preterm premature rupture of membranes .22 spontaneous preterm labor and delivery cases included women whose medical records reported that a physician diagnosed spontaneous labor onset ( with intact fetal membranes ) and delivery occurred prior to completing 37 weeks gestation . preterm premature rupture of membranes cases included women whose medical records reported that a physician diagnosed rupture of fetal membranes ( prior to onset of labor ) and delivery before completing 37 weeks of gestation . when medical intervention was identified as the reason for the woman delivering prior to 37 completed weeks of gestation , she was not eligible for this study .23 preterm birth cases were also further categorized based on gestational age at delivery ( ie , very ptb , defined as those who delivered prior to completing 32 weeks gestation ; moderate ptb , defined as delivering between 32 and 34 weeks gestation ; and late ptb , defined as delivering between 34 and 36 weeks gestation ) . information gathered from the interview included age , marital and employment status during pregnancy , medical history , and substance ( alcohol and cigarette ) consumption during pregnancy . exposure to serious life events during pregnancy was determined by a previously used standard list of life events . the women responded to the questions : over the past 69 months ( during the pregnancy ) , did any of the following life events occur ? the list of events included : death of a first - degree relative or significant other ; divorce or separation from your partner ; fired or forced to change jobs ; financial trouble or bankruptcy ; a serious fight or argument with husband or boyfriend ; and attendance at the wedding of a close friend or relative . response options for each event were : no ; once ; twice ; three or more times . women who responded no to any of these life events were classified as never exposed to any serious life events during their pregnancy . other covariates considered in this analysis included maternal age , reproductive history , and medical history . also considered were maternal prepregnancy weight , educational attainment , annual household income , occupation , cigarette smoking , and alcohol consumption during pregnancy . parity was reported as the number of previous pregnancies lasting more than 22 weeks gestation . using chi - squared tests , we examined the distribution of maternal sociodemographic characteristics , and medical and reproductive histories according to preterm and term delivery status . in order to estimate the association between exposure to serious life events and the risk of ptb , we used logistic regression procedures to calculate maximum likelihood estimates of odds ratios ( ors ) and 95 % confidence intervals ( cis ) that were also adjusted for confounding .24 the following variables were considered as possible confounders : age , marital status , educational attainment , parity , planned pregnancy , prepregnancy weight , use of prenatal care services , employment status , smoking cigarettes , consuming alcohol , and use of illicit drugs during pregnancythese potential confounders were tested individually in a logistic model and the unadjusted and adjusted ors were compared . final logistic regression models included covariates only if their inclusion changed the unadjusted ors by at least 10 % .24 the final models were adjusted for maternal age , prepregnancy weight , pregnancy not planned , and not receiving prenatal care , ie , the variables that met the requirement for inclusion . these procedures were also used in stratified analyses to assess risk of subtypes of ptb ( ie , spontaneous preterm labor and delivery , preterm premature rupture of membranes , very ptb , moderate ptb , and late ptb ) . all reported p - values are two - tailed and cis were calculated at the 95 % level . before beginning the study , we estimated that a study sample size of 400 cases and 400 controls would be sufficient ( 85 % power ) for estimating ors of 2.0 if the exposure frequencies were 10 % , and if we set significance at 0.05 . all analyses were performed using stata version 9.0 statistical software ( stata - corp , college station , tx , usa ) . detailed methods have been described previously .17 this case - control study was conducted among women who delivered live births from january 2009 through july 2010 at the hospital nacional dos de mayo , the instituto nacional materno perinatal de lima , and the hospital edgardo rebagliati martins in lima , peru . the study procedures and protocol were approved by the ethical review boards of the participating institutions . women with singleton pregnancies without any gross malformations who spontaneously delivered before completing 37 weeks of gestation were defined as cases . women from the same hospital , delivering immediately after a case patient and who delivered a singleton infant at term ( 37 weeks of gestation ) were defined as controls . there was no difference in sociodemographic and lifestyle characteristics between the groups of women with prior ptb , a risk factor for consequent ptb . spontaneous ptb cases at participating hospitals were identified by monitoring all deliveries at postpartum wards on a daily basis .17 a total of 515 eligible cases were identified and approached . of those , a total of 479 ( 93 % ) eligible cases agreed to participate in the study . a total of 546 eligible controls were identified and approached , and of those , 480 ( 88 % ) agreed to participate . written informed consent was sought and obtained prior to participation in the study . those who provided informed consent were asked to participate in a 45 - minute in - person interview using a spanish - language structured questionnaire . the questionnaire , administered by experienced and trained research personnel , collected data about maternal sociodemographic , behavioral , reproductive , and medical histories . trained obstetricians ( research fellows ) reviewed labor and delivery medical records as well as prenatal medical records using a standardized abstraction form to collect information about medical and reproductive histories , blood pressure values , any pregnancy complications experienced by the participant , and the condition of the newborn after delivery .17,20 we defined ptb in accordance with the guidelines set by the american college of obstetricians and gynecologists .21 the date of the last menstrual period was used to define gestational age and confirmed by an ultrasound examination before 20 weeks of gestation . ptb cases were categorized based on the three pathophysiological groups previously described , ie , spontaneous preterm labor and birth and preterm premature rupture of membranes .22 spontaneous preterm labor and delivery cases included women whose medical records reported that a physician diagnosed spontaneous labor onset ( with intact fetal membranes ) and delivery occurred prior to completing 37 weeks gestation . preterm premature rupture of membranes cases included women whose medical records reported that a physician diagnosed rupture of fetal membranes ( prior to onset of labor ) and delivery before completing 37 weeks of gestation . when medical intervention was identified as the reason for the woman delivering prior to 37 completed weeks of gestation , she was not eligible for this study .23 preterm birth cases were also further categorized based on gestational age at delivery ( ie , very ptb , defined as those who delivered prior to completing 32 weeks gestation ; moderate ptb , defined as delivering between 32 and 34 weeks gestation ; and late ptb , defined as delivering between 34 and 36 weeks gestation ) . information gathered from the interview included age , marital and employment status during pregnancy , medical history , and substance ( alcohol and cigarette ) consumption during pregnancy . exposure to serious life events during pregnancy was determined by a previously used standard list of life events . the women responded to the questions : over the past 69 months ( during the pregnancy ) , did any of the following life events occur ? the list of events included : death of a first - degree relative or significant other ; divorce or separation from your partner ; fired or forced to change jobs ; financial trouble or bankruptcy ; a serious fight or argument with husband or boyfriend ; and attendance at the wedding of a close friend or relative . response options for each event were : no ; once ; twice ; three or more times . women who responded no to any of these life events were classified as never exposed to any serious life events during their pregnancy . other covariates considered in this analysis included maternal age , reproductive history , and medical history . also considered were maternal prepregnancy weight , educational attainment , annual household income , occupation , cigarette smoking , and alcohol consumption during pregnancy . parity was reported as the number of previous pregnancies lasting more than 22 weeks gestation . using chi - squared tests , we examined the distribution of maternal sociodemographic characteristics , and medical and reproductive histories according to preterm and term delivery status . in order to estimate the association between exposure to serious life events and the risk of ptb , we used logistic regression procedures to calculate maximum likelihood estimates of odds ratios ( ors ) and 95 % confidence intervals ( cis ) that were also adjusted for confounding .24 the following variables were considered as possible confounders : age , marital status , educational attainment , parity , planned pregnancy , prepregnancy weight , use of prenatal care services , employment status , smoking cigarettes , consuming alcohol , and use of illicit drugs during pregnancy . these potential confounders were tested individually in a logistic model and the unadjusted and adjusted ors were compared . final logistic regression models included covariates only if their inclusion changed the unadjusted ors by at least 10 % .24 the final models were adjusted for maternal age , prepregnancy weight , pregnancy not planned , and not receiving prenatal care , ie , the variables that met the requirement for inclusion . these procedures were also used in stratified analyses to assess risk of subtypes of ptb ( ie , spontaneous preterm labor and delivery , preterm premature rupture of membranes , very ptb , moderate ptb , and late ptb ) . all reported p - values are two - tailed and cis were calculated at the 95 % level . before beginning the study , we estimated that a study sample size of 400 cases and 400 controls would be sufficient ( 85 % power ) for estimating ors of 2.0 if the exposure frequencies were 10 % , and if we set significance at 0.05 . all analyses were performed using stata version 9.0 statistical software ( stata - corp , college station , tx , usa ) . we found that cases and controls were similar with regards to a number of characteristics , ie , the mean maternal age was 28 years , approximately 40 % of the women were primiparous , about 67 % had a high school education or less , and 40 % were employed during their pregnancy . compared with controls , cases were less likely to have planned the pregnancy , taken prenatal vitamins , and less likely to have received prenatal care . unadjusted and adjusted ors of ptb according to maternal exposure to serious life events during pregnancy are summarized in table 2 . adjustment was made for confounding by including maternal age , prepregnancy weight , unplanned pregnancy , and not receiving prenatal care in the final logistic regression model . compared with women who did not experience any serious life events during pregnancy , the odds of ptb were increased more than two - fold for women who experienced the following events : death of a first - degree relative ( adjusted or 2.10 ; 95 % ci 1.383.20 ) , divorce or separation ( adjusted or 2.09 ; 95 % ci 1.104.00 ) , financial troubles ( adjusted or 2.70 ; 95 % ci 1.853.94 ) , or a serious fight with their partner ( adjusted or 2.40 ; 95 % ci 1.783.17 ) . as the total number of events experienced during pregnancy increased , the odds of ptb also increased ( p for trend 0.001 ) . for instance , women who experienced three or more serious life events during pregnancy had a 3.62-fold ( adjusted or 3.62 ; 95 % ci 2.086.29 ) increased odds of delivering preterm compared with women who experienced no events during pregnancy . the adjusted ors of preterm subtypes , spontaneous preterm labor , and preterm premature rupture of membranes , according to maternal exposure to serious life events , are shown in table 3 . compared with women who did not experience any serious life events during pregnancy , the odds of spontaneous preterm labor and of preterm premature rupture of membranes increased by 2.5-fold and 2.0-fold , respectively , for women who experienced the death of a relative or significant other , a divorce or separation , financial troubles , or a serious fight with their partner . compared with women who did not experience any serious life events , experiencingbeing fired or forced to change jobs or the wedding of a close relative or friend were associated with an increased odds of spontaneous preterm labor , but the associations did not reach statistical significance . women who experienced any serious life events had 2.29-fold higher odds ( adjusted or 2.29 ; 95 % ci 1.653.18 ) of experiencing spontaneous preterm labor and 2.19-fold higher odds ( adjusted or 2.19 ; 95 % ci 1.563.08 ) of experiencing preterm premature rupture of membranes compared with women who did not experience any such life events during pregnancy . those who experienced two events during the study pregnancy had a 2.73-fold higher odds ( adjusted or 2.73 ; 95 % ci 1.764.26 ) of spontaneous preterm labor and a 2.89-fold higher odds ( adjusted or 2.89 ; 95 % ci 1.854.53 ) of preterm premature rupture of membranes . women who experienced three or more events had a 4.26-fold higher odds ( adjusted or 2.26 ; 95 % ci 2.268.03 ) of spontaneous preterm labor and a 3.16-fold higher odds ( adjusted or 3.16 ; 95 % ci 1.636.14 ) of preterm premature rupture of membranes , compared with women who experienced no such events . the risk of very ptb ( 32 weeks ) , moderate ptb ( 3233 weeks ) , and late ptb ( 3436 weeks ) in relation to maternal exposure to serious life events is shown in table 4 . women who experienced the following life events : death of a first - degree relative or significant other , financial trouble or bankruptcy , or a serious fight with their partner , had higher odds of very ptb , moderate ptb , and late ptb . experiencing a divorce or separation or experiencing a wedding of a close friend or relative was associated with increased odds of late ptb ( adjusted or 2.35 ; 95 % ci 1.164.76 and adjusted or 1.59 ; 95 % ci 1.062.40 , respectively ) . compared with women who experienced no such events , those who experienced more than one serious life event had higher odds of ptb and the strength of association increased with increased occurrence of serious life events ( ptrend 0.001 ) . women in our study who experienced serious life events during pregnancy were more likely to deliver preterm . our analysis identified specific serious life events that were associated with ptb , and we also showed a linear relationship for the association of ptb with number of serious events experienced during pregnancy . our findings are consistent with the results of studies that evaluated serious life events with ptb10 ,25 and differ from studies that found significant associations only when analyzing specific timing of exposure to an event during pregnancy11 ,14,26 and those where the associations did not reach significance .7,16,27,28 studies identifying serious life events have typically been carried out in developed countries or among minority populations in the us . to the best of our knowledge , this is the first study examining the association of serious life events with ptb among peruvian women . of the events included in our analysis , experiencing the death of a first - degree relative , separation or divorce , arguing or fighting with a partner , and financial troubleswere each shown to significantly increase the odds of ptb for the women by more than two - fold . this pattern held true for preterm subtypes , spontaneous preterm labor , and preterm premature rupture of membranes . investigators in a us cohort study of african american and american indian women reported that women identified partner - related , finance - related , and trauma - related items to be stressful . however , the authors found no evidence of a statistically significant association between the stress constructs evaluated and ptb risk .7 there are a number of events that could be used as a measure of stress , but generally an event can be considered stressful if it is a challenge , whether physical or psychological , that threatens to alter the homeostasis of the individual .2 the three types of life events , ie , death of relative , partner troubles , and financial troubles , we found to be associated with ptb have been the focus of other studies . a population - based study of 2.6 million pregnancies in sweden examined the association of stress , as defined by having a family member die during pregnancy , and found that the risk for ptb was elevated when the event occurred during the 5th and 6th month of pregnancy ( or 1.24 ; ci 99 % 1.081.42 ) .11 in denmark , a population - based study of 1.38 million singleton live births assessed death or serious illness of a first - degree relative as the exposure and found that there was a significant association with birth weight but not with ptb .12 partner - related serious life events were considered in a german study . the investigators found in a sample of 589 pregnant women that those who felt they were in a very unhappy partnership had twice as many ptbs compared with women who reported being in a happy partnership ; 29 however , due to small numbers , the results did not reach statistical significance . an integrative review aimed at identifying studies regarding the association between economic contraction ( ie , loss of employment , reduced income ) and birth outcome found that socioeconomic stressors were more strongly and consistently associated with birth weight . however , there was little to no evidence supporting associations of socioeconomic stressors with ptb .30 another important point that merits consideration is that the standard list of events included experiencing the wedding of a close relative or friend , which is typically considered to be a positive experience . however , in a setting such as lima , peru , where culturally the family ties are strong ,31 weddings place additional stress and consume resources from the entire family . demand on resources , such as time and money , we also found a significant linear increase in odds of delivering preterm with an increase in number of events experienced during pregnancy . similarly , a prospective study carried out in the people s republic of china in 2008 evaluated the effects of maternal exposure to serious life events , included financial , emotional , traumatic , and spousal - related events . after adjustment for confounders , the authors reported an increased risk of ptb , with increasing numbers of life events during the first and second trimesters .26 experiencing more than one serious life event during pregnancy may impact ptb in part due to the cumulative effect of stress8 or may be due to the increased chance that any one of the events will occur at a time period when the pregnancy is more vulnerable to stress . discussions around the timing and number of events occurring during pregnancy indicate that studies should also examine the type of psychosocial stress and perceived stressfulness of events experienced , as well as the cumulative impact of lifelong , chronic stress .27,32 our results , combined with those described previously , highlight the importance of investigating the association of serious life events with ptb , which is a growing public health concern . these results suggest that the risk of ptb may increase in women who experience one or more serious life events while pregnant . future work should include prospective studies to explore the type and intensity of such events in order to understand the magnitude of maternal stress experienced . stress is thought to be involved in inducing preterm labor via behavioral pathways , such as poor nutrition or poor prenatal care .32,33 stress may induce ptb via the physiological responses mediated by stress hormones and neurotransmitters .34 one pathway is related to cortisol , the hormone released by the hypothalamic pituitary gland in response to stress , which is also the hormone involved in normal parturition .34 as levels of cortisol rise , they prepare the physiological mechanisms for release of oxytocin , the hormone responsible for uterine contractions , and rising levels of cortisol due to experiencing stress may lead to an early rise in oxytocin , which in turn , may lead to early labor and delivery .33 future research is needed to establish the biological pathway from stress to ptb , with a specific focus placed on understanding independent and interactive effects of exposures to stressors and genetic determinants of ptb among women in low , middle , and high income countries . first , its cross - sectional nature prevents inference on any causal relationship between experiencing serious life events and ptb . the interview was conducted after delivery , allowing for possible recall bias regarding the events experienced . second , the list of stressful life events may not have captured all possible serious life events , and we could not account for reverse causality in some items ( ie , due to a difficult pregnancy , the woman may have been forced to change jobs or leave her job ) . third , there was the possibility of substantial heterogeneity among the different types of serious life events . it is possible that the grouping of different types of life events in a single composite score might have attenuated the magnitude of the association towards the null . future studies need to evaluate the impact of frequency , timing , and severity of serious life events on ptb . additionally , the list of events is appropriate primarily for women who are able to have the experiences in the list , such as being family - centered and engaged in traditional partnerships . this list does not capture the serious events for women living beyond the range of these experiences . finally , although we adjusted for confounding factors , we can not exclude the possibility of some residual confounding by unmeasured factors . experiencing serious life events during pregnancy was associated with increased risk of ptb among peruvian women . interventions aimed at identifying and assisting women who are experiencing serious life events may reduce the risks of ptb . future studies should consider perceived stress , exposure to stressors across the life course , and available social support that could mitigate the impact of such stress . studies should also include objective measures of stress and the stress response to understand better the biological underpinnings of the observed associations .\noutput:\n" }, { "from": "agent", "value": "backgroundthe purpose of this study was to examine the risk of preterm birth ( ptb ) in relation to serious life events experienced during pregnancy in peruvian women.methodsthis case - control study included 479 ptb cases and 480 term controls . in - person interviews asked information regarding sociodemographics , medical and reproductive histories , and serious life events experienced during pregnancy . multivariate logistic regression procedures were used to estimate adjusted odds ratios ( ors ) and 95 % confidence intervals ( cis ) . resultscompared with women who did not experience a serious life event during pregnancy , those who experienced the following life events had a more than two - fold increased odds of ptb : death of first - degree relative ( adjusted or 2.10 ; 95 % ci 1.383.20 ) , divorce or separation ( adjusted or 2.09 ; 95 % ci 1.104.00 ) , financial troubles ( adjusted or 2.70 ; 95 % ci 1.853.94 ) , or serious fight with partner ( adjusted or 2.40 ; 95 % ci 1.783.17 ) . women who experienced any serious life events during pregnancy had higher odds ( adjusted or 2.29 ; 95 % ci 1.653.18 ) of suffering spontaneous preterm labor and preterm premature rupture of membranes ( adjusted or 2.19 ; 95 % ci 1.563.08 ) , compared with women who did not experience any such events . associations of similar directions and extent were observed for severity of ptb ( ie , very , moderate , or late ptb ) . the magnitude of the associations increased as increased frequency of serious life events ( ptrend < 0.001 ) . conclusionexperiencing serious life events during pregnancy was associated with increased odds of ptb among peruvian women . interventions aimed at assisting women experiencing serious life events may reduce the risk of ptb . future studies should include objective measures of stress and stress response to understand better the biological underpinnings of these associations ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: root resorption is a multifactorial process that is classified as internal or external according to location . internal root resorption is less common and occurs isolatedly as a result of chronic inflammation or pulpal infection , orthodontic movement , herpes zoster , or idiopathic factors . external root resorption has several causes , such as mechanical stimulation , inflammatory conditions , luxation injuries , and neoplastic conditions . external root resorption has been also reported to occur in some endocrine disturbances and systemic conditions such as hypoparathyroidism , hyperparathyroidism , hypocalcemia , gaucher 's disease , paget 's disease , hypophosphatemia , stevens johnson syndrome , odontodysplasia , dentin dysplasia , and dentinogenesis imperfect . irr is infrequent and was first reported by mueller and rony in 1930 in a 37 - year - old female . several cases related to irr in permanent dentition have been reported in the literature but cases reported in primary dentition are very few [ table 1 ] . therefore , the aim of this review is to report a case of bilateral external irr of second primary molars in a 7 - year - old patient . reported cases of idiopathic root resorption irr is an infrequent type of root resorption that can occur in both the cervical and apical regions of the tooth . according to most case reports , it seems that this type of root resorption is more frequent in young females . according to the results of this survey , in most reported cases , only a single tooth was affected and in 19 of 179 cases , more than one tooth was involved . massler and perreault , in a study of 301 patients with irr in at least four teeth , reported that this type of root resorption is mostly found in the maxillary premolars and mandibular incisors and molars exhibiting the least resorption . liang et al . reviewed the literature on multiple idiopathic root resorption ( mirr ) and found that all cases were asymptomatic and that mirr was usually detected incidentally on routine radiographs . however , some patients have reported cold sensitivity , loss of restorations , tooth mobility , and tenderness in the surrounding gingival tissues or involved teeth . in 1989 , two 14 - year , 7 - month - old black females were referred to a dental clinic . clinically and radiographically , no carious lesions were noted , but root resorption was found in all posterior mandibular teeth and maxillary premolars on panoramic radiographs . because no possible etiologic factor was found , a diagnosis of mirr was made for both patients . although local environmental factors can not be completely ruled out , on the basis of this case report and the newman study , it seems that genetic factors may also be involved in the pathogenesis of this condition . however , in most case reports and in the case of this study , no familial history of root resorptionis reported . in a large series of case reports of irr , stafne and slocumb failed to find any correlation between this type of root resorption and any specific systemic conditions . kim and heffez reported a case of mirr in the primary teeth of a 7 - year - old girl who was referred because of early shedding of multiple primary teeth . in her medical history , the parents did not report any systemic disease except for congenitally missing middle ear ossicles . irr is an infrequent type of root resorption that can occur in both the cervical and apical regions of the tooth . according to most case reports , it seems that this type of root resorption is more frequent in young females . according to the results of this survey , in most reported cases , only a single tooth was affected and in 19 of 179 cases , more than one tooth was involved . massler and perreault , in a study of 301 patients with irr in at least four teeth , reported that this type of root resorption is mostly found in the maxillary premolars and mandibular incisors and molars exhibiting the least resorption . liang et al . reviewed the literature on multiple idiopathic root resorption ( mirr ) and found that all cases were asymptomatic and that mirr was usually detected incidentally on routine radiographs . however , some patients have reported cold sensitivity , loss of restorations , tooth mobility , and tenderness in the surrounding gingival tissues or involved teeth . in 1989 , clinically and radiographically , no carious lesions were noted , but root resorption was found in all posterior mandibular teeth and maxillary premolars on panoramic radiographs . because no possible etiologic factor was found , a diagnosis of mirr was made for both patients . although local environmental factors can not be completely ruled out , on the basis of this case report and the newman study , it seems that genetic factors may also be involved in the pathogenesis of this condition . however , in most case reports and in the case of this study , no familial history of root resorptionis reported . in a large series of case reports of irr , stafne and slocumb failed to find any correlation between this type of root resorption and any specific systemic conditions . kim and heffez reported a case of mirr in the primary teeth of a 7 - year - old girl who was referred because of early shedding of multiple primary teeth . in her medical history , the parents did not report any systemic disease except for congenitally missing middle ear ossicles . a 7 - year - old boy was referred to pediatric department of mashhad dental school because of severe mobility in the second primary left mandibular molar . on evaluation of his medical history , laboratory findings , which included a complete blood cell count and electrolyte , calcium , phosphorus , and alkaline phosphatase values , were normal . his oral hygiene was excellent , and there was no abnormal finding on extraoral and intraoral examination except for class ii malocclusion [ figure 1 ] . the patient was caries - free and had no parafunctional habits such as bruxism and no wear facets , or premature contacts were detected ; the only chief complaint was increased mobility of the lower left second molar . there was no family history of early exfoliation of primary teeth , abnormal root resorption or spontaneous loss of permanent teeth . there was no history of hypersensitivity of the patient 's teeth to thermal stimuli , spontaneous pain , or pain with mastication . intraoral examination showed no abnormal findings except for increased mobility of the left second lower molar ( the tooth was removed prior to photography ) . ( a ) frontal view of patient 's occlusion ( b ) occlusal view of mandibular arch ( c ) occlusal view of maxillary arch an orthopantomogram ( opg ) x - ray was taken for thorough evaluation of the patient 's dentition , and posteroanterior ( pa ) views were obtained for a more detailed examination of the affected tooth . on radiographic examination , there was no sign of caries or any other abnormal finding except root resorption in both of the second mandibular molars . opg and pa views showed extensive root resorption of the left second mandibular molar and mild external root resorption of the right second mandibular molar [ figure 2 ] . ( a ) orthopantomogram x - ray showed severe inflammatory root resorption of left second mandibular molar and mild replacement of root resorption of right mandibular molar . ( b and c ) posteroanterior x - rays of affected areas on clinical examination , the color and texture of the gingival tissue around the involved teeth were normal . except for the right mandibular primary second molar that had severe mobility , the mobility of the other teeth was within normal range . the pulp test revealed pulp vitality of the right mandibular primary second molar , but we could not test the left affected tooth because as we were taking the familial history , the patient wiggled and pulled the tooth out with his hand . on macroscopic examination of the exfoliated second molar , the roots were thoroughly resorbed , and the caries - free crown was undermined [ figure 3 ] . gross examination of exfoliated left mandibular molar showing a complete root resorption and undermined crown with resorbed dentin and intact thin enamel . ( a ) occlusal view of exfoliated crown ( b ) internal view of exfoliated crown histological evaluation of the exfoliated tooth was impossible due to complete resorption of roots , but histological evaluation of the soft tissue removed from the socket of the exfoliated tooth showed nonspecific chronic inflammation [ figure 4 ] . langerhans cells were found on microscopic examination , so immunohistochemical staining with cd1a was performed . however , a negative result for this test ruled out langerhans cell disease . ( c ) cd1a staining ( negative ) on the basis of the history , oral examination , and radiographic evaluation , and because there was no specific cause for this condition , a diagnosis of localized irr was made , and after placement of a band and loop space maintainer , the patient was followed for 18 months [ figure 5 ] . there were no abnormal signs or symptoms in the follow - up visit in the follow - up period over 18 months , the right involved tooth was clinically asymptomatic ; hence , the patient 's father did not agree to take new pa radiographs to determine if there was any progression of the root resorption . cervical irr begins in the cementoenamel junction area of the teeth , exhibiting an irregular radiolucency initiating in the periodontal ligament ( pdl ) on radiography . in the apical types , the resorption starts apically and progresses coronally and radiographicallyis characterized by gradual shortening and rounding of the remaining root , caused by replacement of the root with normal - appearing trabeculated bone , but ankylosis ( fusion of tooth to bone ) does not occur and the pdl space is usually visible throughout the entire root surface except for the most apical part . apical irr has been reported more frequently in males while cervical irr is more common in females . the localized type irr is defined as one to three posterior teeth while the multiple type occurs in more than three teeth ; eventually , most of the dentition is involved in a symmetric pattern . in the multiple tooth cases , the process usually progresses and eventually may lead to the loss of several teeth , while the localized types appear to be self - limiting . however , this is not always the case . in our patient , despite root resorption being localized , it had progressed to the point that the left mandibular primary second molar could be removed by hand . furthermore , in 2005 , iwamatsu - kobayashi et al . reported a case of multiple cervical irr with no progression during the follow - up period . hopkins and adam reported that the interproximal areas appeared to be involved more severely than the buccal and lingual aspects . a higher level of attachment or a higher level of pdl activity in this region may be a possible etiologic factor for these findings . lindskog and hammarstrm have shown that precementum has anti - collagenase factors that can prevent the enzymatic destruction of this tissue . consequently , it is suggested that any trauma to the cervical area or developmental defects such as hypoplasia or hypomineralization of the cementum can be considered etiologic factors for cervical irr . however , in this case , there was no history of trauma in the affected regions . in the absence of occlusal functionelimination of the cushioning effect of the pdl can lead to increased occlusal stress to the tooth and can induce inflammation . followingit has been suggested that a long - term hypofunctional condition may be a possible etiological factor in root resorption . the process of root resorption involves a complex interaction of inflammatory cells , resorbing cells , hard tissue , cytokines , and enzymes . therefore , any factor that incites the inflammatory process may initiate the process of root resorption . furthermore , it has been reported that the process can result from acute microbiologically induced osteoclastic activation . histological examination of any soft tissue or bone removed from this type of root resorption represents nonspecific chronic inflammation . in the histological evaluation of tissue removed from the socket in our case , nonspecific chronic inflammation was evident . langerhans cells were also observed on the initial microscopic evaluation , but after immunohistochemical staining with cd1a , langerhans cell disease was ruled out . however , in the affected right molar , it seems that there was replacement root resorption . we can speculate that there was replacement root resorption at the affected left tooth first , and after mobility was increased to some extent so that bacteria could penetrate into the pdl , it was contaminated by microorganisms and , therefore , became infection - related resorption . although many treatments have been proposed to arrest the process of irr and a number of these methods have been reported useful in animal studies , none of these treatment options are effective clinically in humans , and no interceptive therapeutic regimens are fully indicated . however , based on presented case reports , treatment options , depend on symptoms , and the extension and severity of root resorption , include : observation , endodontic therapy ( in cases with pulpal involvement or cases with root resorption near the pulp ) , curettage , restoration of cervical lesions and extraction . in general , a patient with an abnormal pattern of root resorption , especially in the primary dentition , should alert the clinician to rule out all important causes of resorption . more studies\noutput:\n" }, { "from": "agent", "value": "idiopathic root resorption ( irr ) is an infrequent condition that is usually found as an accidental finding on radiography . a significant number of cases of irr in permanent dentition have been presented but are rarely reported in primary dentition . the aim of this case report is to present a case of localized irr in a 7 - year - old boy . the patient was referred because of increased mobility of the left mandibular primary second molar . on radiographic evaluation , severe root resorption of that tooth , and mild root resorption of the right mandibular primary second molar were evident ; the patient was caries - free . the left affected tooth was lost , and after placing a band and loop space maintainer , the patient was followed for 18 months . a patient with an abnormal pattern of root resorption , especially in the primary dentition , should alert the clinician to rule out the known important local and systemic factors . the exact causes of and treatments for irr continue to be discovered ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: there is considerable evidence from epidemiological research , meta - analysis , and prospective clinical trials to support an independent role for fasting and postprandial plasma triglycerides ( tg ) as a risk factor for cardiovascular disease ( cvd ) . increased plasma remnants of triglyceride - rich lipoproteins ( trls ) , caused by delayed elimination of the same , has been shown to be prospectively associated with angiographic evidence of atherosclerosis and cardiac events . postprandial hypertriglyceridaemia is associated with two other well established cardiovascular risks ir and obesity both of which are prevalent in pcos . an increase in postprandial lipoproteins is often found in ir states and hyperinsulinaemia itself appears to delay and exacerbate postprandial accumulation of intestinally derived chylomicrons . obesity , especially visceral adiposity , also contributes to a magnified postprandial tg response . postprandial hypertriglyceridaemia may be a plausible mechanism by which pcos increases cardiovascular risk . whilst numerous studies have investigated plasma lipid profile under fasting conditions in women with pcos , few have investigated changes in the postprandial setting . in a previous study by velzquez m et al . a strong positive correlation between postprandial tg and increasing waist - to - hip ratio ( whr ) was demonstrated . that study evaluated overweight ( bmi 27.410.50 kg / m ) pcos women and compared them to lean pcos women and lean control subjects . there were no obese controls and there was no analysis of the influence of androgens on postprandial hypertriglyceridaemia . a separate study by bahceci et al . evaluated postprandial responses to an oral fat tolerance test , comparing lean pcos women with lean controls ( bmi 23.52.6 kg / m versus 23.14.0 kg / m ; p 0.05 ) they showed that pcos women had higher baseline insulin levels , ir as assessed by homeostatic model assessment - ir ( homair ) , auc - tg , auc - total - cholesterol , auc - very - low - density lipoprotein cholesterol ( auc - vldl - chol ) , and auc - apob . surprisingly , though , auc - insulin did not differ between the two groups . as with the study by velzquez m et al . it is also unclear whether postprandial hypertriglyceridaemia is mainly due to the contribution of intestinally derived apob - 48 containing chylomicrons or hepatically derived apob - 100 containing vldl particles . both vldl and chylomicrons share a common lipolytic pathway and are hydrolysed by lipoprotein lipase ( lpl ) , an enzyme predominantly found on the endothelial surfaces of the capillaries of adipose tissue , heart , and skeletal muscle . there are a number of described receptor mediated pathways through which these particles may eventually be cleared from the circulation . traditionally it has been difficult to assess what proportions of trls are chylomicrons and vldl . however , using elisa , it is now possible to directly measure the quantity of apob - 48 and hence chylomicron particles , in whole plasma . we sought to investigate whether the postprandial glucose and insulin and lipid and lipoprotein responses , including that of apolipoprotein b - 48 ( apob - 48 ) containing chylomicrons , to a mixed meal are different in obese pcos women when compared to obese control subjects and whether differences , if any , are related to obesity , insulin resistance ( ir ) , hyperandrogenaemia , or pcos status . fifty - two obese premenopausal women with ( n = 26 ) and without ( n = 26 ) pcos were recruited . women with pcos were recruited from the endocrinology outpatient clinics ( tallaght hospital , dublin , ireland ) . pcos was defined according to the national institute of health ( nih ) criteria as chronic oligomenorrhea ( fewer than nine menstrual cycles per year ) and clinical and / or biochemical evidence of hyperandrogenism , in the absence of other disorders causing the same phenotype . clinical criteria included hirsutism with a ferriman - gallwey score greater than 9 , acne , or male pattern alopecia ; biochemical criteria included total testosterone , androstenedione , or dehydroepiandrosterone sulphate ( dheas ) greater than the laboratory reference range . all normal subjects were eumenorrheic with testosterone levels within the normal range and were studied in the follicular phase of the menstrual cycle . subjects were excluded if they were younger than 18 years old or older than 45 years old ; were non - caucasian , pregnant , or lactating ; had a recent or chronic illness or medication likely to influence results ; or were taking any medications likely to influence the results including hormonal contraception , antihypertensives , lipid - lowering medications , and antiplatelet or anti - inflammatory agents . fourteen women in the pcos group and 3 women without pcos had a first - degree relative with type 2 diabetes mellitus . all study subjects gave their written signed consent to the study , which was approved by the research ethics committee of tallaght hospital and st . all subjects had their height measured with a harpenden stadiometer and weight measured in light clothing . waist circumference ( wc ) and hip circumference ( hc ) were measured with a nondistensible flexible tape , and whr was calculated accordingly . all subjects also underwent estimation of body composition including percentage body fat ( % bf ) and percentage lean mass ( % lm ) using bioimpedance analysis using the bodystat 1500 system ( bodystat ltd . , uk ) . subjects attended the clinical investigation unit after a 12 - hour overnight fast and were requested to refrain from vigorous exercise and alcohol on the day prior to their fsivgtt . on the morning of the fsivgtt , two cannulae were inserted into the antecubital veins of both forearms . then a bolus of 50 % glucose solution ( 0.3 g / kg body weight ( bw ) ) was infused into cannula 2 over a 1 - minute period followed by 20 ml of 0.9 % saline . twenty minutes later , a dose of insulin ( 0.03 u / kg bw ) was infused into the same cannula ( cannula 2 ) , which was then removed at 30 min after initiation of glucose administration . meanwhile , blood was sampled through cannula 1 at frequent intervals over a 3 - hour period ( 5 , 0 , 2 , 4 , 8 , 19 , 22 , 30 , 40 , 50 , 70 , 90 , and 180 min after the start of the glucose injection ) for determination of glucose and insulin at each time point . blood samples were spun at 3000 rpm for 10 min after which the plasma was aliquoted and stored at 80c until required for future analysis . insulin sensitivity ( si ) , glucose effectiveness ( sg ) , acute insulin response ( airg ) , and disposition index ( di ) were estimated using the minmod computer program ( version 3.0 , copyright r. n. bergman ) . following a 12 - hour overnight fast , subjects came to the clinical investigation unit in tallaght hospital for blood sampling and a high calorific meal .48 % of the total calories were derived from fat ( 20 % saturated , 16 % monounsaturated , and 8 % polyunsaturated ) .36 % and 15 % of the calories were derived from carbohydrate and protein , respectively . bloods were taken at 2 , 4 , 6 , and 8 hours after ingestion of the meal . subjects were advised to restrict their physical activity to the minimum until the end of the sampling period . glucose was measured by an enzymatic ( hexokinase ) method on the roche p module ( roche , stockholm , sweden ) and insulin was measured by electrochemiluminescence immunoassay on the roche e module ( coefficients of variation ( cvs ) 5 % for both ) . nonesterified fatty acids ( nefa ) were measured by a kit using the randox colorimetric method ( randox , antrim , uk ) and analyzed on a hitachi modular analyzer ( tokyo , japan ) ( cv 5 % ) . luteinising hormone ( lh ) , follicle stimulating hormone ( fsh ) , sex hormone binding globulin ( shbg ) , dheas , oestradiol , thyroid stimulating hormone ( tsh ) , free thyroxine ( ft4 ) , prolactin , and cortisol were measured by standard chemiluminescence immunoassays ( cvs 5 % for all ) . free androgen index ( fai ) was calculated by the following formula : fai = 100 total testosterone / shbg . total - cholesterol , tg , and hdl - c were measured using standard laboratory techniques ( cv 5 % ) . apolipoproteins a - i ( apoa - i ) , a - ii ( apoa - ii ) , and b ( apob ) were measured by standard nephelometry on a bnii nephelometer ( dade behring , deerfield , il ) ( cv 5 % ) . apob - 48 was measured using a commercially available elisa kit ( akhb48 , gentaur bvba corporation ) and using a modified version of the method described by lorec et al . . the appropriately diluted samples are added to the plate and left to react for one hour . samples were diluted 1 : 250 to ensure that the concentration was not above the assay range . the plate was subsequently washed 4 times , and biotin - conjugated anti - apob - 48 antibody is added . this binds to human apob - 48 bound to the anti - apob - 48 antibody immobilised on the coated plate . the avidin and biotin readily bind to ensure that the horseradish peroxidase enzyme is immobilised on the plate . the reaction stopper ( 1 m h2so4 ) is added , resulting in a yellow colour formation which is proportional to substrate concentration . analysis of covariance ( ancova ) was used to compare differences between the two groups adjusting for 3 separate covariates : bmi , homair , and si . multiple linear regression analysis was used to identify independent contributors to postprandial tg , apob - 48 , and hdl - chol . independent variables that correlated significantly in univariate analysis were entered into the multiple regression models in forward stepwise fashion . statistical significance was defined as p 0.05 . women with pcos were more insulin resistant with a higher homair ( 4.400.41 mol / l in controls ) and lower si ( 1.990.1810 min / mu / l in pcos versus 4.050.46 table 2 shows the pre - and postprandial results of tg , hdl , and nefa . postprandial tg at 2 hours was significantly greater in pcos women ( 2.180.18 mmol / l , p = 0.019 ) and nonsignificantly greater at the other time points compared to controls ( figure 1 ) . auc - tg , but not the iauc - tg , was also significantly higher in women with pcos . conversely , hdl - chol was significantly lower in pcos women compared to controls at t = 0 , 2 , 4 , and 6 hours ( figure 2 ) . there were no significant differences in apoa - i , apoa - ii , apob , and apob - 48 at any of the time points and the auc or iauc of these apolipoproteins between the two groups . glucose levels were nonsignificantly greater at 2 hours and significantly greater at 4 hours in women with pcos compared to controls ( figure 3 ) . auc - glucose was also greater in pcos . with the exception of insulin at 8 hours , insulin level at all other time points , auc - insulin , and iauc - insulin were all greater in women with pcos ( figure 4 ) . tables 4 and 5 show results following adjustment for bmi , homair , and si . after adjusting for bmi , androgens remained higher and shbg lower in pcos women compared to control subjects ( table 4 ) . there were no differences in tg , hdl , and apob - 48 at any time points nor in auc - tg , auc - hdl , auc - apob - 48 . auc - insulin and iauc - insulin were also significantly higher ( table 5 ) . following adjustment for homair , androgens and shbg were significantly different between the two groups ( table 4 ) . apob - 48 at 4 hours was significantly ( p = 0.034 ) higher in the pcos women ( 19.81.68 g / ml ) compared to controls ( 15.21.64 g / ml ) and insulin at 4 and 6 hours as well as auc - insulin and iauc - insulin also remained significantly higher ( table 5 ) . finally , following adjustment for si , androgens remained significantly greater in pcos women , but shbg was no longer significantly different ( table 4 ) . only insulin at 4 hours was higher in the pcos women , but auc - insulin and iauc - insulin were not different between the two groups ( table 5 ) . apob - 48 was nonsignificantly ( p = 0.058 ) greater at 4 hours in pcos women ( 19.21.90 g / ml ) compared to controls ( 16.82.00 g / ml ) but not at other time points ( table 5 ) . there were no significant differences in apob , apoa - i , or apoa - ii at any of the time points or in the auc or iauc between the two groups . table 6 shows the correlations between auc - tg , auc - hdl , auc - apob - 48 , auc - apob , auc - glucose , auc - insulin , and all other variables . taking the entire cohort of 52 subjects , auc - tg correlated positively ( p 0.05 for all variables unless otherwise specified ) with wc ( r = 0.314 ) , weight ( r = 0.357 ) , bmi ( r = 0.316 ) , and body fat content ( r = 0.378 ) and negatively with body water content ( r = 0.342 ) and shbg ( r = 0.378 , p 0.01 ) . auc - tg did not correlate with androgens except for fai ( r = 0.294 ) and this is likely to be a result of the inverse correlation with shbg , which causes fai to be higher . figures 58 show the correlations graphically between auc - tg and shbg ( figure 5 ) , fai ( figure 6 ) , androstenedione ( figure 7 ) , and dheas ( figure 8 ) , respectively . as expected , auc - tg also correlated strongly with homair , si ( r = 0.601 , p 0.01 ) , and auc - hdl ( r = 0.540 ) . insulin at 0 , 2 , 4 , and 6 hours , auc - insulin , and iauc - insulin also correlated significantly with auc - tg ( figure 9 ) . there were also positive correlations between auc - tg and apob - 48 at 0 , 2 , 6 , and 8 hours , auc - apob - 48 ( figure 10 ) , apob at 2 , 4 , 6 , and 8 hours , and auc - apob suggesting that both chylomicrons and vldl contribute to postprandial hypertriglyceridaemia . glucose at 0 and 2 hours , auc - glucose , sg , and di also correlated with auc - tg . stepwise multiple regression analysis revealed that si , auc - apob - 48 , and auc - apob were independent predictors of auc - tg , accounting for 55 % of the overall variance . this suggests that postprandial chylomicron particles probably play an important role in contributing towards postprandial hypertriglyceridaemia , together with apob and insulin sensitivity . auc - tg was the only independent predictor of auc - apob - 48 , explaining 25.8 % of the variance . auc - hdl correlated significantly negatively with wc ( r = 0.483 , p 0.01 ) , hc ( r = 0.285 ) , weight ( r = 0.439 , p 0.01 ) , bmi ( r = 0.456 , p 0.01 ) , body fat ( r = 0.444 ) , fai ( r = 0.350 ) , homair ( r = 0.499 , p 0.01 ) , auc - tg ( r = 0.540 , p 0.01 ) , auc - glucose ( r = 0.309 ) , and auc - insulin ( r = 0.488 , p 0.01 ) . auc - hdl correlated significantly positively with body water ( r = 0.389 ) , shbg ( r = 0.443 , p 0.01 ) , and si ( r = 0.454 ) . auc - hdl also correlated negatively with tg at all time points , iauc - tg , iauc - b48 , apoa - i at 2 , 4 , and 6 hours and auc - apoa - i , glucose at 0 and 2 hours , auc - glucose , insulin at 0 , 2 , 4 , and 6 hours , auc , and iauc - insulin ( results not shown ) . there was a nonsignificant negative correlation with androstenedione ( r = 0.27 , p = 0.055 ) . auc - tg and wc were the only independent predictors of auc - hdl , explaining 37.2 % of the variance using multiple regression analysis . auc - insulin also correlated strongly with fai , auc - tg , auc - hdl , auc - glucose , pcos status , and anthropometrics . finally auc - insulin was negatively correlated with di , suggesting a correlation with possible subsequent - cell function failure and development of diabetes . dyslipidaemia , including both increased tg and low hdl - cholesterol , is common in pcos and is a well - recognized feature of the metabolic syndrome which confers increased risk of cardiovascular disease . trl consists of hepatically derived vldl , characterised by the presence of apob - 100 , and intestinally derived chylomicrons , which contain apob - 48 . both vldl and chylomicrons share a common lipolytic pathway and are hydrolysed by lipoprotein lipase ( lpl ) and there are a number of described receptor mediated pathways through which these particles may eventually be cleared from the circulation . it is postulated that an excess production and / or a delay in clearance of postprandial lipoproteins of both trl particles may be implicated in atherosclerosis . to the best of the author 's knowledge , this is the first study to compare the postprandial responses in obese pcos women with that of obese control subjects . although some postprandial studies in pcos women have been done previously , this is the first one to evaluate the contribution of the two main metabolic / endocrine disturbances in pcos women ir and hyperandrogenaemia to postprandial dyslipidaemia in obese women with pcos . both are implicated in accelerated atherosclerosis but the relative contribution of either is a subject of controversy . obesity , in particular central obesity , is strongly associated with insulin resistance , whilst androgens are also associated with an android distribution of fat . in a previous study by velzquez m et al . a strong correlation between postprandial triglycerides and waist - to - hip ratio was demonstrated . kg / m ) pcos women and compared them to lean pcos women and lean controls . only free testosterone was measured , and there was no analysis between this and postprandial hypertriglyceridaemia . a separate study by bahceci et al . evaluated postprandial responses to an oral fat tolerance test , in lean pcos women with lean controls ( bmi 23.52.6 kg / m versus 23.14.0 kg / m ; p 0.05 ) . they showed that pcos women had higher baseline insulin , homair , auc - tg , auc - total - cholesterol , auc - vldl - cholesterol , and auc - apob . surprisingly , though , auc - insulin did not differ between the two groups . again , no analyses were reported between androgens and postprandial lipids . in this study , comparing obese women with pcos with obese control subjects , auc - tg , auc - hdl , auc - glucose , and auc - insulin were all significantly different . hdl - chol and insulin were different at most of the time points , but tg was only different at 2 hours . independent predictors of auc - tg included si , auc - apob - 48 , and auc - apob , accounting for 55 % of the variance . this suggests that postprandial chylomicron particles have an important role to play in postprandial hypertriglyceridaemia , together with insulin sensitivity and apob . on the other hand , auc - tg was the only independent predictor of auc - apob - 48 , explaining 25.8 % of the variance . following adjustment for bmi , lipid differences were no longer noted but insulin levels at all time points and auc - insulin and iauc - insulin were still much greater in pcos women consistent with the fact that pcos women are more insulin resistant than their bmi matched counterparts . in this study , ir was determined by the more convenient homair and insulin sensitivity was determined by the more sophisticated fsivgtt derived si . when comparisons were made adjusting for homair , postprandial insulins were still significantly higher in the pcos group . however , these differences were largely no longer present when adjustments were made for si , which may be a better marker for insulin sensitivity than homair , since the latter is calculated from fasting values of insulin and glucose . there was only weak or no correlation between androgens and tg , hdl - chol , apob - 48 , apoa - i , apoa - ii , and apob . there were very strong correlations between shbg and tg , hdl - chol , auc - apob - 48 , auc - apob , and auc - apoa - ii . fai but not testosterone per se also strongly correlated with hdl at all time points , tg at 0 and 2 hours , and both auc - hdl - chol and auc - tg . this suggests that ir , and perhaps obesity , both of which are strongly negatively correlated with shbg , rather than androgens , may be the major determinant of postprandial lipids . however , both groups were obese and results were analyzed with bmi as a covariate . the two groups did not match for ir as assessed by homair nor si as assessed by the fsivgtt . however this is to be expected based on the well accepted notion that women with pcos are more insulin resistant than bmi matched counterparts . in addition , after using homair and si as covariates , results still revealed that hyperinsulinaemia and possibly a low shbg level are the main factors influencing postprandial hypertriglyceridaemia . postprandial chylomicrons also appear to play a significant role in postprandial hypertriglyceridaemia in premenopausal women with and without pcos . in conclusion , this study provides evidence that , in obese women with pcos , ir plays a more important role than hyperandrogenaemia in postprandial dyslipidaemia and cardiovascular risk . targeting obesity andthereby improving ir by lifestyle measures and perhaps the use of agents such as metformin should be a priority in the treatment of obese pcos women .\noutput:\n" }, { "from": "agent", "value": "postprandial dyslipidaemia may be a plausible mechanism by which polycystic ovary syndrome ( pcos ) increases cardiovascular risk . we sought to investigate whether the postprandial glucose and insulin and lipid and lipoprotein responses , including that of apolipoprotein b - 48 ( apob - 48 ) containing chylomicrons , to a mixed meal are different in obese pcos women when compared to obese control subjects and whether differences , if any , are related to obesity , insulin resistance ( ir ) , hyperandrogenaemia , or pcos status . 26 women with pcos ( age 30.4 1.2 years ( mean sem ) , body mass index ( bmi ) 36.8 1.5 kg / m2 ) and 26 non - pcos subjects ( age 34.1 0.9 years , bmi 31.5 1.0 kg / m2 ) were studied before and up to 8 hours following a standard mixed meal . auc - triglyceride ( auc - tg ) was higher and auc - high - density lipoprotein ( auc - hdl ) lower in pcos women . these differences were not apparent when bmi was accounted for . insulin sensitivity ( si ) , auc - apob - 48 , and auc - apolipoprotein b ( auc - apob ) were found to be independent predictors of auc - tg , accounting for 55 % of the variance . only auc - insulin remained significantly elevated following adjustment for bmi . obesity related ir explains postprandial hypertriglyceridaemia and hyperinsulinaemic responses . management of obesity in premenopausal women with pcos is likely to reduce their cardiovascular risk burden ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: coronary artery fistulae ( caf ) are abnormal connections between coronary arteries and cardiac chambers ( coronary - cameral ) or major intrathoracic vessel ( arteriovenous ) . , most coronary fistulae are congenital . in general , they are asymptomatic and discovered about 0.1 % of adult patients undergoing routine coronary angiography . in rare cases , they may cause angina or symptoms related to the hemodynamic repercussions of significant arteriovenous shunt such as fatigue , dyspnoea and heart failure . transcatheter closure of caf is feasible and should be considered in symptomatic patients . in this case , we report a symptomatic patient with multiple caf and significant left anterior descending artery stenosis that was consealed by cafa 83 years old man with diagnosis of unstable angina pectoris who underwent coronary angiography in a different hospital was refered to us for occlusion of cfa originating from left anterior descending ( lad ) and empting to the pulmonary artery . he had huge caf ( video 1 ) and subtotal stenosis of mid right coronary artery ( rca ) lesion ( figure 1 ) . decision of closure of fistulae with amplatzer vascular plug 4 and stenting of right coronary artery mid lesion was taken . at first , we aimed to treat mid rca lesion . during the engagement of rca ostium , sequential and simultaneous contrast injection demonstrated that both of fistulae were openning to the pulmonary artery at the same place ( video 3 ) . vigorous attempts were done to proceed multi - purpose and right judkings catheter through fistulae . then , we decided to use thrombus aspiration catheter ( tac ) as a delivery guide . after wiring the fistula with the 0.014 - inch guidewire , tac was advanced over the guidewire . after the optimal position of aspiration catheter was obtained ( video 4 ) , amplatzer vascular plug ( avp ) was loaded into the aspiration cathater and advanced carefully . after the optimal device position was assured , vascular plug was released and control image demonstrated completely closure of fistulae and significant lad stenosis just distal to the origin of fistulae that was not seen in previous coronary angiography ( video 5 , 6 ) . we gave nitroglycerine in order to be sure that this image was not due to the spasm . there was no effect of nitroglyserine and lesion was stented with 3.5 mm 15 mm bare metal stent and postdilated with 4 mm 12 mm noncompliant balloon . final image was satisfactory . because of high dose use of contrast media ( about 300 ml ) and patient renal function ( creatine was 1.6 ) , the other caf was untreated . after a month later , patient was taken to the catheter laboratory for occlusion of second coronary to pulmonary artery fistulae . vascular plug 2 was loaded in guiding catheter and was advanced as further as possible . after confirming the correct positon of device ( video 7 ) , it was released . congenital coronary artery fistula is a rare malformation that may involve any or all coronary artery branches and any cardiac chamber . elective closure of coronary artery fistula by surgery or percutaneous transcatheter technique is generally accepted in the presence of symptoms . although surgical ligation has been performed for caf , the transcatheter approach may be preferred over the surgical approach due to lower cost , shorter recovery time , and less morbidity , including avoidance of thoracotomy or sternotomy and cardiopulmonary bypass . multiple different transcatheter techniques have been used successfully including coils , detachable balloons , umbrellas polyvinyl alcohol foam and other occlusive devices . the vascular plug is made of nitinol , a shape memory alloy of nickel and titanium . it is generally loaded into diagnostic angiography catheters in order to advance the device to the target area . eventhough we followed the same principles by using different types of catheters , we could n't succeed to advance the catheter to the fistulae because of anatomical reasons . therefore , we decided to use thrombus aspiration catheter as a delivery guide given that it is more flexible and easy to advance in coronary arteries . we loaded the device into tac and advanced it to the fistulae with a bit difficulty . according to the best of our knowledge , this is the first case of using tac as a delivery guide for treating coronary fistulae . thrombus aspiration catheters can be used in cases with difficult anatomy that prevents the diagnostic catheters advancing through fisulae .\noutput:\n" }, { "from": "agent", "value": "in this case report , we present the occlusion of multiple coronary artery fistulae originating from proximal left anterior descending ( lad ) and right sinus valsavla and empting to the pulmonary artery at the same place . we occluded lad fistulae by using thrombus aspiration catheter as a delivery guide . to the best of our knowlege , this is the first case of occlusion of coronary fistulae with the help of thrombus aspiration catheter . our experience may suggest that thrombus aspiration catheters can be used in treating coronary artery fistulae with difficult anotomy ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: coronary artery disease ( cad ) is a leading cause of morbidity and mortality in developed countries and is emerging as an epidemic in developing countries 1 . traditional risk factors such as serum cholesterol , blood pressure and smoking account for not more than 50 % of cad mortality 2 . there is strong evidence that oxidative free radicals have a role in the development of degenerative diseases including cad 3 . oxidative free radicals increase the peroxidation of low density lipoprotein ( ldl ) thereby increasing its uptake by macrophages with increased foam cell formation and atherosclerosis , though other mechanisms may exist 4 . each antioxidant has different and important mechanisms of action since oxidative damage can be caused by lipid - or water - soluble molecules . lipid - soluble antioxidants are likely to be very important in preventing the peroxidation of ldl and this action could be paramount in the prevention of atherosclerosis . as lypophilic molecules , vitamin e and beta - carotene are incorporated into the ldl particle . previous experimental and epidemiologic evidence suggested that some antioxidant vitamins appear to be important in reducing the risk of cad 6 . studies on the roles of trace elements in health and disease over the past 50 years have led to a good understanding of their mode of action and why they are essential to life 7 . some studies have assessed the association between iron status and cad risk but the results have been inconsistent 8,9 . the aim of the present study was to investigate the changes occurring in the serum level zinc ( zn ) , copper ( cu ) , iron ( fe ) , cadmium ( cd ) , lead ( pb ) , manganese ( mn ) , vitamins a ( retinol ) , d ( cholecalciferol ) and e ( - tocopherol ) in patients with cad . the study population included 30 patients having angiographically demonstrated cad and 20 patients having normal coronary arteries attending cardiology clinic at yuzuncu yil university hospital . the study was approved by the local ethics committee according to the declaration of helsinki , and patients gave written informed consent . serum was obtained by centrifugation at 2500 rpm for 15 minutes and stored at 80c until assayed . serum - tocopherol , retinol and cholecalciferol were measured simultaneously by high performance liquid chromatography ( hplc ) 10 - 12 . serum concentrations of zn , cu , fe , cd , pb and mn were determined by atomic adsorption spectrophotometer . chicago , il , usa ) , data between the groups were compared with student 's t test for continuous variables and chi - square t - test for continuous variables . mann - whitney 's u - test was used for variables without normal distribution . a two - tailed p - value of 0.05 was considered significant . serum was obtained by centrifugation at 2500 rpm for 15 minutes and stored at 80c until assayed . serum - tocopherol , retinol and cholecalciferol were measured simultaneously by high performance liquid chromatography ( hplc ) 10 - 12 . serum concentrations of zn , cu , fe , cd , pb and mn were determined by atomic adsorption spectrophotometer . data were presented as meanstandard deviation ( sd ) . using spss package 16.0 ( spss inc . chicago , il , usa ) , data between the groups were compared with student 's t test for continuous variables and chi - square t - test for continuous variables . mann - whitney 's u - test was used for variables without normal distribution . a two - tailed p - value of 0.05 was considered significant . clinical characteristics and serum cholesterol levels were not significantly different in patients with and without cad ( table 1 ) . comparisons of the levels of the vitamins ( retinol , tocopherol and cholecalciferol ) , and trace elements and heavy metals ( zn , cu , fe , cd , pb and mn ) in patients with cad and the control group are shown in table 2 . compared with the control group , serum concentrations of retinol , tocopherol , cholecalciferol and iron were significantly lower in patients with cad . in this study , we found that serum concentrations of retinol , tocopherol , cholecalciferol and fe were significantly decreased in patients with cad . in addition , while not statistically significant , serum cu concentrations tended to be lower in patients with cad , whereas serum fe concentrations tended to be higher . cad has been associated with several risk factors including family history , age , elevated blood cholesterol , diabetes mellitus , cigarette smoking and hypertension 13 . the results of the present study show that serum zn concentrations were significantly lower in the control group . lower zn levels in cad may be a cause or a result of another unknown parameter . ( 1988 ) observed a slight increase in serum cu and a signficant increase in urine cu levels in patients suffering from myocardial infarction ( mi ) 15 . ( 1996 ) found increased levels of serum cu in patients with cad 14 . in contrast , in our study , the serum cu concentrations tended to be lower in patients with cad . epidemiological investigations that associate body fe stores with cad risk have produced conflicting results ; these may in part be explained by the use of nonspesific measures of body fe stores , such as serum transferrin 16 - 19 . the strongest supporting evidence that fe is a risk factor for cad stems from a cohort study of eastern finnish men , in which high levels of serum ferritin and dietary fe intake were positively associated with the incidence of myocardial infarction . ( 1994 ) reported an increased risk of nonfatal mi or fatal cad with fe intake 17 .1981 ) proposed that depletion of body fe stores reduced the risk of cad 16 . most subsequent prospective studies investigating whether fe status or dietary fe intake is associated with an increased risk of mi or cad have not supported the hypothesis that high body fe stores increase the risk of cad 20,21,18 . because of its possible role in preventing heart disease researchers have taken interest in fat - soluble tocopherol . recent studies have suggested that - tocopherol supplementation can help reduce the incidence of coronary disease 1,22 . however , a large prospective study found no benefit of tocopherol supplemantation in preventing cad . levels of tocopherol were reported to be decreased in coronary artery disease 23 . our results also demonstrate that serum tocopherol levels were lower in cad patients compared to controls . as far as we know , there is no study examining serum cd levels in cad in the literature . mn is an element essential for health in trace amounts , but toxic at higher levels . there are a few reports in the literature examining the effects of excess oral exposure of humans to mn . the urine of cad patients also shows higher mn concentrations than that of healthy controls 24 . in atherosclerotic subjects , the mn content of the heart and aorta of atherosclerotic subjects is lower and plasma levels are higher than in healthy controls 25 - 27 . this increase is so rapid and specific that it may be used as a diagnostic indicator of a recent mi . in the present study however , blood pb level was not found to be associated with coronary heart disease incidence 28 . studies in general populations have identified a positive association of pb exposure with clinical cardiovascular , cad and stroke mortality ; and peripheral arterial disease , but the number of studies is small 29,30 . numerous experimental studies in animals have shown irrefutable evidence that chronic exposure to low pb levels results in arterial hypertension that persists long after the cessation of pb exposure 29 . we could n't found information about pb levels among patients with cad having no history of pb exposure in literature . in the present study , it was found that mean levels of serum pb tended to be higher in cad patients . we found that mean values for retinol were significantly lower in patients with cad compared to the control group . in other studies , levels of retinol were similar in patients with cad compared to controls 5,6,31,32 . results of large randomized controlled trials of the impact of antioxidant vitamin supplements have been ambiguous or contradictory 33 . the current evidence does not support indiscriminate use of retinol to prevent or to reduce cad 4,33 . similar to results reported in previous studies , we found serum cholecalciferol levels to be lower in cad . cholecalciferol deficiency is associated with increased cardiovascular risk , above and beyond established cardiovascular risk factors 34,35 . clinical studies have reported cross - sectional associations between lower cholecalciferol levels and plasma renin activity , blood pressure , coronary artery calcification and prevalent cardiovascular disease 36 - 41 . in conclusion , the higher or lower levels may be both a cause and effect of atherosclerosis or the result of another unknown parameter . in this relatively small study we found that serum levels of retinol , tocopherol , cholecalciferol , fe and cu may be lower whereas serum pb concentrations may be increased in patients with cad .\noutput:\n" }, { "from": "agent", "value": "aim : in the present study , we aimed to assess serum concentrations of zinc ( zn ) , copper ( cu ) , iron ( fe ) , cadmium ( cd ) , lead ( pb ) , manganese ( mn ) , vitamins a ( retinol ) , d ( cholecalciferol ) and e ( - tocopherol ) in patients with coronary artery disease ( cad ) and to compare with healthy controls.methods : a total of 30 cad patients and 20 healthy subjects were included in this study . atomic absorption spectrophotometry ( unicam - 929 ) was used to measure heavy metal and trace element concentrations . serum - tocopherol , retinol and cholecalciferol were measured simultaneously by high performance liquid chromatography ( hplc ) . results : demographic and baseline clinical characteristics were not statistically different between the groups . serum concentrations of retinol ( 0.35210.1319 vs. 0.43130.0465 mmol / i , p = 0.013 ) , tocopherol ( 3.86301.3117 vs. 6.91241.0577 mmol / i , p < 0.001 ) , cholecalciferol ( 0.02090.0089 vs. 0.03040.0059 mmol / i , p < 0.001 ) and fe ( 0.56640.2360 vs. 1.06890,4452 g / di , p < 0.001 ) were significantly lower in cad patients . in addition , while not statistically significant serum cu ( 1.01640.2672 vs. 1.19340.4164 g / di , p = 0.073 ) concentrations were tended to be lower in patients with cad , whereas serum lead ( 0.14490.0886 vs. 0.10190.0644 g / di , p = 0.069 ) concentrations tended to be higher.conclusions : serum level of trace elements and vitamins may be changed in patients with cad . in this relatively small study we found that serum levels of retinol , tocopherol , cholecalciferol , iron and copper may be lower whereas serum lead concentrations may be increased in patients with cad ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: fibrous dysplasia is a congenital developmental anomaly of bone which may occur in localised , regional or systemic forms . in this conditionthe normal bone is replaced by immature fibro cellular tissue , which may be considered to be a fertile soil for a plethora of lesions like aneurysmal bone cyst , solitary bone cyst , and non specific cystic degeneration . however , the occurrence of an epithelial lined cyst in the maxilla affected by fibrous dysplasia has never been reported . we present a rare case in which an epithelialised inflammatory cyst lining was present along with sequestrum in the maxilla affected by fibrous dysplasia . a 24 yr old man reported in march 2007 , with complaints of swelling and pus discharge from right side of cheek since 3 weeks . the patient was apparently well 8 years back when he first noticed slight asymmetry of right cheek region . the swelling slowly increased in size for next three years and was latent since then ( about 5 years ) . recently , he had toothache in relation to right maxillary molar teeth and noticed pus discharge from the same quadrant . this prompted him to seek treatment and was then referred to our institution by a general physician . he appeared to be a well built young man with no history of any systemic diseases . there was an obvious swelling over the right side of maxilla extending over the body of zygoma . the infraorbital rim was expanded but ocular level in the vertical and horizontal plane was unaltered . on intraoral examination , a full complement of teeth was present in the right maxillary quadrant . teeth # 17 was grossly carious with a small sinus tract in the alveolus of tooth # 15 and 16 . on palpation , the swelling was hard , non tender and appeared to blend with the right zygoma and uninvolved surface of right anterior maxilla [ figure 1 ] . conventional radiographs showed haziness and opacification over the region of right maxilla and zygomatic bones , containing an ill - defined radiolucency with another small central radiopacity anteriorly . overall the radiopacity was homogenous and generally appeared to blend with the adjacent bone except for that portion of radiolucency circumscribing another small central diffuse radiopacity . ct scan showed enlargement of right zygomatic and maxillary bones with a diffuse ground glass appearance obliterating the maxillary sinus [ figure 2 ] . there was an irregular small cavity in the alveolar process of right maxilla around the roots of teeth # 15 and 16 . a stellate shaped bony sequestrum was seen inside this cavity with a sinus opening on the buccal surface of tooth # 16 [ figure 3 ] . preoperative photograph showing swelling over right zygomatic region ct scan coronal section showing the extent of lesion with typical ground glass appearance and cystic lesion with sequestrum . the cystic lining appears to be in continuity with root apex ct scan showing stellate shaped sequestrum surrounded by cystic lining and perforation in the lining wall towards the buccal cortex laboratory investigations like serum alkaline phosphatase , serum calcium , phosphorus and complete blood count were normal . a clinical diagnosis of osteomyelitis superimposed on fibrous dysplasia of right maxilla and zygoma was formed . it was decided to perform facial recontouring and curettage with extraction of involved teeth as a single stage procedure . after a brief course of antibiotics the patient was scheduled for surgery under local anesthesia . under right maxillary nerve block supplemented with local infiltration for haemostasis , a mucoperiosteal flap was raised and the lesion was exposed till the infraorbital rim superiorly and body of zygoma posterosuperiorly . in the alveolar regionthe cystic lining contained little bit of pus and three small pieces of necrotic bone . then the residual bone was curetted particularly over the anterior surface of maxilla , body of zygoma and infraorbital rim [ figure 4 ] . since there was no paresthesia or compression symptom in infraorbital nerve , the rim of bone surrounding it was left untouched . pathologic specimens showing epithelial lining attached to tooth roots , pieces of sequestrum and shaved bone on histopathology , the bony pieces retrieved after recontouring revealed uniformly distributed curvilinear trabeculae in a fibrocellular stroma with numerous fibroblasts and a few blood vessels , overall picture appeared to be consistent with mature stage of fibrous dysplasia [ figure 5 ] . h and e stained 10 photomicrograph showing chinese pattern dysplastic bone diagnostic of fibrous dysplasia the lining exhibited a nonkeratinised stratified squamous epithelium with proliferating and arcading rete ridges and an underlying connective tissue capsule showing intense infiltration by chronic inflammatory cells chiefly lymphocytes and plasma cells [ figure 6 ] . the three pieces of bone contained within the lining were necrotic i.e. sequestrum [ figure 7 ] . h and e stained 10 photomicrograph showing epithelial lining h and e stained 10 ( zoom ) photomicrograph showing avascular bone one year postoperatively good symmetry was maintained in the frontal view but slight expansion was still visible on the worm 's eye view . no recurrence of cystic cavity was observed in one year post operative ct scan and the bony defect healed completely . three years postoperatively the patient came back seeking correction of facial asymmetry caused by bony growth in the same region [ figure 8 ] . facial recontouring was performed again and the bone pieces removed showed microscopic picture consistent with fibrous dysplasia . post op ( 3 year ) showing facial enlargement as a result of continued growth of fibrous dysplasiaunder right maxillary nerve block supplemented with local infiltration for haemostasis , a mucoperiosteal flap was raised and the lesion was exposed till the infraorbital rim superiorly and body of zygoma posterosuperiorly . in the alveolar regionthe buccal cortex was destroyed and replaced by thick cystic lining . teeth # 14 - 17 were extracted and cystic lining was curetted out . the cystic lining contained little bit of pus and three small pieces of necrotic bone . then the residual bone was curetted particularly over the anterior surface of maxilla , body of zygoma and infraorbital rim [ figure 4 ] . since there was no paresthesia or compression symptom in infraorbital nerve , the rim of bone surrounding it was left untouched . pathologic specimens showing epithelial lining attached to tooth roots , pieces of sequestrum and shaved bone on histopathology , the bony pieces retrieved after recontouring revealed uniformly distributed curvilinear trabeculae in a fibrocellular stroma with numerous fibroblasts and a few blood vessels , overall picture appeared to be consistent with mature stage of fibrous dysplasia [ figure 5 ] . h and e stained 10 photomicrograph showing chinese pattern dysplastic bone diagnostic of fibrous dysplasia the lining exhibited a nonkeratinised stratified squamous epithelium with proliferating and arcading rete ridges and an underlying connective tissue capsule showing intense infiltration by chronic inflammatory cells chiefly lymphocytes and plasma cells [ figure 6 ] . the three pieces of bone contained within the lining were necrotic i.e. sequestrum [ figure 7 ] . h and e stained 10 photomicrograph showing epithelial lining h and e stained 10 ( zoom ) photomicrograph showing avascular bone one year postoperatively good symmetry was maintained in the frontal view but slight expansion was still visible on the worm 's eye view . no recurrence of cystic cavity was observed in one year post operative ct scan and the bony defect healed completely . three years postoperatively the patient came back seeking correction of facial asymmetry caused by bony growth in the same region [ figure 8 ] . facial recontouring was performed again and the bone pieces removed showed microscopic picture consistent with fibrous dysplasia . post op ( 3 year ) showing facial enlargement as a result of continued growth of fibrous dysplasiafacial region may be affected by a form of fibrous dysplasia that is not strictly monostotic , but may be confined to a single anatomical region . these lesions affect primarily the maxilla and simultaneously cross sutures and enter into the adjacent facial bones . this type of fibrous dysplasia does not meet the precise criteria for the monostotic or polyostotic forms and has been termed craniofacial fibrous dysplasia . in the present case , fibrous dysplasia affected the maxilla and adjacent zygomatic bone and thus may be termed as craniofacial type . as per the current belief fibrous dysplasia results from a defect in bone maturation that begins in the embryo . the classical division of fibrous dysplasia into monostotic , polyostotic and mccune albright forms may reflect the timing of the mutation and thereby , the initial size of the mass of fibrous dysplasia precursor cells . the polyostotic form may arise in foetal life whereas the monostotic form may arise postnatally . this correlates with the evidence that the monostotic form is not a precursor of the polyostotic form . thus fibrous dysplasia may reflect a programmed field effect of abnormal osseous development in congenitally predisposed bone matrix . this may account for the fusiform expansion of affected bone . although the shape of affected maxilla appears to be more complex , reflecting its structure , the overall effect is similar to that seen in the mandible . the above pattern is altered if the fibrous dysplasia undergoes cystic degeneration , then the affected part may lose its anatomical shape and becomes spherical . aneurysmal bone cyst and simple bone cyst are well defined entities that sometimes occur as secondary phenomenon in many benign and malignant bone tumours . secondary cystic lesions consisting of blood filled cavities in bone that are lined by a thick layer of fibrous tissue termed as nonspecific cystic degeneration have also been reported . the development of cystic degeneration in fibrous dysplasia can pose a diagnostic and therapeutic dilemma as it may present clinically as a rapidly enlarging mass that can be alarming to both patient and physician . another clinical implication of cystic degeneration , and consequentially ensuing rapid growth in a relatively quiescent fibrous dysplasia , is alteration in the management protocol necessitating early surgical intervention . the affected part may lose its anatomical shape and become spherical , thus may appear more cosmetically deformed . however , this is a first case of its kind reporting an epithelial lined cyst in fibrous dysplasia occurring with chronic suppurative osteomyelitis . maxillary osteomyelitis occurs rarely in a healthy host and fibro osseous lesions particularly fibrous dysplasia , which is considered as one of the local factors that predispose to this type of infection . chang et al . have described a case of fibrous dysplasia with chronic osteomyelitis of mandible . osteomyelitis complicating the fibrous dysplasia affected frontal bone subsequent to trauma has been reported in the literature . sequestrum formation has been reported in fibrous dysplasia affecting tibial bone without any clinical or pathological evidence of osteomyelitis , but never in maxillofacial region . increased predisposition may be due to vascular compromise subsequent to replacement of bony medullary cavity with immature fibrocellular tissue having relatively poor vascularity . presence of a carious exposed tooth in such setting may initiate chronic inflammatory response which may cause : stimulation of epithelial rests of malassez resulting into initiation of a radicular cyst.propagation of an inflammatory response which may cause the usual sequelae of abscess formation and discontinuity of cyst lining.presence of chronic foci of infection leading to osteomyelitis and sequestrum formation.persistence of chronic infection resulting into enlargement of cyst lining , granulation tissue and eventually engulfing the sequestrum . propagation of an inflammatory response which may cause the usual sequelae of abscess formation and discontinuity of cyst lining . persistence of chronic infection resulting into enlargement of cyst lining , granulation tissue and eventually engulfing the sequestrum . fibrous dysplasia , epithelialised inflammatory cyst and osteomyelitis with sequestrum formation at one site is an exceptional and unique pathologic event . it is vital to sort the time frame and sequence in which these three must have occurred to understand the pathogenesis . any one of these could have been the primary event leading to rest which means that there are three possible series of events . carious exposed tooth as the first event leading to radicular cyst formation abscess formation initiation of garre 's type of response with fibrous dysplastic bone.existing craniofacial fibrous dysplasia carious exposed tooth leads to formation of radicular cyst abscess formation and rupture of cyst lining osteomyelitis with sequestration and engulfing by the cystexisting fibrous dysplasia carious exposed tooth with periapical infection osteomyelitis with sequestration and sinus tract epithelial ingrowth encircling the sequestrum carious exposed tooth as the first event leading to radicular cyst formation abscess formation initiation of garre 's type of response with fibrous dysplastic bone . existing craniofacial fibrous dysplasia carious exposed tooth leads to formation of radicular cyst abscess formation and rupture of cyst lining osteomyelitis with sequestration and engulfing by the cyst existing fibrous dysplasia carious exposed tooth with periapical infection osteomyelitis with sequestration and sinus tract epithelial ingrowth encircling the sequestrum the probability of a radicular cyst occurring as the primary event in a pre - existing fibrous dysplasia is much higher ( hypothesis 2 ) because the cyst lining was attached to the tooth roots as noted intraoperatively and in preoperative ct scans . the reverse sequence of osteomyelitis and sequestrum formation as the primary event with its surrounding granulation getting epithelialised would lead to a cyst which will be entirely disassociated from the carious teeth . both these hypotheses are based on the presumption that maxilla was affected by fibrous dysplasia before the tooth became carious . this is supported by the patient 's history and the extent of fibrous dysplasia involving maxilla and zygoma and not just confined to alveolar region ( garre 's type response ) . thus , it appears to be a unique scenario in which there is occurrence of radicular cyst in the bone affected by fibrous dysplasia , and osteomyelitis develops subsequently as a consequence of altered vascularity and chronic infection . recurrence has been reported following surgical removal of non epithelial lined bone cyst occurring in fibroosseous lesions and prudence dictates similar possibility with its epithelialised counterpart . rapid growth in such a dysplastic bone should raise suspicion about sarcomatous or cystic transformation thus necessitating prompt intervention .\noutput:\n" }, { "from": "agent", "value": "fibrous dysplasia can present clinically in varied forms which may appear as collision of different pathologic processes . we report a rare case of craniofacial fibrous dysplasia with coexisting epithelial lined cyst and superimposed osteomyelitis with sequestrum formation . its clinical features and management with possible hypotheses are described along with the post operative course . pertinent literature has been reviewed with emphasis on pathogenesis of this unique occurrence ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: n - glycosylation of proteins is a highly conserved process in all eukaryotes whereby complex oligosaccharides ( glycans ) are cotranslationally appended to the side - chain asparagine - nitrogen of the consensus motif nxs / t ( figure 1 ) . n - glycans display a rich structural diversity and are vital for both the correct folding of nascent glycoproteins , where interactions with the chaperone lectins calnexin and calreticulin are key , and also for the correct functioning of the mature glycoproteins , where glycans play crucial roles in such processes as protein targeting , intercellular signaling , and host pathogen recognition . common to these diverse roles and the many structural possibilities for n - glycans is the conserved presence of an invariant core pentasaccharide ( man3glcnac2 ) ( figure 1a ) . this presence in all mammalian n - glycoproteins ( regardless of protein location or function ) and the highly conserved nature of n - glycosylation among eukaryotes suggests an indispensable ( and perhaps general ) role for the core pentasaccharide in facilitating the proper functioning of n - glycans . despite its ubiquity , however , the underlying physical reasons for its conservation are not yet fully understood . nmr measurements of model glycopeptides in aqueous solution , coupled with molecular dynamics investigations , have exposed the influence of the proximal chitobiose ( glcnac - glcnac ) stem on the local peptide conformation and suggested an explanation of nature s choice of n - acetyl - d - glucosamine ( glcnac ) over the more plentiful d - glucose . does the notably rare - mannoside ( man ) central linkage between this stem and the trimannoside ( man3 ) unit impart any unique structural or functional benefits and do these units ( and other building blocks ) function independently or in concert ? similar nmr and molecular dynamic investigations of the naturally occurring man9glcnac2n - glycan in aqueous solution have suggested enduring structural features in the core pentasaccharide , incorporating locally bound water molecules . does the core pentasaccharide present any favored water pockets and are its shape and stiffness influenced by solvent - mediated interactions ? ( a ) the conserved core pentasaccharide motif , ( man3glcnac2 shown in gray box ) , is attached to asparagine residues of glycoproteins ( n , s , and t denote asparagine , serine , and threonine , x denotes any amino acid but not proline ) . proteins are cotranslationally modified with a tetradecasaccharide which is tailored by glycosyl - hydrolase and transferase enzymes to create diverse glycans with varying antennae but all based upon the conserved core pentasaccharide ( gray box ) . ( b ) the structures and symbol representations of the core pentasaccharide 4 and the building blocks 13 from key regions of 4 used in this study . the site of the benign chromophore used in this study mimics the location of the protein scaffold or truncated glycan ( shown by a red star ) . one approach to these various questions is to explore the structural mechanics of the individual building blocks , in isolation and then linked together , using a combination of synthetic oligosaccharide assembly , mass - and conformer - selected infrared laser spectroscopy under molecular beam conditions , molecular mechanics , and quantum chemical calculations . this allows determination of their preferred ( inherent ) conformational structures when isolated in the gas phase to provide basic structural benchmarks ; then interrogation of the locations and structural consequences of their microhydration ; and finally , their response to a bulk , aqueous environment . early stages of this approach have previously been applied to the nxs sequon and the trimannoside unit . we now report the culmination of this strategy , applied here to dissect the unbiased structure of the entire core pentasaccharide and then to understand the effects of hydration upon it . target oligosaccharide building blocks ( 14 , figure 1b ) were designed in a form that provided a chromophore required for detection through mass - selected ultraviolet ( uv ) photoionization . syntheses of the chitobiose ( glcnac -- 1,4 - glcnac ) stem 1 , the connecting disaccharide ( man -- 1,4 - glcnac ) 2 , the extended trisaccharide ( man -- 1,4 - glcnac -- 1,4 - glcnac ) 3 , and finally the complete core pentasaccharide ( man3glcnac2 ) 4 , all as their phenyl ( ph ) glycosides , were achieved on the gram - scales required for their gas - phase interrogation . their conformational preferences have been determined in the gas phase using infrared ion depletion ( irid ) laser spectroscopy coupled with molecular mechanics , density functional and ab initio theoretical calculations . those of their discretely hydrated ( and blocked ) complexes were determined through theoretical calculation . comparisons with their preferred conformations in aqueous solution , reported for chitobiose and the trimannoside ( man3 ) and computed here for the core pentasaccharide through molecular mechanics calculations , reveal a unique insight into the inner workings of the core pentasacccharide and the molecular scaffolding provided by it and its components . full details of all synthetic procedures and characterization are provided in the supporting information ( si ) . the carbohydrates were vaporized by laser desorption into an expanding supersonic jet of argon before passing through a 2 mm skimmer to create a collimated molecular beam which then intersected tunable uv and ir laser beams in the extraction region of a linear time - of - flight mass spectrometer ( jordan ) . conformer - specific , mass - selected spectra were recorded in the uv and ir using uvthe calculations began with completely unrestricted and exhaustive surveys of the conformational landscapes of each of the carbohydrate building blocks and their singly hydrated complexes , using a molecular mechanics method ( mmffs force field ) . structures with relative energies 15 kj mol , together with additional representative structures that might have a significant population in the cooled adiabatic expansion ( see si ) , were reoptimized through density functional theory calculations ( b3lyp / 6 - 311 + g * ) using the gaussian 09 program package ( and two supercomputers , i2basque and sgiker , employing up to 96 processors per calculation ) to provide a more accurate energy ranking of the lowest - energy structures and their associated harmonic vibrational spectra . zero - point corrected relative energies were computed through subsequent single point ab initio calculations ( mp2 / 6 - 311 + + g * * ) , and final optimizations were based upon comparisons with the experimental spectra themselves , to provide feedback and guide the fine - tuning of the predicted structures . the core pentasaccharide conformational structure was also explored exhaustively , using the molecular mechanics opls2005 and glycam06 / amber force fields . ( opls2005 possessed the fewest low - quality stretch , bend , and torsional parameters when benchmarked for the carbohydrate segments against all other native force fields found in the macromodel software ; glycam06 / amber ( not included in macromodel ) is referenced specifically , for carbohydrate structures ) . all stereogenic centers were preserved in the computational search , and the ring - opening method of still was used to explore additional ring conformations ( full details of all calculations are given as si ) . the target core pentasaccharide 4 and its building blocks 13 ( figure 1b ) were synthesized as phenyl - glycosides , to provide a uv chromophore , installed at the structurally benign reducing terminus . the target sugars were all required in gram - scale quantities to provide sufficient material for spectroscopic investigation in the gas phase . while such scales have been accomplished for certain smaller mono - and disaccharides , large - scale synthesis is rare on larger glycans , such as the core pentasaccharide , and required the development of efficient synthetic routes . this dictated a global approach to all targets that would allow flexible reuse of key building blocks and intermediates in more than one target ( figure 2 ) . an additional key synthetic challenge was the formation of the central - d - mannoside linkage in 24 , notoriously difficult in carbohydrate chemistry . several elegant methods have been reported for the direct stereoselective synthesis of - d - mannosides , however selectivities can sometimes be low , giving unwanted - mannoside side products that are difficult to remove through purification . notably , 90 % - selectivity is the best reported to date for direct - mannosylation of the oh - 4 position of a glcnac precursor that would correspond to the synthesis of the core pentasaccharide . since this would place severe limitations on the effective construction of grams of the chromophore - equipped targets , an alternative strategy , with potential for greater selectivity for the - mannoside linkage , this took advantage of neighboring group participation of a levulinate ester stereodirecting group ( lev ) at the c - 2 position of an unnatural glucoside residue to allow the formation of a corresponding - glucoside linkage . subsequent stereospecific inversion of the configuration at c - 2 ( i in figure 2 ) would then allow conversion of this unnatural residue from the - d - gluco to the natural - d - manno configuration . we chose to accomplish this critical inversion through sn2 displacement at a late stage of our syntheses , envisaging that , despite the strategic risk , this might afford more rigid intermediates that , by virtue of their reduced conformational flexibility , would be less prone to unwanted decomposition ( e.g. , elimination ) pathways . synthesis of the core pentasaccharide 4 and its building blocks 13 shown using symbol representations . the chromophore used in this study , phenyl , is shown by a red star . for full synthetic details and structuressee figure s1 for the steps describing the conversion of 5 to 13 and intermediate 9 ; figure s2 for conversion of 18 , 19 , and 9 onward to 4 . all glycosylations were accomplished with 98 % stereoselectivity for - ( g ) or - ( g ) glycosidic linkages through the use of participatory c - 2 ester substituents ( ac or lev ) . a suitably chromophoric stem unit of the core pentasaccharidewas prepared as the phenyl - chitobioside 1 ( figures 2 and s1 ) from parent monosaccharide sugar d - glucosamine 5 . a common thioglycoside divergent precursor 6 ( 41 ) was prepared with participatory phthalimide n - 2 protection in six steps from d - glucosamine .6 was divergently elaborated to both donor 7 ( 42 ) and acceptor 8 ( 43 ) ( through oh -4-regioselective reductive benzylidene ring opening ) ; use of a trichloroacetimidate donor group in 7 allowed its activation by tmsotf without disruption ( or aglycon exchange ) of the s - ethyl ( set ) group in acceptor 8 ( figures 2 and s1 ) to assemble 9 . the phenyl chromophore was then introduced using phenol through activation of the set group in 9 with n - iodosuccinimide ( nis ) and tmsotf ; global deprotection of resulting phenyl - glycoside 10 , afforded the free , chromophore - tagged stem ( glcnac ) 2 disaccharide unit 1 . the central disaccharide man -- 1,4 - glcnac unit 2 contains the unusual and challenging - d - mannoside linkage . an acceptor 12 already containing the phenyl chromophore was prepared from 6 ( using phenol and nis / tmsotf - mediated activation followed by regioselective reductive benzylidene ring opening to reveal oh - 4 ) .12 was glycosylated using the thio - d - glucoside donor 11 containing a c - 2 lev stereodirecting group ( figures 2 and s1 ) ; activation ( nis / tmsotf ) gave disaccharide 13 with excellent ( 98 % ) - d - stereoselectivity . the crucial c - 2 epimerization ( vide supra ) from - d - gluco - to - d - manno - configuration ( 1314 , figure s1 ) was accomplished in 80 % yield over three steps ( selective lev cleavage , triflate formation , and ultrasound - assisted sn2 displacement with acetate ) . the necessity for ultrasound treatment to promote triflate displacement was consistent with the expected stability afforded by the conformational restriction of the glucoside 13 by its 4,6 - o - benzylidene acetal ; this stability also ensured minimal side reaction through competing elimination . global deprotection of 14 yielded chromophore - tagged 2 in 70 % yield over four steps . utilizing the intended divergency of common synthetic intermediates ( figure 2 ) , a strategically similar synthetic route gave 3 ; this reused intermediates used for 1 and 2 . thus , lev - bearing donor 11 ( used for 2 ) was again used for the ultimate installation of the challenging - d - mannoside .11 was combined with ( glcnac ) 2 - disaccharide 10 ( used for 1 ) in which the phenyl chromophore was already present ; 10 was converted to a suitable acceptor 15 through regioselective 4,6 - o - benzylidene opening to reveal oh - 4b ( figure s1 ) .11 and 15 gave trisaccharide 16 containing the desired ( 1,4 ) - linkage ( 98 % stereoselectivity ) . creation of the desired - d - mannoside linkage ( 1617 ) successfully employed the same inversion - epimerization strategy used for 2 ; global deprotection gave 3 in a very good yield of 55 % over 7 steps . consistent with our strategy , the most challenging target , the core pentasaccharide 4 , was created ( figures 2 and s2 ) using previously generated intermediate ( glcnac ) 2s - ethyl disaccharide 9 . this ( glcnac ) 2 disaccharide was elaborated to a suitable acceptor 20 , again through regioselective protecting group manipulation to reveal oh - 4 and coupled in a convergent manner with disaccharide donor 22 .22 itself was assembled from d - manno trichloroacetimidate 18 ( 48 ) and the thioglucoside diol 19 . although 19 contains two potential sites for reaction ( oh - 2 and oh - 3 ) , tmsotf - activated glycosylation proceeded with both excellent regio - ( oh - 3 over oh - 2 ) and stereo - ( 98 % - manno ) selectivities to give 21 ( 50 ) in 76 % yield . advantageously , this left free the oh - 2 ; direct installation of the stereodirecting lev group onto oh - 2 gave 22 . unusually , our intended disaccharide 20 + disaccharide 22 [ 2 + 2 ] glycosylation utilized a donor and an acceptor both containing the same set anomeric substituent ; ordinarily this would give rise to unwanted coincident activation during glycosylation . however , by using an iterative glycosylation strategy , thioglycoside 22 was successfully preactivated first ( with triflic anhydride and diphenylsulfoxide in the presence of stabilizing base dtbmp , allowing its successful use as a donor ) . subsequent addition of 20 then led to its reaction only as an acceptor nucleophile ( without set activation ) and gave tetrasaccharide 23 , in good yield and with excellent stereoselectivity for the critical central - linkage ( 98 % ) . this therefore directly provided 23 bearing a subsequently useful set group , thereby avoiding functional group manipulations at this reducing terminus . before installation of the final ( 1,6 ) - d - mannosyl unit of the core pentasaccharide , we performed the critical inversion of the central unit from - d - gluco - to - d - manno - configuration ( 2324 ) ( figures 2 and s2 ) as for blocks 2 and 3 ( chemoselective lev deprotection , triflate formation , and ultrasound - mediated sn2 displacement with acetate ) , again in excellent yields . regioselective oh - 6 glycosylation with mannosyl donor 18 ( used for 22 ) gave pentasaccharide 26 ; here the use of a compatible trichloroacetimidate donor again led to retention of the useful set group at the reducing terminus . acetylation and subsequent nis / tmsotf - mediated activation of the set with phenol installed the chromophore into protected , phenyl - pentasaccharide 27 . three high - yielding deprotection reactions gave the final chromophore - tagged , core pentasaccharide 4 in gram - scale quantities . the r2pi spectrum of 1 , the chitobiose ( glcnacb -1,4-glcnaca ) stem that links the core pentasaccharide to protein , presented two overlapping components ( shown later in figure 5 and in figure s3 ) . their associatedirid spectra were in best accord with its two lowest - energy conformers , termed 1 - trans and 1 - cis ( figure 3a ) , in which the two coplanar pyranose rings are anti- or syn - periplanar , respectively ( see also figure s5 ) . the ir ion depletion ( irid ) spectra , computed vibrational spectra and structures of 1 , 2 , and 3 .1,2 , ... and nh indicate the oh and nh vibrational mode assignments ; relative energies ( at 0 k ) and free energies ( at 298 k ) , kj mol , are shown in brackets . structural assignments are based first on the correspondence between the experimental ( irid ) and computed vibrational spectra and second on their relative energies , favoring the most stable conformer ( s ) . ( a ) the computed vibrational spectrum of the trans conformation of 1 predicted as the global minimum , corresponded best with the experimental irid spectrum associated with the major conformer ( 1 - trans ) while the lowest - lying cis conformation corresponded to the irid signature of the minor conformer ( 1 - cis ) . ( b ) the irid and computed vibrational spectra associated with the three lowest - energy conformations of manc -1,4-glcnacb2 ; the two lowest ( which differ only in the orientation of the hydroxymethyl group on the mannopyranoside ring ) both display 2 - cis conformations . the commonly observed b - ring acetamido oh - 3 interaction in the two units 1 and 2 lends further support to the building block approach adopted here . cis conformer of 3 is in good qualitative agreement with the irid spectrum of the trisaccharide 3 , manc -1,4-glcnacb-1,4-glcnaca . the glucopyranoside rings in the 1 - trans conformer are supported by two inter - ring hydrogen bonds , oh - 3a oh - 6b ( o - 5b ) , while a third , stronger oh - 3b o = c ( nh ) b bond pulls the b - ring acetamido group into the plane of the pyranose ring . the 1 - cis conformer ( figure 3a ) , which has a similar relative energy at 0 k but a higher free energy at 298 k , is supported by a strong oh - 6b oh - 6a hydrogen bond ; a further inter - ring interaction , nhb oh - 3a contributes to a cooperative chain , oh - 4b oh - 3b o = c ( nh ) boh - 3a o = c ( nh ) a , to provide additional stabilization . since both acetamido groups are now able to interact with their neighboring oh - 3a / oh - 3b groups , both are rotated toward the plane of their respective pyranose rings . the disaccharide unit manc -1,4-glcnacb 2 straddles the unusual - mannoside linkage . its irid spectrum is in good accord with a superposition of the vibrational spectra associated with its two lowest - energy conformers ( 2 - cis ) , but is quite unlike that of the lowest - lying 2 - trans conformer ( 9.9 kj mol higher , figure 3b ) . the 2 - cis conformation is supported by two inter - ring hydrogen bonds , oh - 2c o - 3b and oh - 6c o - 6b , and the b - ring acetamido group is again hydrogen bonded to its nearest neighbor , oh - 3b o = c ( nh ) b . the irid spectrum of the manc -1,4-glcnacb-1,4-glcnaca trisaccharide 3 , ( figure 3c ) , which extends from 3200 to 3600 cm , displays three broad maxima below 3500 cm and congested weaker features at higher wavenumbers , indicating contributions from strong and weakly hydrogen - bonded oh groups . although poorly resolved , its contour is in qualitative correspondence with the ir spectrum associated with its minimum - energy structure . this presents cis - oriented manc - glcnacb and glcnacb - glcnaca segments , linked together by two very strong hydrogen bonds that connect the terminal manc and the central glcnacb units , and a third that links glcnacb with glcnaca . the next conformation lies 12.2 kj mol higher in energy ; it only presents a single inter - residue hydrogen bond , and its calculated vibrational spectrum does not reproduce the experimental band at low wavenumber ( figure s11 ) . the structural information obtained from irid spectroscopy was developed further through computation , to explore the effect of explicit hydration andblocking ( to cap hydroxyls that would be absent in extended oligosaccharides ) . the lowest - energy computed structures of the monohydrate 1h2o and also 2h2o ( figures 4a , b , s6 , and s8 ) now both present trans conformations , supported by the bound water molecule which bridges across the two pyranose rings . in 1h2o this creates an extended cooperative chain , oh - 4boh - 3b o = c ( nh ) b h2o oh - 6a o - 1a , which greatly strengthens the inter - ring binding by linking nhb to o - 6a and , as a consequence , also strengthens the supporting inter - ring bond , oh - 3a oh - 6b ( o - 5b ) ( r [ oh3ao6b ] 2.162.07 ) . its relative energy now lies 4.5 kj mol below that of the lowest - lying cis hydrate , cf . 0.6 kj mol in the bare unsolvated disaccharide 1 ( figure s6 ) . this contrasts markedly with hydrated cellobiose ( glc -1,4-glc ) where a cis conformation is retained . explicit hydration therefore locks the trans conformation of 1 , enhancing the rigidity of thestem . nmr studies of chitobiose in an aqueous environment at 298 k also identify a very similar average conformation in solution . the two acetamido groups continue to adopt a trans relative disposition , consistent with the maintenance of a rigid conformation about the inter - ring glycosidic bond , reinforced perhaps by transiently bound , bridging water molecules . hydrated and blocked structures of the core pentasaccharide building blocks . the computed lowest - energy structures of ( a , b ) , the monohydrates 1h2o and 2h2o and ( c , d ) the blocked subunits 2 - b and 2 - bh2o , in which the 6 - ohc group is modified to the methyl ether , and ( e ) the blocked subunit 3 - b . note the effect of blocking ; in 2 - bh2o it removes the water bridge present in 2h2o ( and 1h2o ) , and in 2 - b and 3 - b it switches the conformation about the manc - 1,4 c - glcnacb linkage from cis to trans . blocked sites , explored here through the use of a methyl ether capping group . the central glycosyl residue in the core pentasaccharide , manc , is itself glycosylated on hydroxyl groups oh - 6 and oh - 3 , thereby precluding donor hydrogen bonds from these positions . the dramatic structural consequences of this are revealed in the finding that the lowest - energy conformer of theblocked man ( 6 - ome ) c -1,4-glcnacb disaccharide 2 - b ( and also its hydrate , 2 - bh2o ) adopts a trans orientation , in contrast to the strongly preferred cis conformation of 2 ( compare figures 3b and 4c ) ; the lowest - energy 2 - b - cis conformer now lies 5 kj mol above the global minimum . unlike 2 - cis ( figure 3b ) , the trans conformer of 2 - b is only supported by a single , weak inter - ring hydrogen bond , oh - 3b o - 5c . the trans conformation is also retained in the hydrate ( figure 4d ) where the water molecule localizes on the glcnacb ring , inserted between the acetamido group and o - 3 rather than forming an inter - ring bridge , again in contrast to hydrated chitobiose . the reduced inter - ring bonding increases the flexibility about the manc - glcnacb glycosidic linkage , to provide a fluxional pivot . similarly , in 3 - b the blocked manc oh - 6 group lacks the hydrogen bond found in 3 that linked the manc and glcnacb units ( figure 4e ) . the manc - glcnacb segment again switches from cis to trans to create a more flexible local structure about the - mancpivot , very similar to that of 2 - b , and the trisaccharide adopts a more extended structure , with r [ o - 4co - 1a ] increasing from 11.2 to 14.5 . the r2pi spectrum of the core pentasaccharide 4 ( figure 5a ) is centered at the same wavenumber as the trans conformer of 1 and 3 ( also trans about glcnacb - glcnaca ) , providing circumstantial evidence for a possible preference for a trans glcnacb - glcnaca conformation in 4 also . since the pentasaccharide contains 14 hydroxy and 2 acetamido groups , structures that optimize global oho and nho hydrogen bonding are to be expected in the gas phase : not surprisingly , its irid spectrum ( figure 5b ) presents a broad red - shifted quasi - continuum , ranging from 3100 to 3700 cm . this suggests a highly congested set of overlapping bands associated with a large number of both strong , and weak , hydrogen bonded oh and acetamido groups . ( a ) resonant two - photon ionization ( r2pi ) spectra of the chitobiose stem , 1 , the trisaccharide linker , 3 , and the complete core pentasaccharide , 4 . molecular mechanics simulations , undertaken partly in response to the limitations of the experiment ( see also supporting information methods and results and figures s13 and s14 ) , also predicted a preference for a large number of hydrogen bonds ( defined by r [ oho ] 2.5 , [ oho ] 120 ) in the isolated pentasaccharide , see figure 6a ( i ) , and also its triply hydrated complex , figure 6a ( ii ) , with 68 being the optimal number for the isolated molecule ( using the opls2005 force field , figure s13 ) . the simulations in bulk water , figure 6a ( iii ) , predicted disruption of the intramolecular networks , leaving only 24 hydrogen bonds in the low - energy ensemble ( figure s13 ) . ( a ) the lowest - energy structures of the core pentasaccharide calculated on the opls2005 and glycam06 / amber potential energy surfaces : ( i ) the isolated molecule ; ( ii ) the triply hydrated complex ( the water molecules were initially located at binding sites based upon the preferences of singly hydrated 1 , 2 , and the trimannosyl mane ( mand ) manc head unit ) ; and ( iii ) in bulk water , ( hydrogen bonds shown in red ) . ( iv ) an overlay of the open conformer of the trimannosyl mane ( mand ) manc head unit and the core pentasaccharide in ( v ) ;( v ) the preferred aqueous structure of the high mannose glycan , man9glcnac2 , determined through nmr measurements and molecular dynamics simulations . ( b ) distributions of the longest intramolecular distances ( for conformers with energies 30 kj mol ) in the core pentasaccharide , predicted by molecular mechanics ( opls2005 ) simulations : isolated , unsolvated ( red ) , explicitly hydrated ( green ) , and in bulk water ( black ) . as a consequence , the unsolvated pentasaccharide 4 , preferentially adopted compact structures with the distal man3 head unit folded back , supported by hydrogen - bonded interactions with the proximal glcnac2 unit , which presented a cis conformation about the glcnacb - glcnaca linkage ( although trans conformations , generally associated with more extended structures , were also present at higher relative energies ) . the addition of water molecules in the gas phase , figure 6a ( ii ) , disrupted the intramolecular hydrogen - bonding pattern . the lowest - energy conformers of the triply hydrated complex , figure 6a ( ii ) , presented more extended structures , now with a trans configuration about the glcnacb - glcnaca linkage ( figure 4 ) , supported by water bridging across the inter - ring bond and extended cooperative hydrogen - bonded networks ( which were conserved in both low and high energy structures ) . in bulk water , the intramolecular hydrogen bonds were largely washed out ; the ( near identical ) lowest - energy structures predicted by opls2005 and glycam06 / amber , figure 6a ( iii ) , again presented a trans glcnacb - glcnaca stem , but now part of a fully extended structure in which the distal man3 unit was completely unfurled . strikingly , apart from the difference in the dihedral angle ( h1 - c1 - o6 - c6 ) between manc and mane , the preferred structure of the solvated core pentasaccharide was very similar to that of the core unit in the high - mannose glycan , man9glcnac2 , determined through coupled nmr measurements and molecular dynamics simulation using the glycam93 / amber force field , figure 6a ( iv , v ) . there were also remarkable similarities between the conformations of the distal man3 head unit in bulk water , found here , and the isolated ( hydrated ) man3 unit , determined in solution and predicted through investigations in the gas phase , figure 6a ( iv ) , and also between the conformation ( and flexibility ) of the manc - glcnacb segments in thethe analysis of intramolecular distances ( using the opls2005 simulations ) , shown in figures 6b and s14 , provided a way of estimating molecular size and hence the favorability of extended versus compact structures . the longest end - to - end distribution for the unsolvated , isolated core pentasaccharide reflected flexibility , but the most favored distance ( 16.7 ) indicated a compact structure corresponding to a geometric cross - section ( 230 ) similar to the gas kinetic cross - section ( 260 ) reported for the doubly sodiated core pentasaccharide ion , which is also likely to be compact . addition of three water molecules resulted in a broad distribution with peaks at 21.5 and 23.5 , indicating a more extended but still flexible structure . in bulk water , however , the structures were exclusively extended and relatively inflexible , with a narrow spread of end - to - end distances peaked at 23.4 . naked core pentasaccharide that uncurled as it became hydrated , with conserved structural motifs taking shape , in particular the trans conformation of the proximal chitobiose unit , to provide an extended , well - defined structure in aqueous solution . a recent bioinformatics analysis of thousands of glycoproteins listed in the pdb found that many n - glycans showed significantly similar substructures close to the protein , suggesting their use as fragments in glycan modeling ( and supporting the approach employed in the present , experimentally based study ) . the n - glycans also displayed a rigid protein - proximal glcnacb - glcnaca stem . the acetamido groups of the stem appear to play a key role ; in the gas phase the preferred trans conformation of 1 is strengthened by microhydration through an inter - ring bridging water molecule linking the glcnacb acetamide to o - 6a . in bulk water , molecular dynamic simulations predict the absence of a direct inter - ring bond between these groups , which suggests the trans chitobiose stem is held in a rigid extended conformation throughthe other glcnaca acetamide is predicted to be unbonded , leaving it free to act as a hydrogen - bond donor / acceptor and anchor the glycan to the peptide backbone of the glycoprotein . hexoses ( such as the more abundant d - glucose , glc ) that lack this acetamide could not form such strong hydrogen bonds ( if they were to play the roles of glcnaca and glcnacb ) and would not match the rigidity of the glcnac2 stem nor the potential for anchoring with the protein backbone . the next structural feature , provided by the central - mannoside manc - glcnacb , also contains a glycosidic linkage formed through oh6c that precludes formation of the oh6c o6b inter - ring hydrogen bond found in the isolated unit 2 . instead of the compact cis conformation adopted by 2 , supported by two inter - ring hydrogen bonds , the deletion of one of them has the key effect of greatly increasing the flexibility of the - mannoside linkage , which adopts a trans conformation that is unaffected by discrete hydration . its inherent flexibility allows the - mannosyl residue to act effectively as a pivot between the rigid chitobiose stem and the outer trimannosyl head . unsolvated structures of 4 are compacted by many intramolecular hydrogen bonds ( figure 6a ( i ) ) . however , discrete hydration sees the structure begin to unfurl with a water molecule stabilizing the rigid chitobiose stem ( vide supra ) , while the trimannosyl head unit folds over to encapsulate water in another pocket . in a fully aqueous environment , a picture emerges ( figure 7 ) of an n - linked glycan accommodating an extended core pentasaccharide structural unit that incorporates a rigid proximal chitobiose stem , anchored at one end to the adjoining protein and at the other connected through a more flexible - mannoside pivot to the branched mannosyl d and e arms . an extrapolated structural model for the n - glycan core in an aqueous environment . in the absence of water ( a ) , the pentasaccharide would adopt a compact conformation , but the interactions between the building blocks of the core pentasaccharide and water ( b ) lead , in solution ( c ) , to a rigid chitobiose stem that is anchored at one end to the peptide and at the other , through a flexible pivot , to a - mannosyl structure that projects the information - rich distal head of the glycan for interaction with other partners . the red dots indicate favored water - bridging sites identified here or in previous investigations . this combines both structural integrity and freedom of movement to allow interaction with binding partners . the extended display of the n - glycan would leave the distal branch - tip sugars free to function as potential ligands for receptors and also provide the potential for levered interactions promoting a conformationalthe latter could explain the apparent ability of the calnexin / calreticulin chaperone system to bind the tips of the sugars found on n - glycoproteins while still being able to stimulate proper folding of the underlying n - glycoprotein . the selection of chitobiose , with its two acetamido groups rather than cellobiose for the stem , appears to be critical , facilitating hydrogen - bonded interactions with neighboring amino acid residues and suggesting a mechanism by which the core pentasaccharide influences the structural stability of the adjacent peptide chain and its folding kinetics . the central mane ( mand ) manc unit , which unfurls upon hydration , presents the information - rich outer extremities of n - glycans to the environment ( for solubility , recognition , or transport ) .\noutput:\n" }, { "from": "agent", "value": "n - glycosylation of eukaryotic proteins is widespread and vital to survival . the pentasaccharide unit man3glcnac2 lies at the protein - junction core of all oligosaccharides attached to asparagine side chains during this process . although its absolute conservation implies an indispensable role , associated perhaps with its structure , its unbiased conformation and the potential modulating role of solvation are unknown ; both have now been explored through a combination of synthesis , laser spectroscopy , and computation . the proximal glcnac - glcnac unit acts as a rigid rod , while the central , and unusual , man -- 1,4 - glcnac linkage is more flexible and is modulated by the distal man -- 1,3 and man -- 1,6 branching units . solvation stiffens the rod but leaves the distal residues flexible , through a - man pivot , ensuring anchored projection from the protein shell while allowing flexible interaction of the distal portion of n - glycosylation with bulk water and biomolecular assemblies ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: unaltered intra - abdominal fat is manifested by a broad echogenicity range , which makes the identification of its nature difficult . the signs that can aid the interpretation include : smooth outlines , homogeneous structure , no infiltration of adjacent tissues , relatively high elasticity and no vascularization . the deposited fat can present itself as diffuse , regional or tumor - like thickening . any doubts must be verified in ct or mri , or sometimes by a biopsy , preferably the core - needle one . autorzy nie zgaszaj adnych finansowych ani osobistych powiza z innymi osobami lub organizacjami , ktre mogyby negatywnie wpyn na tre publikacji oraz roci sobie prawo do tej pracy .\noutput:\n" }, { "from": "agent", "value": "unaltered fat is a permanent component of the abdominal cavity , even in slim individuals . visceral adiposity is one of the important factors contributing to diabetes , cardiovascular diseases and certain neoplasms . moreover , the adipose tissue is an important endocrine and immune organ of complex function both when normal and pathological . its role in plastic surgery , reconstruction and transplantology is a separate issue . the adipose tissue has recently drawn the attention of research institutes owing to being a rich source of stem cells . this review , however , does not include these issues . the identification of fat is relatively easy using computed tomography and magnetic resonance imaging . it can be more difficult in an ultrasound examination for several reasons . the aim of this paper is to present various problems associated with us imaging of unaltered intra - abdominal fat located beyond organs . based on the literature and experience , it has been demonstrated that the adipose tissue in the abdominal cavity has variable echogenicity , which primarily depends on the amount of extracellular fluid and the number of connective tissue septa , i.e. elements that potentiate the number of areas that reflect and scatter ultrasonic waves . the normal adipose tissue presents itself on a broad gray scale : from a hyperechoic area , through numerous structures of lower reflection intensity , to nearly anechoic regions mimicking the presence of pathological fluid collections . the features that facilitate proper identification of this tissue are : sharp margins , homogeneous structure , high compressibility under transducer pressure , no signs of infiltration of the surrounding structures and no signs of vascularization when examined with the color and power doppler . the accumulation of fat tissue in the abdominal cavity can be generalized , regional or focal . the identification of the adipose tissue in the abdominal cavity using ultrasonography is not always easy . when in doubt , the diagnostic process should be extended to include computed tomography or magnetic resonance imaging , or sometimes biopsy ( preferably the core - needle one ) ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: many animals spend their entire or some of their life cycle attached to other organisms or substrates . this life strategy is common in ectoparasites , epizoic species , sedentary benthic organisms , and inhabitants of wave - swept shores . a wide variety of attachment mechanisms are found in invertebrates such as monogeneans ( platyhelminthes ) , gastropods and bivalves ( mollusca ) , barnacles ( crustacea ) , beetles ( insecta ) , spiders and mites ( arachnida ) , and sea urchins ( echinodermata ) . attachment structures vary in structure , localization , and origin , and their classic examples are suckers , food pads , hooks , claws , spines , and clamps . the ability for permanent or temporary attachment may also be enabled by gland ( s ) producing a sticky substance that is released outside of the body . such an attachment mechanism is common and well known in monogeneans , mussel byssus , spiders , barnacles , and sea urchins ( whittington et al .2004 ; bromley and heinberg 2006 ; brazee and carrington 2006 ; aldred and clare 2008 ; santos et al . 2009 ; dodou et al . 2011 ; farsad and sone 2012 ; sahni et al . spiders produce a sticky substance that has a variety of applications and may be used not only for attachment but also for dispersal , procuring food , and cocoon production . a highly specialized structure used only for temporary attachment to the carrier , which recently has been examined ( bajerlein and witaliski 2012 ; bajerlein et al . phoresy as a way of dispersal is common in mites inhabiting unstable and patchily distributed microhabitats such as animal dung , compost soil , social hymenopteran insect ( e.g. , bumblebees ) and bird nests , and carrion ( faasch 1967 ; evans 1992 ; athias - binche 1994 ; man 2001 ; bajerlein et al . if the microhabitat is ephemeral or its conditions become unfavorable , deutonymphs of uropodina disperse by using coexisting arthropods in order to colonize a new habitat , more suitable for further development . phoretic deutonymphs of uropodina mites use primarily insects for dispersal and among these mostly beetles from the families aphodiidae , brenthidae , cerambycidae , geotrupidae , histeridae , passalidae , scarabaeidae , silphidae , and staphylinidae ( athias - binche et al . phoretic relationships between deutonymphs of uropodina and beetles date back to the eocene ( dunlop et al . , the pedicel resembles a straight stalk of variable length with enlarged termini ( faasch 1967 ; bajerlein and witaliski 2012 ; bajerlein et al . one terminus of the pedicel adheres to the deutonymph s anus , and the second terminus is attached to the surface of the carrier . from the biomechanical point of view , the termini of the pedicel constitute an example of a mushroom shaped attachment structures . such adhesive biological structures are common and known , e.g. , in molluscs ( mussel byssus threads ) , spiders ( dragline attachment ) , echinoderms ( tube feet ) , and cnidaria ( polyp foot ) , and were studied in detail by various authors ( gorb and varenberg 2007 ; gorb et al . 2007 ; carbone et al . 2011 ) . the substance for the pedicel is produced by the pedicellar gland occurring dorsally over the colon in the rear part of the deutonymph s body and is secreted outside through the anus ( bajerlein and witaliski 2012 ) . the formation of a pedicel occurs when a phoretic deutonymph situates itself with its anus on the carrier , secretes the pedicellar substance , and gradually straightens its fourth pair of legs . longer pedicels are formed as a result of elongation of one that has already been produced , i.e. , a deutonymph attached to the carrier via a pedicel starts to walk forward and extends the latter . after colonizing a new habitat , the deutonymph detaches from its carrier and the pedicel usually remains on the carrier s body ( faasch 1967 ) . the pedicel is a temporary structure , and a single deutonymph may produce many pedicels throughout life . phoretic deutonymphs of uropodina may attach to various parts of the carrier , and topical specificity was found in deutonymphs of some species ( schwarz et al . phoretic deutonymphs attached to their host were already noticed and illustrated in the eighteenth century ( de geer 1768 ) , but the first detailed observations were presented by faasch ( 1967 ) , who analyzed adaptation to phoresy and phoretic behavior in uropoda orbicularis ( mller , 1776 ) and uroobovella marginata ( c. l. koch , 1839 ) . ( 2013 ) described the anatomy and fine structure of the pedicellar gland as well as morphological diversity of pedicels by transmission ( tem ) and scanning electron microscopy ( sem ) , but also revealed that pedicels within the same species are highly variable in length . vitzthum ( 1943 ) noted that pedicels may be short or long . in the laboratory , more detailed observations were conducted by faasch ( 1967 ) who found that in the absence of food , pedicels of u. marginata become shorter and eventually cease to be produced . moreover , in u. orbicularis , the frequency of pedicel production is negatively correlated with pedicel length . according to faasch ( 1967 ) , pedicels in u. marginata are characterized by variable length , whereas in u. orbicularis , the length is relatively constant . since the latter observation is in contrast to our previous results ( bajerlein et al .2013 ) , we carried out ecomorphological studies to determine the factors affecting pedicel length and , in particular , to examine whether deutonymph localization and density on the carrier are important for pedicel length . thus , two hypotheses were tested as follows : ( 1 ) pedicel length differs between different attachment sites on the carrier body , and ( 2 ) pedicel length is affected by deutonymph density . the study was conducted on a common phoretic uropodid species u. orbicularis and two dung beetle species aphodius prodromus ( brahm , 1790 ) and aphodius distinctus ( o. f. mller , 1776 ) ( aphodiidae ) . adults of aphodiid beetles with phoretic deutonymphs of u. orbicularis were collected in may and june of 20032004 during field studies on a pasture grazed by cattle in the western part of poland ( wielkopolska region ) . beetles and mites were collected using six dung - baited pitfall traps filled with ethylene glycol solution . every 7 days , insects and mites were gathered and then stored in 75 % ethylene alcohol . is a mite species recorded in europe and north america ( winiewski and hirschmann 1993 ; majka et al . it is present in unstable microhabitats such as animal dung and compost soil , and phoretic dispersal is a vital life strategy in this species ( bajerlein 2011 ) . phoretic deutonymphs are found on various beetles , but most frequently on coprophilous beetles from the families of aphodiidae , geotrupidae , scarabaeidae , histeridae , and hydrophilidae ( winiewski and hirschmann 1993 ; bajerlein 2011 ) . phoresy of u. orbicularis on coprophilous beetles including the two studied aphodius species was observed in poland in spring and autumn ( bajerlein 2011 ) . a. prodromus and a. distinctus are beetles of the family aphodiidae and dominate dung beetle communities in poland in early spring and in autumn . both species are saprophagous and are often found in dung of herbivorous mammals , compost and in decaying plants ( stebnicka 1976 ) . in order to determine whether the site of deutonymph attachment affects pedicel length , we compared pedicel length between deutonymphs attached to the following six body parts of a. prodromus : ( 1 ) area formed by femora and trochanters of the third pair of legs ; ( 2 ) ventral surface between second and third pair of legs ; and ( 3 ) apex , ( 4 ) slope , ( 5 ) upper part , and ( 6 ) lateral surfaces of elytra ( fig . measurements of 40 pedicels collected from each of the six body parts were made . to exclude the possible influence of deutonymph density on pedicel length , we analyzed cases with one pedicel attached to a given body part of the carrier or cases in which the distance between the site of pedicel attachment of two or more deutonymphs was at least three times larger than deutonymph body length .1 lateral ( a ) and ventral ( b ) view of the body of aphodius prodromus with indication of the analyzed body parts lateral ( a ) and ventral ( b ) view of the body of aphodius prodromus with indication of the analyzed body parts to determine the relationship between density of phoretic deutonymphs and pedicel length , we compared the length of pedicels attached to the area that is formed by the femur and trochanter of the third pair of legs in a. prodromus and a. distinctus , one of the most frequently infested body parts of these beetles ( bajerlein and boszyk 2004 ) . u. orbicularis does not show preferences toward either of these two aphodiid species ( bajerlein and boszyk 2004 ; bajerlein 2011 ) . we calculated mean pedicel length ( mpl ) for five categories of deutonymph density ( 15 ) . the first category ( 1 ) involved cases when only one deutonymph was attached to the considered area of hind legs . the other categories ( 25 ) included cases when two , three , four , and five deutonymphs were attached . in fact , this part of the body of the beetle can be infested by more than five deutonymphs , but this is less frequently observed and we excluded such cases from analyses . to examine the relationship between size of phoretic deutonymphs and the size of infested body part , we measured the area of 40 phoretic deutonymphs chosen randomly and the area formed by the femora and trochanters of a. prodromus ( n = 40 ) and a. distinctus ( n = 40 ) . all measurements were taken from digital images obtained using an olympus sz61 stereomicroscope fitted with a camera and cell a software ( olympus corporation , tokyo , japan ) . first , a beetle with attached deutonymphs was taken from the alcohol and gently dried using a paper towel . then , it was placed on a styrofoam pad covered with double - sided sticky tape . next , photos of the following beetle body parts were taken : dorsal side ( for measurement of beetle length , i.e. , distance from the front edge of the pronotum to the posterior end of elytra ) , and body parts with attached deutonymphs . after taking photographs , pedicel carrier termini were detached from the beetle using a dissection needle . in this way , pedicels were still attached to the deutonymphs . in order to measure the length of the pedicel , such deutonymphs were placed dorsally on a styrofoam pad with their pedicels parallel to its surface and photographs were taken . the length of the pedicel was routinely measured as the distance between its two termini . differences in length between pedicels attached to different body parts of a. prodromus were tested using one - way analysis of variance ( anova ) . for the purpose of multiple pairwise comparisons , tukey s honest significant difference ( hsd ) test was used . in order to analyze whether deutonymph density affected pedicel length , first we used one - way anova to evaluate the significance of carrier species ( a. prodromus and a. distinctus ) on pedicel length . although differences in body size between these species were statistically significant ( f ( 1,78 ) = 189.19 , p 0.05 ) , carrier species did not significantly affect pedicel length ( f ( 1,652 ) = 0.34906 , p 0.05 ) . in the next step , we combined deutonymph densities from these species and used one - way anova to test how deutonymph density affected pedicel length . the numbers of analyzed cases within particular categories of deutonymph density were as follows : n = 80 for category 1 , n = 82 for category 2 , n = 60 for category 3 , n = 39 for category 4 , and n = 14 for category 5 . for the purpose of multiple pairwise comparisons , tukey s hsd test for unequal samples was used . additionally , pearson s correlation coefficient ( r ) was calculated for deutonymph densities and pedicel length . a 5 % level of significanceour study revealed that the localization of phoretic deutonymphs of u. orbicularis on adult a. prodromus ( fig .2 ) affects pedicel length ( anova ; f ( 5,234 ) = 28.894 , p 0.05 ) ( fig . 3 ) . the longest pedicels are produced by phoretic deutonymphs attached to the upper part of elytra : mpl = 563.4 m ( confidence interval ( ci ) : 518.2608.6 ) and the shortest by deutonymphs attached to the area formed by femora and trochanters of the third pair of legs : mpl = 282.6 m ( ci : 256.5308.8 ) and the apex of elytra : mpl = 311.0 m ( ci : 285.2336.8 ) ( fig . mpls of deutonymphs attached to other parts of the carrier were similar in size : 447.6 m ( ci : 400.7494.4 ) for lateral surfaces of elytra , 427.7 m ( ci : 389.4466.1 ) for the slope of elytra , and 419.0 m ( ci : 378.1459.8 ) for the ventral surface between the second and third pairs of legs of beetles ( fig . 3 ) . fig . a two deutonymphs attached to the slope and one ( arrow ) attached marginal to the lateral surface of the elytron . b one deutonymph and a number of pedicels attached to the apex of elytra . a group of pedicels is visible on the upper part of the right elytron . c upper and lateral parts of elytron showing one attached deutonymph and many pedicels of variable length , much longer on the upper part than the lateral part . inset : three pedicels collected from apex , slope , and upper part of elytra ( from left to right ) . note difference in length . d a group of deutonymphs and free pedicels attached to the femur and trochanter of the hind leg . despite the close location of several pedicellar attachments on the beetle leg ( indicated by a bracket ) , the deutonymphs are distant from each otherfig .3 mean pedicel length in deutonymphs ( n = 40 ) attached to different parts of aphodius prodromus . apex , slope , upper and side represent apex , slope , upper flat surface and lateral surfaces of elytra , respectively ; legs femora and trochanters of the third pair of legs , and ventral ventral surface between the second and the third pair of legs . boxes and vertical bars denote standard errors of the means and 0.95 confidence intervals , respectively . different letters denote significant differences between experimental groups in pairwise comparison ( p 0.05 ) examples of localization of phoretic deutonymphs of uropoda orbicularis on aphodius prodromus . a two deutonymphs attached to the slope and one ( arrow ) attached marginal to the lateral surface of the elytron . b one deutonymph and a number of pedicels attached to the apex of elytra . a group of pedicels is visible on the upper part of the right elytron . c upper and lateral parts of elytron showing one attached deutonymph and many pedicels of variable length , much longer on the upper part than the lateral part . inset : three pedicels collected from apex , slope , and upper part of elytra ( from left to right ) . d a group of deutonymphs and free pedicels attached to the femur and trochanter of the hind leg . despite the close location of several pedicellar attachments on the beetle leg ( indicated by a bracket ) , the deutonymphs are distant from each other mean pedicel length in deutonymphs ( n = 40 ) attached to different parts of aphodius prodromus . apex , slope , upper and side represent apex , slope , upper flat surface and lateral surfaces of elytra , respectively ; legs femora and trochanters of the third pair of legs , and ventral ventral surface between the second and the third pair of legs . boxes and vertical bars denote standard errors of the means and 0.95 confidence intervals , respectively . different letters denote significant differences between experimental groups in pairwise comparison ( p 0.05 ) our analysis did not falsify the hypothesis that increasing density of phoretic deutonymphs of u. orbicularis affects pedicel length ( anova ; f ( 4,649 ) = 6.4486 , p 0.05 ) ( fig . 4 ) . we found a strong positive correlation between mpl and deutonymph density r = 0.8 ( p 0.05 ) ( fig . 5 ) . the shortest pedicels are formed in cases when only one phoretic deutonymph is attached to the third pair of legs of beetles . the highest mpl was observed when five deutonymphs were attached . in cases of high deutonymph density ( 4 ) , we often observed that the attached mites formed pedicels of variable length ( fig . one or two deutonymphs have pedicels of standard length , i.e. , characteristic for the case of only one attached deutonymph . other deutonymphs produced longer pedicels , some of which were unusually long ( fig . the mean areas of the femur and trochanter in a. prodromus and a. distinctus were 655,141.6 m and 465,162.5 m , respectively . the mean area of the body of phoretic deutonymphs of u. orbicularis was 272,971.8 m . thus , there are 2.4 and 1.7 tightly packed deutonymphs for each potential attachment site in a. prodromus and a. distinctus , respectively.fig .4 mean pedicel length of phoretic deutonymphs of uropoda orbicularis found in different deutonymph density categories ( number of deutonymphs attached to the femur and trochanter of the third pair of legs ) . boxes and vertical bars denote standard errors of the means and 0.95 confidence intervals , respectively . different letters denote significant differences between experimental groups in pairwise comparisons ( p 0.05 ) fig .5 scatter plot between mean pedicel length in uropoda orbicularis and five categories of deutonymph density ( 15 ) . the categories ( 15 ) include cases when one , two , three , four , and five deutonymphs were attached . number of measurements for each category of density is as follows : n ( 1 ) = 80 , n ( 2 ) = 164 , n ( 3 ) = 180 , n ( 4 ) = 156 , n ( 5 ) = 70 mean pedicel length of phoretic deutonymphs of uropoda orbicularis found in different deutonymph density categories ( number of deutonymphs attached to the femur and trochanter of the third pair of legs ) . boxes and vertical bars denote standard errors of the means and 0.95 confidence intervals , respectively . different letters denote significant differences between experimental groups in pairwise comparisons ( p 0.05 ) scatter plot between mean pedicel length in uropoda orbicularis and five categories of deutonymph density ( 15 ) . the categories ( 15 ) include cases when one , two , three , four , and five deutonymphs were attached . number of measurements for each category of density is as follows : n ( 1 ) = 80 , n ( 2 ) = 164 , n ( 3 ) = 180 , n ( 4 ) = 156 , n ( 5 ) = 70the mechanisms of attachment in uropodina have rarely been studied ; u. orbicularis is one of the species that has received more attention ( faasch 1967 ; bajerlein and witaliski 2012 ; bajerlein et al . previous experiments by faasch ( 1967 ) were focused on biological factors affecting pedicel length in u. orbicularis and u. marginata such as starvation and the frequency of pedicel formation and shown that under prolonged starvation , phoretic deutonymphs produce shorter pedicels or even cease production altogether . further , if a deutonymph produces a series of successive pedicels , the subsequent pedicels are shorter . in contrast to faasch ( 1967 ) , we examined pedicel length using deutonymphs collected in the field , i.e. , in non - starved individuals and analyzed pedicel length in relation to the site of attachment and deutonymph density . a study on topical specificity of u. orbicularis has shown that phoretic deutonymphs of this species may attach to various parts of a beetle , but some parts are preferred ( bajerlein and boszyk 2004 ) . most frequently phoretic deutonymphs of this species are found on elytra and on the third pair of legs . in general , the number of phoretic deutonymphs is higher on the rear part of the beetle . we have shown that deutonymphs attached to the legs of the carrier form shorter pedicels in comparison to deutonymphs fixed to the elytra , especially their upper part . in general , deutonymphs form longer pedicels when attached to the exposed parts of the carrier ( upper part and lateral surfaces of elytra ) , and shorter pedicels when attached to non - exposed parts ( apex of elytra and third pair of legs ) . differences in pedicel length in mites recorded on different parts of the carrier may reflect the risk of being detached . short pedicels are likely produced when deutonymphs are attached to safe body parts , i.e. , sites that protect the deutonymph from being dislodged when a beetle digs a tunnel in soil or in dung . in particular , such safe places include the legs and the apex of the elytra . deutonymphs attached to legs are situated underneath the beetle and are protected by its body . similarly , deutonymphs that settle on the apex of the elytra are located behind the carrier , so they do not have direct contact with the surrounding soil . presumably , a mite with a long pedicel can walk on the surface of its carrier and position itself in places with a lower risk of being detached . this explanation seems to be most probable and evidenced by decreasing length of pedicels from upper part of elytra to the apex . another explanation for the limited length of pedicels is related to the mode of elongation . during pedicel formation , a mite walks forward to extend the pedicel ( faasch 1967 ) , what is possible due to pedicel high expandability , but requires a free surface on which the mite can walk . probably , this is easier for deutonymphs attached to the upper surface of elytra than to the apex . nevertheless , this hypothesis seems rather unlikely , since our results have shown that even deutonymphs attached to the femur are able to produce long pedicels and , moreover , the pedicels of subsequently attached deutonymphs can be longer than those previously attached . the formation of pedicels of various length by deutonymphs attached to the elytra may be associated with flight of the beetle . during flight aphodiid beetleshold the elytra open and long pedicels may facilitate keeping deutonymphs attached , but presently we know nothing about deutonymph behavior during carrier flight . the adhesive strength of a glue is affected by its chemistry and roughness of the substrate . previous studies on the pedicel have shown that it is used for attaching to smooth surfaces of the carrier ( faasch 1967 ; mertins and hartdegen 2003 ; bajerlein and boszyk 2004 ) . the influence of topography of the carrier body on attachment in phoretic uropodina was discussed in detail by bajerlein et al . our observations have shown that most deutonymphs attached to elytra have the pedicellar disk fixed to the flat surface between pit rows ( fig . this confirms that not only surfaces covered by setae or bristles but also sculptured surfaces with microridges are avoided ; instead , flat surfaces without sculpture are preferred . on the other hand , topical specificity in uropodina can not simply be explained by the topography of the surface , since in most cases deutonymphs occupied the rear parts of elytra , although the topography of different parts of elytra is quite similar . our results have revealed that the length of the pedicel within a species may be associated with the site of attachment . however , we did not find differences in pedicel length collected from a. prodromus and a. distinctus , although differences in body size between these beetles were statistically significant . this is in accordance with ecomorphological studies on attachment structures in parasitic associations , e.g. , between monogeneans and fishes , and between feather lice and birds ( bush at al . the pedicel enables phoretic deutonymphs to use a wide variety of hosts on the one hand , and , on the other hand , due to its chemical and physical properties , allows modification of its length . in this way , phoretic deutonymphs can adjust to the prevailing dispersal conditions and increase the probability of successful dispersal . our study showed that the density of phoretic deutonymphs on the carrier affects pedicel length . the mean length of pedicels increases with increasing mite density and , consequently , longer pedicels allow more deutonymphs to disperse . in our opinion , this is caused by decreasing surface availability , making the attachment of additional deutonymphs difficult . we have shown that the surface of a phoretic deutonymph is only about two times smaller compared to the area of the femur and trochanter in a. distinctus and only two and a half times smaller if compared with the same area in a. prodromus . this means that if phoretic deutonymphs of u. orbicularis would produce very short pedicels such as , e.g. , deutonymphs of uroobovella pulchella ( berlese , 1904 ) ( bajerlein et al . u. pulchella is the smallest uropodina species studied by us ; phoretic deutonymphs of this species form an extremely short pedicel ( ca. 13 m ) and appear as if they were placed directly on the carrier . the formation of a longer pedicel maintains the deutonymph at a certain distance from the attachment site and enables more deutonymphs to become attached . moreover , the variable length of pedicels allows many deutonymphs to be distributed in three - dimensional space instead of one plane of the carrier surface . in our study , we often observed four , five , or more deutonymphs attached to the femur and a few of them produced pedicels of standard length ( i.e. , the length of the pedicel when only one deutonymph is attached ) and one or two deutonymphs had longer pedicels . this suggests that pedicel length may reflect the sequence of deutonymph attachment : deutonymphs with shorter pedicels attach earlier , whereas deutonymphs with longer pedicels attach subsequently . a commonly recorded phenomenon in phoresy of u. orbicularis is that deutonymphs travel in groups , and frequently , one deutonymph is attached next to the other , even if other beetle body parts are free of mites . as previously hypothesized ( bajerlein et al .2013 ) , dispersal in groups of immature stages may increase the chance to find a partner to mate after reaching the new habitat . such intraspecific aggregation , known as the aggregation model of coexistence , has been studied for many ectoparasites and facilitates their coexistence ( morand et al . observations on phoresy made by faasch ( 1967 ) have shown that phoretic deutonymphs prefer places already infested by deutonymphs . moreover , faasch ( 1967 ) noticed that even pedicels without deutonymphs stimulate attachment of additional deutonymphs . our earlier observations on the localization of u. orbicularis on beetles ( bajerlein and boszyk 2004 ) have shown that phoretic deutonymphs are characterized by topical specificity . attaching to the proper sitethus , two factors should be accounted when the phenomenon of group formation in u. orbicularis is explained : ( 1 ) the presence of previously attached mites of the same species , increasing the probability of finding a mating partner after reaching the new habitat , and ( 2 ) selection of a site that will provide safe dispersal . as we confirmed in this study , phoretic deutonymphs are able to produce pedicels of varying length according to localization on the host and deutonymph density , which is related to the availability of area for attachment . however , the pedicel is a structure that not only enables phoretic dispersal but also the ability to control its length allows an increase in number of carried deutonymphs , increasing the chance of successful colonization of and mating in a new habitat . it should be emphasized that the costs of longer and shorter pedicel formation seems to be comparable , since pedicel length and diameter are inversely proportional ( bajerlein et al . 2013 ) . this means that the diameter decreases as the length increases due to the expansion of newly formed pedicel without additional secretion of pedicellar substance . although mushroom - shaped adhesive organs have been the subject of many biomechanical studies , none of them involved termini of the pedicel in phoretic uropodina . in fact , up to now , the pedicel has been described only morphologically and ecologically . therefore , investigations on its biomechanical properties are needed to better understand the mechanism of phoretic deutonymph attachment to the carrier . moreover , biomechanical and biochemical approaches are desirable , since many biomaterials known from arthropods may be of medical importance ( kuhbier et al . 2011 ; kundu et al .\noutput:\n" }, { "from": "agent", "value": "the phoretic stage of uropodina mites is a deutonymph with developed morphological adaptations for dispersal by insects . phoretic deutonymphs are able to produce a pedicel , a stalk - like temporary attachment structure that connects the mite with the carrier . the aim of our study was to determine whether localization and density of phoretic deutonymphs on the carrier affect pedicel length . the study was conducted on a common phoretic mite uropoda orbicularis ( uropodina ) and two aphodiid beetles aphodius prodromus and aphodius distinctus . our results show that pedicel length is influenced by the localization of deutonymphs on the body of the carrier . the longest pedicels are produced by deutonymphs attached to the upper part of elytra , whereas deutonymphs attached to femora and trochanters of the third pair of legs and the apex of elytra construct the shortest pedicels . in general , deutonymphs attached to more exposed parts of the carrier produce longer pedicels , whereas shorter pedicels are produced when deutonymphs are fixed to non - exposed parts of the carrier . a second factor influencing pedicel length is the density of attached deutonymphs . mean pedicel length and deutonymph densities were highly correlated : higher deutonymph density leads to the formation of longer pedicels . the cause for this correlation is discussed , and we conclude that pedicel length variability can increase successful dispersal ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: binge drinking , defined as consuming five or more drinks on one occasion , is a common occurrence among many teen patients of family practitioners . despite the fact that these teens are under the legal age for purchasing alcohol , many adolescents engage in underage drinking , in general , and binge drinking , in particular . an estimated 19 % of underage american adolescents 1220 years of age were involved in binge drinking behavior at least once per month . there are many negative short - term and long - term outcomes of binge drinking . driving while intoxicated and subsequent alcohol related motor vehicle accidents are higher among adolescent binge drinkers . other alcohol related injuries and deaths such as choking on one 's vomit and alcohol poisoning are also consequences of binge drinking . adolescent binge drinkers are also more likely to be involved in physical fighting and to be injured and / or injure others when compared to nonbingers . binge drinking among adolescents is also associated with earlier initiation of sex , higher rates of sexual activity , more sexual partners , and increased prevalence of unprotected sex . binge drinking adolescent women also experience higher rates of sexual victimization , teen pregnancy , and parenting . even adolescent girls who consume moderate amounts of alcohol may experience disrupted growth and puberty . by their early 20s , individuals who had been underage binge drinkershave higher rates of health problems and unsafe health behaviors such as smoking , unprotected sex , and drunk driving . furthermore , they are much more likely to have not completed high school or college , and to be selling drugs . binge drinking is associated with subsequent alcoholism , adult binge drinking , and substance abuse problems . the monetary and economic cost of underage drinking is estimated to be 62 billion dollars annually . a constellation of risk factors are predictors of adolescents becoming binge drinkers : parental alcoholism , alienation , greater susceptibility to peer pressure , peers who are drinkers and / or taking illegal drugs , less parental monitoring , and lower academic functioning . males and white adolescentsare more likely to be binge drinkers than are females and visible minority members . adolescents are more likely to see family doctors than any other professional health care provider . little information is known about how many doctors discuss binge drinking with their adolescent patients . brief interventions by family physicians to reduce high risk drinking have been shown to result in significant long - term reductions in binge drinking behavior . in particular , there is the need for gender - specific analyses using representative community samples from countries other than the usa or uk . in order to address these gaps , this study 's objective was to determine the gender - specific demographic , health and health care utilization profile of binge drinking canadian youth aged 15 through 17 . the cchs 1.1 is a national cross - sectional survey of a representative sample of individuals aged 12 years and older . face - to - face interviews were conducted with 88 % of the sample and telephone interviews were conducted with the remaining 12 % . extensive details on the surveys ' methodologies and sampling strategies are provided elsewhere ( see ) . in canada , we chose to focus on 15 to 17 year olds because these individuals were below the legal drinking age in every province . of these 78 had missing data on the binge drinking variable ; therefore , the final sample size for our study was 6607 . the logistic regression analyses included only the 6,198 respondents who had complete data on all the variables included in the model . because of the cchs 's stratified , multistage sampling design , all data are weighted using a weighting variable statistics canada designed to address household nonresponse and oversampling . respondents were identified as binge drinkers if they reported that , at least one time per month during the past 12 months , they had 5 or more drinks on one occasion . individuals who reported having 5 or more drinks at least once a month during the last 12 months were asked additional questions to determine alcohol dependence . alcohol dependence was assessed through the composite international diagnostic interview - short form ( cidi - sf ) developed by kessler et al . to operationalize both criterion a and criterion b of the dsm - iii - r diagnoses for psychoactive substance use disorder . sensitivity of the cidi - sf was 93.6 % and specificity was 96.2 % with a total classification accuracy of 95.8 % for alcohol dependence in comparison to cidi . respondents were classified as probably alcohol dependent if they had a probability of 85 % or higher on the scale , which means that the respondent reported at least three of the following symptoms of alcohol dependence in the past month : being drunk or hungover while at work or school or while taking care of children , engaging in a risk - taking behavior while drunk or hungover , having psychological problems related to alcohol use , experiencing a persistent desire for alcohol , drinking too much or too long , or experiencing increased tolerance . the following demographic variables were investigated : ( 1 ) currently attending school or college ( yes / no ) ; ( 2 ) race ( self - report : white versus non - white ) ; ( 3 ) living arrangement ( living with 2 parents , living with single parent , unattached and not living with a parent , other ) ; ( 4 ) income adequacy ( low / middle / high ) was based on total household income adjusted for the number of people living in the household ; ( 5 ) food insecurity was defined as sometimes or often not having enough food to eat because of a lack of money . self - reported health status was based on individual 's response when asked , in general , would you say your health is excellent , very good , good , fair , poor . response categories were dichotomized into excellent , very good , or good , versus fair or poor . self - reported health decline was assessed through respondents ' answers to the question compared to one year ago , how would you say your health is now ? the responses were dichotomized into much better / somewhat better now than a year ago or the same versus somewhat worse or much worse . if individuals answered no to the first question asking if they were usually free of pain and discomfort , they were asked a subsequent question on how many activities were limited by pain or discomfort prevented ( none , a few , some , most ) . from these two questions , dichotomous categories were created ( usually no pain or discomfort or pain prevents no activities versus pain prevents few activities , some activities , or most activities ) . the respondents were asked if a health professional had diagnosed them with any of the following 17 chronic conditions which had to be of six months or longer duration : fibromyalgia , arthritis or rheumatism , cataracts , chronic bronchitis , emphysema or chronic obstructive pulmonary disease , diabetes , epilepsy , heart disease , inflammatory bowel disease , cancer , stomach or intestinal ulcers , effects of a stroke , glaucoma , and chronic fatigue syndrome , asthma , back problems ( excluding fibromyalgia and arthritis ) , and migraine headaches . these conditions were subsequently summed and categorized as no chronic conditions , 1 chronic condition , and 2 or more chronic conditions . only the latter three conditions were present in at least 5 % of the 1517 - year - old sample . depression was assessed using the composite international diagnostic interview short form , which was designed to operationalize criteria a through c of the dsm - iii - r diagnosis of major depressive episode . the cidi - sf has been shown to have very high sensitivity , specificity , and classification accuracy for a major depressive episode in comparison to cidi . the respondents were considered to experience depression if their depression score was 5 or more ( 90 % likelihood of a positive diagnosis of major depressive episode ) . certain health regions opted to include the following question on suicidal ideation , have you ever seriously considered committing suicide or taking your own life . the first self - report subscale , affection , assesses the amount of affection received by the respondent ( e.g. , whether there is someone who loves them , hugs them , and makes them feel wanted ) . another mos subscale assesses the availability of tangible social support ( e.g. , whether there is someone who , if asked , could help them if they were confined to bed or needed to be taken to the doctor ) . the third mos subscale evaluated emotional and informational support ( e.g. , whether there was someone to listen and advise them in a crisis or to understand their problems ) . the self - esteem scale measures positive self - regard and is a subset of the rosenberg self - esteem scale . the extent to which respondents used family doctors was determined by the question : not counting when you were an overnight patient ( in the hospital ) , in the past 12 months , how many times have you seen or talked to on the telephone to a family doctor about your physical , emotional or mental health . number of mental health visits to any professional was determined through the question : how many times in the past 12 months have you seen , or talked on the telephone , to a health professional about your emotional or mental health ? respondents were then asked to identify all the types of health professionals , including family doctors , whom they had seen or spoken to about their emotional or mental health . unmet mental health care need ( yes / no ) was assessed through two questions : ( 1 ) during the past 12 months , was there ever a time when you felt that you needed health care but you did not receive it ? ( 2 ) thinking of the most recent time , what was the type of care that was needed : treatment of an emotional or mental health problem ? use of self - help groups was determined through the question asking if they had attended a self - help group such as alcoholics anonymous or a cancer support group in the past 12 months . the analysis of the data essentially was to compare the demographic , health and health care utilization characteristics associated with binge drinking monthly among male adolescents ( n = 528 binge drinkers , 2,783 nonbinge drinkers ) and female adolescent aged 1517 ( n = 361 binge drinkers , 2935 non - binge drinkers ) . using spss version 20 , the authors conducted frequencies , chi - square tests for categorical data , and two - way anovas for continuous variables ( e.g. , 4 types of social support and self - esteem ) and logistic regression analysis . an estimated 13.5 % of 1517 - year - old teenagers were binge drinking at least one time per month . males were more likely to binge drink at least once monthly as compared to females ( 16.0 % versus 10.9 % ) . although binge drinking was rarer among females than males , binging females were more likely to be classified as alcohol dependent than binging males . as a result , a comparable percentage of canadian 1517 - year - old males and females were found to be alcohol dependent ( 2.3 % of men , 2.2 % of women ) . despite these high rates of heavy drinking , only one in ten ( 9 % ) binge drinking adolescents had spoken with any health professional about a mental health or emotional issue in the previous year . fewer than 5 % of binge drinking teens had attended a self - help group . three out of every four binge drinking adolescents ( 74 % ) had seen or talked on the telephone with their family physician in the past year , suggesting that family doctors are a major source of health care for this population . unfortunately , only 1 % of these underage binge drinkers had spoken with their family doctor about a mental health or emotional issue in the preceding year . both female and male binge drinkers were more likely to be white ( please see table 1 ) . both genders were less likely to be enrolled in school or to be living with parents . females who lived in single parent families were more likely to binge drink than those in two parent families . males from richer households binged more than those from poorer households . however , among females the opposite relationship existed : poorer females binge drank more than their richer peers . women who were sometimes without enough food to eat because of a lack of money were much more likely to binge than those with adequate food . males and females who reported poor or fair health had much higher rates of binge drinking than did those in good or excellent health . those who had experienced a health decline in the previous year were likely more to be binge drinkers than those who had not . male and female adolescents who had activities prevented by pain also had much higher rates of binge drinking than did individuals who were not constrained by pain . among women , but not men , those with more chronic conditions were more likely to binge drink , and back problems and migraines were both associated with a higher prevalence of binging . although having more chronic conditions , in general , was not associated with binge drinking among males , those with back problems were more likely to binge drink and those with asthma were less likely to binge . for both genders , smokers and those who were sexually active had a much higher prevalence of binge drinking . there was no relationship between physical activity and binge drinking for women . the two - way anova analyses revealed that binge drinkers had significantly lower levels than non - binge drinking adolescents of three types of social support ( emotional / information support , affection and tangible social support ; p .001 ) and self - esteem ( p = .01 ) . there was a much wider difference in levels of emotional / information support between binge drinking and non - binge drinking males than between their female counterparts ( p .001 ) . there was a statistical trend ( p = .07 ) indicating that opposite was true for self - esteem : female binge drinkers had very low self - esteem compared to non - binging women , while the gap in self - esteem levels between binging and non - binging men was quite small . there were several factors which were much more prevalent among binge drinkers than non - bingers . of particular relevance to family physicians , binge drinking adolescents had much higher rates of suicidal ideation than non - bingers ( 10.2 % versus 3.0 % , p .001 ) . teens who were binge drinkers also had a higher prevalence of depression than non - binging adolescents ( 13.1 % versus 6.1 % ; p .001 ) . the logistic regression analysis ( please see table 2 ) indicated that males had twice the odds of binge drinking and teens not attending school or university had almost 50 % higher odds of binge drinking compared to their school - attending peers . whites had four times the odds of binge drinking in comparison to non - whites . in comparison to those living with two parents , those living on their own had more than two times the odds of binge drinking at least monthly . teens who reported a decline in health status in the preceding year had 85 % higher odds of binge drinking in comparison to those whose health had remained the same or improved . adolescents with back problems had 87 % higher odds of binge drinking than their peers without back problems . depressed teens had 62 % higher odds of binge drinking than those who were not depressed . adolescents who smoked had more than five times the odds of binge drinking in comparison to nonsmokers . the nagelkerke r - square statistic ( see table 3 ) indicates that demographic characteristics explained 7.5 % of the variability in binge drinking . physical health characteristics contributed an additional 2.4 % and depression explained an additional 0.8 % of the variability in binge drinking . when smoking status was added to the equation , it explained an additional 11.3 % of the variability in binge drinking , doubling the total amount explained to 22.2 % . the finding that one in fifty underage adolescents was classified as alcohol dependent is very worrisome . the odds of binge drinking were higher among males , whites , those living away from parents , teens who reported a decline in health status , and those experiencing back problems and depression . three - quarters of all binge drinking teens had seen or spoken with a family physician at least once in the past year although fewer than 10 % have consulted with any health professional about mental health or emotional issues during that time period , suggesting the need for improved outreach and screening . knowledge of those factors associated with binge drinking in underaged adolescents could help family doctors and other health professionals target those most at risk for binge drinking . family doctors need to be aware of the health problems associated with an elevated prevalence of binge drinking . in the bivariate analyses , we found that back problems and pain were correlated with alcohol abuse as has been previously documented . research proposes that alcohol may in some cases be used to self - medicate when feeling physical pain , which may also support our finding that those in declining health had almost twice the odds of binge drinking . similar to the findings of jukkala and colleagues , we observed that a lack of social support was associated with binge drinking . many of our other findings were also in keeping with previous studies , such as our data suggesting non - whites binge drink less than white adolescents ( e.g. , ) . in contrast to previous findings , males with lower socioeconomic status were less likely to engage in binge drinking , possibly due to prohibitive costs in canada , where alcohol is heavily taxed . family doctors should be particularly cognizant that binge drinking may be a marker for other negative outcomes including suicidal ideation and depression , both of which were found at a much higher prevalence among binge drinking teens than nonbinging adolescents . according to miller and colleagues , young girls who engage in binge drinking and heavy alcohol use are twice as likely to attempt suicide compared to girls who do not drink . alcoholism is also associated with risky sexual behaviour , and people who exchange sex for food due to extreme poverty are also more likely to use alcohol . lower social support and self - esteem play a major role in alcohol abuse and binge drinking among women . bonomo and her colleagues conclude that prevention and early intervention strategies have a significant impact on the trajectories of early adulthood alcohol use . used a brief intervention in a health care setting in which physicians delivered 2 short counseling sessions over a 4 - week period to binge drinking young adults . during the 4 - year follow - up periodit was found that the young adults who received the intervention experienced a long - term reduction in alcohol use , including binge drinking . such an intervention could be done in conjunction with other school and community based programs to decrease binge drinking in underaged individuals . other promising programs include educating parents about the risks of supplying alcohol to teenagers , enhancing penalty enforcement for licensed liquor sellers who sell to minors , implementing life skills training with inner city youth while educating them on the risk of binge drinking , and providing multi - year curricula starting in middle school to address binging behavior , including peer participation and task force activities involving the community . unfortunately , our analyses did not allow us to evaluate many aspects of the adolescent 's environment . other researchers have suggested that early onset of drinking is strongly related to social factors such as availability of alcohol and peer influence . the high prevalence of binge drinking found in this research underlines the importance of family physicians actively screening their adolescent patients for binge drinking as is routinely done with smoking and other risky behaviors . our findings indicate the vast majority of binge drinking adolescents are not proactively turning to their family doctors with this issue . the profile of those at risk will help physicians assess need and create a course of action to help their patients recover from such hazardous behavior .\noutput:\n" }, { "from": "agent", "value": "context . binge drinking ( more than five drinks on one occasion ) is a major public health problem among teenagers in the us , canada , and europe . negative outcomes to binge drinking include alcohol related injuries and accidental death . family physicians are the main point of contact between binging adolescents and the health care system . design and setting . this study was based on a secondary analysis of 6,607 respondents aged 1517 from the regionally representative data acquired through the canadian community health survey 1.1 . results . according to our findings , one in every eight teens aged 1517 binge drank monthly . the odds of binge drinking were higher among males , whites , those living away from parents , teens who reported a decline in health status , and those experiencing back problems and depression . smoking status was strongly associated with the binge drinking behavior . three - quarters of binge drinking adolescents had seen their family doctor in the past year but only one in ten had spoken with any health professional about a mental health issue . conclusions . family physicians need to screen their adolescent patients for binge drinking in order to provide timely and effective interventions . awareness of the profile of binge drinkers could improve the accuracy of targeting and outreaching strategies ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: retinopathy of prematurity ( rop ) is an important cause of vision loss in children , especially in extremely premature infants . the survival rates of extremely premature infants have been increased with the improvement in the neonatal intensive care technologies and increased availability of healthcare services in recent years . infants with gestational age ( ga ) less than 28 weeks have particularly more risk for the development of rop in developed countries . in developing countries , the incidence of rop is rising with the improvement of the survival rates of extremely premature infants . these infants are more tending to develop severe rop and require treatment . in the present study , we aimed to determine the incidence and the severity of rop in extremely premature infants in southeast part of turkey . the medical records of the premature infants examined between september 2010 and august 2012 in retina department of dicle university medical faculty were retrospectively reviewed . the patients who died prior to retinal screening examination and had lack of relevant data in their medical records were excluded . all patients were first examined using indirect ophthalmoscope at 31 weeks of ga and follow - up examinations were performed twice per week to every 3 weeks , depending on the zone and severity of the disease . the pupil was dilated with 2.5 % phenylephrine ( mydfrin , alcon , usa ) and 0.5 % tropicamide ( tropamide , bilim , turkey ) . the infants were examined after instillation of a topical anesthesthetic , 0.5 % proparacaine ( alcaine , alcon , usa ) . all examinations were performed by the same ophthalmologist ( a. . ) experienced in screening premature infants for rop . the following data were reviewed : gender , ga , birth weight ( bw ) , zone and stage of rop , presence of plus disease , and treatment for rop if needed . the endpoints of data collection in the study defined as completely vascularization of the retina or rop progressed to the stage require treatment according to et - rop recommendations . group 1 included infants of gas 25 weeks and under ; group 2 included infants of gas less than 28 weeks and over 25 weeks . the incidence of any rop , type 1 rop , by means of bw and ga , was also evaluated with respect to gender . infants requiring treatment for rop were defined as having onset of type 1 rop as used in etrop study . treatments were performed either with laser photocoagulation or intravitreal bevacizumab injection . even though etrop study recommended ablative laser photocoagulation in the treatment of prethreshold rop , we preferred intravitreal bevacizumab ( ivb ) monotherapy since august 2011 . a logistic regression analysis was used to evaluate the association of ga and bw with development of any rop and type 1 rop . from september 2010 to august 2012 , the medical records of 526 premature infants were reviewed in the hospital of dicle university , and 109 of them were eligible for the study .22 of the premature infants were 25 weeks of ga ( group 1 ) and 87 of them were over 25 weeks of ga ( group 2 ) . the mean bw in groups 1 and 2 was 825.5211.4 and 997.4206.2 , respectively ( p 0.001 ) . the mean ga in groups 1 and 2 was 24.410.8 weeks and 26.460.5 weeks , respectively ( p 0.001 ) . the incidence of any rop in groups 1 and 2 was 95.5 % and 58.6 % , respectively ( p = 0.001 , = 11.15 ) , with an odds ratio of 15.54 ( 95 % ci 1.99120.78 ) . the overall incidence of type 1 rop was 35.8 % ( 39 of 109 infants ) . type 1 rop incidence in group 1 and group 2 was 59.1 % and 29.9 % , respectively ( p = 0.011 , = 6.51 ) , with an odds ratio of 3.38 ( 95 % ci 1.298.90 ) . table 2 summarizes the incidence of the stages of rop and type 1 rop according to groups . the mean ga of infants who had any rop was 25.81.12 weeks and the mean bw was 924.4205.0 grams . the mean ga of infants who did not have rop was 26.40.6 weeks ( p = 0.002 ) , and bw was 1036.2223.8 grams ( p = 0.014 ) . we did not find any significant difference with respect to the mean bw and ga between patients with and without type 1 rop ( table 3 ) . ga was independently associated with any rop ( p = 0.018 ) and type 1 rop ( p = 0.038 ) . however bw was not independently associated with any rop and type 1 rop ( p = 0.178 and p = 0.714 , resp . ) . with respect to gender , the comparisons of the incidence of any rop , type 1 rop , the mean bw , and the mean ga were not statistically significant ( p = 0.75 , p = 0.76 , p = 0.22 , and p = 0.75 , resp . ) . the survival rate of extremely premature infants continuously increases as a consequence of the advancement of neonatal care . these infants are at a particularly high risk for developing more severe rop and they usually need treatment . in developing countries , , there is another risk for the development of the severe rop is the increase of the survival rates of the extremely premature infants , which may affect the incidence and the severity of rop in the developing countries . in the current study , the overall incidence of any rop was 66.0 % , which was lower than the 85 % incidence reported in the etrop study . however , similarly , isaza and arora reported the overall incidence of any rop was 64.7 % , and teed and saunders reported 71 % . the overall incidence of any rop was 95.5 % in group 1 and 58.6 % in group 2 . similarly , teed and saunders reported the overall incidence of any rop in the 25 weeks group and in the 25 to 27 weeks group as 87 % versus 62 % , respectively . on the other hand , the overall incidence of type 1 rop was found to be higher in our study ( 35.8 % ) than that of previously reported one . teed and saunders reported 13 % and isaza and arora reported 11.6 % of patients had type 1 rop . reported that more mature infants were tending to develop severe rop in less developed countries compared with developed countries . reported that frequency of rop in turkey was similar to that in the united states ; however , according to their results , the rate of severe rop necessitating treatment seems to be higher in turkey . in the current study , the mean bws in group 1 and group 2 were 825.5211.4 and 997.4206.2 grams , which were higher compared to the previously reported studies conducted in usa and canada . the survival rates of the infants in newborn intensive care units in developing countries are lower than those of developed countries . we suggest that higher mean bw in our study , compared to developed countries , is the result of lower survival rates of extremely premature infants with relatively lower bw in turkey . in sweden , . the survival rate of extremely premature infants ( 27 weeks and under ) in our newborn intensive care unit was 39 % . the mean bw in surviving and nonsurviving infants in this group was 1036.1273 gr and 780154 gr , respectively ( unpublished data ) . we found that the development of type 1 rop was associated with lower ga but not associated with bw . suggested that ga is a better predictor of rop than bw according to their twin - paired study . they concluded that maturity is more important in the pathogenesis of rop than intrauterine growth . teed and saunders reported similar findings in their study in infants with a ga under 25 weeks . they suggested that it was a unique characteristic of rop in extremely premature infants and proposed that other neonatal risk factors may also have some additional effect in the severity and progression of rop in such infants . in conclusion , our findings suggested that development of any rop was associated with both lower bw and lower ga . furthermore , type 1 rop development was independently associated with ga . on the other hand , no association was found between type 1 rop and bw in extremely preterm infants with a ga of less than 28 weeks . although the incidence of any rop was similar to that of previous reports , the incidence of type 1 rop in our study population is higher.these results represent only the experience of single center in turkey and may not be generalized to other different populations . larger prospective , cohort studies are needed to clarify the relationship of type 1 rop with bw and ga in extremely premature infants .\noutput:\n" }, { "from": "agent", "value": "purpose . to investigate the incidence and the severity of retinopathy of prematurity ( rop ) in extremely preterm infants born before 28 weeks of gestation in southeastern turkey . methods . a retrospective chart review was performed for infants born before 28 weeks of gestation . the following data were reviewed : gender , gestational age ( ga ) , birth weight ( bw ) , zone and stage of rop , presence of plus disease , and treatment for rop if needed . infants were divided into 2 groups according to ga as follows : group 1 included infants of gas 25 weeks and under ; group 2 included infants of gas less than 28 weeks and over 25 weeks . results . the incidence of any rop in the whole cohort , in group 1 , and in group 2 , was 66.0 % , 95.5 % , and 58.6 % , respectively . incidence of any rop was significantly associated with bw and ga ( p = 0.014 and p = 0.002 , resp . ) . the overall incidence of type 1 rop was 35.8 % ( 59.1 % in group 1 and 29.9 % in group 2 ) . development of type 1 rop was independently associated with ga . conclusion . any rop was significantly associated with bw and ga . extremely premature infants with lower ga were found to be more likely to develop type 1 rop . bw can not predict the development of type 1 rop ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: tuberculosis ( tb ) is thought to be one of the oldest human diseases and the history is almost as old as mankind . the european kings of the middle ages imparted the royal touch to cure the king 's evil to which mycobacterial lymphadenitis referred . india has the highest tb burden accounting for one - fifth of the global incidence and nearly 40 % of the indian population is infected with the tb bacillus . since the mid-1980s , both in developing and developed countries , there is increasing incidence of extrapulmonary tb has been noted . in india , extrapulmonary tb accounting 20 % of all tb cases and its prevalence in the country varies between 8.3 % and 13.1 % in different districts according to cohort analysis by the central tb division , ministry of health and family welfare in 2002 . in india and other developing countries , tb lymphadenitis is the most common form of extrapulmonary tb and it comprises 35 % of cases . infection with the human immunodeficiency virus / acquired immunodeficiency syndrome ( hiv / aids ) is associated with an increased frequency of both pulmonary and extrapulmonary tb especially lymphadenitis . tb lymphadenitis is usually more common in females and in younger age groups in contrast to pulmonary tb which is more common in males and in the older age group and a peak age of onset of 20 - 40 years . there are various diagnostic modalities available for the diagnosis of tb lymphadenitis viz fine - needle aspiration cytology ( fnac ) , histopathological examination excised lymph nodes , culture , ziehl - neelsen ( zn ) staining for acid fast bacilli ( afb ) , imaging studies , and molecular tests . even though culture is considered as gold standard for the diagnosis , fnac to be used as the initial diagnostic test in suspected cases of tb as it has excellent sensitivity and specificity , and also it is a simple and less expensive outpatient diagnostic procedure . the present study was undertaken to evaluate cytomorphological patterns of tuberculous lymphadenitis including hiv / aids positive cases , to correlate the afb positivity with cytomorphological patterns and also to find out overall afb positivity . the present retrospective study was undertaken at department of pathology in our institution , a tertiary care center , conducted over the period of 3 years from march 2012 to march 2015 , after obtaining approval from the institutional ethical committee . a total of 212 cases with cytologically proven tuberculous lymphadenitis were included in the present study . patients with nontuberculous mycobacterial infections such as mycobacterium scrofulaceum , mycobacterium avium - intracellulare complex and mycobacterium kansasii , pulmonary koch 's , bacillus calmette - guerin vaccination causing lymphadenitis , and periodic acid - schiff positive organisms in fnac smears were also excluded from this study . nontuberculous mycobacterial infections were excluded by identification of only microabscesses , ill - defined granulomas , noncaseating granulomas and a small numbers of giant cells , and pulmonary koch 's , bacillus calmette - guerin vaccination causing lymphadenitis were excluded by detailed clinical history collected from medical records . clinical data such as site of aspiration , number lymph nodes involved , nature of aspirates ( blood mixed material , purulent / pus , caseous , or cheesy ) were obtained from patient medical records . may - grunwald giemsa and hematoxylin and eosin stained smears were studied for pattern analysis . according to the das et al . study , cytology smears revealing cytomorphological features of tuberculous lymphadenitis were grouped into three categories : pattern a : epithelioid granuloma without necrosis [ figure 1a ] , pattern b : epithelioid granuloma with necrosis [ figure 1b ] , and pattern c : necrosis without epithelioid granuloma [ figure 1c ] . ( a ) pattern a : epithelioid granuloma without necrosis ( may - grunwald giemsa , 400 ) . ( b ) pattern b : epithelioid granuloma with necrosis ( h and e , 400 ) . ( c ) pattern c : necrosis without epithelioid granuloma ( may - grunwald giemsa , 400 ) . ( d ) grade 3 + acid fast bacilli positivity ( ziehl - neelsen , 1000 ) zn stained smears were used for screening of afb and grading . these positive smears were categorized into three grades ; 1 + : smears with occasional bacilli , 2 + : smears with singly scattered afb , 3 + : smears with a large number of bacilli arranged in bundles detected under 10 [ figure 1d ] . all the statistical analysis was performed using ibm spss statistics for windows ( version 20.0 , ibm corporation , armonk , new york , usa ) . correlation between various cytomorphological patterns and afb positivity was assessed using chi - square test . the present retrospective study was undertaken at department of pathology in our institution , a tertiary care center , conducted over the period of 3 years from march 2012 to march 2015 , after obtaining approval from the institutional ethical committee . a total of 212 cases with cytologically proven tuberculous lymphadenitis were included in the present study . patients with nontuberculous mycobacterial infections such as mycobacterium scrofulaceum , mycobacterium avium - intracellulare complex and mycobacterium kansasii , pulmonary koch 's , bacillus calmette - guerin vaccination causing lymphadenitis , and periodic acid - schiff positive organisms in fnac smears were also excluded from this study . nontuberculous mycobacterial infections were excluded by identification of only microabscesses , ill - defined granulomas , noncaseating granulomas and a small numbers of giant cells , and pulmonary koch 's , bacillus calmette - guerin vaccination causing lymphadenitis were excluded by detailed clinical history collected from medical records . clinical data such as site of aspiration , number lymph nodes involved , nature of aspirates ( blood mixed material , purulent / pus , caseous , or cheesy ) were obtained from patient medical records . may - grunwald giemsa and hematoxylin and eosin stained smears were studied for pattern analysis . according to the das et al . study , cytology smears revealing cytomorphological features of tuberculous lymphadenitis were grouped into three categories : pattern a : epithelioid granuloma without necrosis [ figure 1a ] , pattern b : epithelioid granuloma with necrosis [ figure 1b ] , and pattern c : necrosis without epithelioid granuloma [ figure 1c ] . ( a ) pattern a : epithelioid granuloma without necrosis ( may - grunwald giemsa , 400 ) . ( b ) pattern b : epithelioid granuloma with necrosis ( h and e , 400 ) . ( c ) pattern c : necrosis without epithelioid granuloma ( may - grunwald giemsa , 400 ) . ( d ) grade 3 + acid fast bacilli positivity ( ziehl - neelsen , 1000 ) zn stained smears were used for screening of afb and grading . these positive smears were categorized into three grades ; 1 + : smears with occasional bacilli , 2 + : smears with singly scattered afb , 3 + : smears with a large number of bacilli arranged in bundles detected under 10 [ figure 1d ] . all the statistical analysis was performed using ibm spss statistics for windows ( version 20.0 , ibm corporation , armonk , new york , usa ) . correlation between various cytomorphological patterns and afb positivity was assessed using chi - square test . out of 212 cases , 118 were afb positive cases and remaining 94 was afb negative , but showed cytological features of tuberculous lymphadenitis . in the present study , the most common site of involved lymph nodes was cervical lymph nodes in 206 ( 97.2 % ) followed by axillary lymph nodes in 4 ( 1.9 % ) and inguinal lymph nodes in 2 ( 0.9 % ) cases . the most common presentation was single palpable cervical lymphadenopathy in 177 ( 83.5 % ) cases followed by multiple unilateral palpable cervical lymphadenopathy in 31 ( 14.6 % ) and multiple bilateral cervical lymphadenopathy in 4 ( 1.9 % ) cases . on the basis of appearance of aspirate , blood mixed aspirate were noted more commonly in 179 ( 84.4 % ) cases followed by purulent / pus material in 26 ( 12.3 % ) cases and caseous or cheesy material in 7 ( 3.3 % ) cases . blood mixed aspirate was predominantly seen in pattern a and b and purulent / pus and caseous or cheesy material were predominantly seen in pattern c. of these 212 cases , pattern a was observed in 40 ( 18.9 % ) cases , pattern b was observed in 102 ( 48.1 % ) cases , and pattern c was observed in 70 ( 33 % ) cases . afb positivity was found in 2 ( 5 % ) cases of pattern a , 62 ( 60.8 % ) cases of pattern b , and 54 ( 77.1 % ) cases of pattern c. the highest percentage of afb positivity ( 64.7 % ) was observed in aspirate containing purulent / pus and caseous / cheesy material . the overall afb positivity was seen in 55.7 % ( 118/212 ) cases . on grading of afb positivity , grade 1 + observed in 29.7 % , grade 2 + observed in 28.8 % 2 , and grade 3 + observed in 41.5 % cases . all the hiv - positive cases showed pattern c and grade 3 + afb positivity . the present study showed significant statistical difference between afb positivity and cytomorphological patterns ( p 0.0001 ) . in the present study , the most common site of involved lymph nodes was cervical lymph nodes in 206 ( 97.2 % ) followed by axillary lymph nodes in 4 ( 1.9 % ) and inguinal lymph nodes in 2 ( 0.9 % ) cases . the most common presentation was single palpable cervical lymphadenopathy in 177 ( 83.5 % ) cases followed by multiple unilateral palpable cervical lymphadenopathy in 31 ( 14.6 % ) and multiple bilateral cervical lymphadenopathy in 4 ( 1.9 % ) cases . on the basis of appearance of aspirate , blood mixed aspirate were noted more commonly in 179 ( 84.4 % ) cases followed by purulent / pus material in 26 ( 12.3 % ) cases and caseous or cheesy material in 7 ( 3.3 % ) cases . blood mixed aspirate was predominantly seen in pattern a and b and purulent / pus and caseous or cheesy material were predominantly seen in pattern c.of these 212 cases , pattern a was observed in 40 ( 18.9 % ) cases , pattern b was observed in 102 ( 48.1 % ) cases , and pattern c was observed in 70 ( 33 % ) cases . afb positivity was found in 2 ( 5 % ) cases of pattern a , 62 ( 60.8 % ) cases of pattern b , and 54 ( 77.1 % ) cases of pattern c. the highest percentage of afb positivity ( 64.7 % ) was observed in aspirate containing purulent / pus and caseous / cheesy material . the overall afb positivity was seen in 55.7 % ( 118/212 ) cases . on grading of afb positivity , grade 1 + observed in 29.7 % , grade 2 + observed in 28.8 % 2 , and grade 3 + observed in 41.5 % cases . all the hiv - positive cases showed pattern c and grade 3 + afb positivity . the present study showed significant statistical difference between afb positivity and cytomorphological patterns ( p 0.0001 ) . on clinical examination , cervical lymph nodes ( 97.2 % ) were more commonly involved and inguinal lymph nodes were least commonly involved in the present study similar to most of the recently published studies . this is because , the organism usually gains access to the cervical lymph nodes through the tonsillar lymphoid tissue . in this study , most common presentation was single palpable cervical lymphadenopathy in 83.5 % cases comparable to chand et al . ( 81.6 % ) study , and higher than nidhi et al . ( 63.3 % ) study . we observed multiple unilateral palpable cervical lymphadenopathy in 14.6 % cases and multiple bilateral cervical lymphadenopathy in 1.9 % cases , which were almost comparable to nidhi et al . study . due to various initiatives by governmental and nongovernmental agencies , this might explain the high number of cases presenting with single lymph node enlargement . according to gross nature of aspirate , blood mixed aspirateswere noted in 84.4 % followed by purulent / pus material in 12.3 % and caseous or cheesy material in 3.3 % cases in the current study , whereas , hemalatha et al . observed blood mixed aspirates in 87.3 % and purulent to cheesy materials in 12.7 % cases . pattern a and b were predominantly observed in blood mixed aspirate , whereas pattern c was predominantly observed in purulent / pus and caseous or cheesy aspirates in the present study similar to hemalatha et alcytomorphological pictures of tuberculous lymphadenitis was described by various authors with minor modifications with different names viz patterns or category . we described cytomorphological pictures in our study as patterns . in our study , most common cytomorphological pattern observed was pattern b ( 48.1 % ) similar to hemalatha et al . and gupta et al . studies , and it was higher than studies done by nidhi et al . , and chand et al . ( 16.4 % and 21.8 % , respectively ) . in the current study , pattern c and pattern a were noted in 33 % and 18.9 % cases , respectively . the formation of granuloma is dependent on a fairly good immune system within the host . in immunocompromised situations , the immunological interplay between lymphocytes , macrophages , the organism , and various interleukins / cytokines may not be efficient to result in granuloma formation . hence , when afb positivity is observed without granuloma formation , other comorbid immunodeficient states should be thought of . similar to few indian studies , we observed more number of afb positivity in pattern c ( 77.1 % ) followed by pattern b ( 60.8 % ) in the current study . pattern a showed 5 % afb positivity in our study , whereas nidhi et al . and chand et al . we found maximum percentage of afb positivity ( 64.7 % ) in aspirate containing purulent / pus and caseous / cheesy material similar to studies done by various authors . if the purulent material is aspirated , slides should be stained for zn staining to rule out tuberculous lymphadenitis , because it can mimic as acute suppurative lesions . the present study showed overall afb positivity in 55.7 % cases comparable to most of the published studies , and lower than nidhi et al . andslides can be decolorized for zn staining if cytological features of tb and necrosis present ; this may increase the afb positivity . yield of afb positivity can be further increased by doing repeat fnac of a lymph node . clinical correlation and microbiological assessment should be done in afb negative cases showing only epithelioid granulomas without necrosis . microbiological assessment is necessary in afb negative cases to confirm the diagnosis of tb as approximately 10,000 - 100,000 mycobacterial organism / ml of the sample should be present for smear afb positivity . in the present study , all the hiv positive cases ( n = 10 ) showed pattern c with grade 3 + afb positivity , whereas hemalatha et al . study , included 4 hiv positive cases , of theses 3 cases showed numerous macrophages with 3 + afb positivity and 1 case showed pattern b with 1 + afb positivity . on grading of afb positivity , 29.7 % cases showed grade 1 + , 28.8 % cases showed grade 2 + , and 41.5 % cases showed grade 3 + positivity in the present study . hence , it can be argued that the bacterial load in the rural population affected by tb seems to be high . there was significant statistical difference between afb positivity and cytomorphological patterns ( p 0.0001 ) similar to hemalatha et al . comparison of patterns of tuberculous lymphadenitis and overall afb positivity in the present study with other studies is shown in table 1 . comparison of patterns of tuberculous lymphadenitis and overall afb positivity in the present study with other studiesfnac is a sensitive , simple , convenient , safe , minimally invasive procedure to diagnose tuberculous lymphadenitis . study of both cytomorphological patterns and zn staining for afb can improve the diagnostic yield . regardless of the presence of granuloma , zn stain must be employed whenever infective pathology is suspected .\noutput:\n" }, { "from": "agent", "value": "background : one of the most common causes of lymphadenopathy in india is tuberculosis . it can be diagnosed by a minimally invasive procedure known as fine - needle aspiration cytology ( fnac ) , and thereby unnecessary surgical interventions are avoided.aim : this study was undertaken to evaluate cytomorphological patterns of tuberculous lymphadenitis including human immunodeficiency virus - positive cases , to correlate the acid - fast bacilli ( afb ) positivity with cytomorphological patterns and also to find out overall afb positivity.materials and methods : in this study , a total of 212 cases of cytologically proven tuberculous lymphadenitis were retrieved and analyzed retrospectively between march 2012 and march 2015 for three different cytomorphological patterns ( epithelioid granuloma without necrosis [ pattern a ] , epithelioid granuloma with necrosis [ pattern b ] , and necrosis without epithelioid granuloma [ pattern c ] ) and bacillary loads on ziehl - neelsen stain ( zn ) for afb.results : pattern a through c was observed in 40 ( 18.9 % ) , 102 ( 48.1 % ) , and 70 ( 33 % ) cases , respectively . afb positivity was found in 2 ( 5 % ) cases of pattern a , 62 ( 60.8 % ) cases of pattern b , and 54 ( 77.1 % ) cases of pattern c. the highest percentage of afb positivity ( 64.7 % ) was observed in aspirate containing purulent / pus and caseous / cheesy material . the overall afb positivity was seen in 55.7 % ( 118/212 ) cases . on grading of afb positivity , grade 1 + was observed in 29.7 % , grade 2 + was observed in 28.8 % , and grade 3 + was observed in 41.5 % cases.conclusion : fnac is a sensitive , simple , convenient , safe , minimally invasive procedure to diagnose tuberculous lymphadenitis . study of both cytomorphological patterns and zn staining for afb can improve the diagnostic yield . regardless of the presence of granuloma , zn stain must be employed whenever infective pathology is suspected ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: although the use of modern anticancer drugs has improved the clinical outcome for patients with a wide range of cancers , the same could not be said for neuroblastoma , which is the most common solid tumor in childhood .1 this is because this tumor often presents with only few symptoms in the early clinical stages . thus , there is an urgent need for newer agents if we are to improve the overall survival of these patients . a recently developed chemotherapeutic agent , gold ( iii ) porphyrin ( gp ) , is a water - insoluble inorganic metal complex and has been demonstrated to have efficacy against a wide range of cancers .24 indeed , its antitumor activity is 100-fold more potent than cisplatin , an agent commonly used for treating neuroblastoma .2,3 possible mechanisms of tumor killing include induction of apoptosis , the mitochondria - mediated apoptotic pathway , and production of reactive oxygen species .5 similarly , another potent anticancer drug , camptothecin , features a closed hydrophobic lactone ring .6 although the hydrophobicity of camptothecin results in more favorable antitumor activity , such as against hepatocellular , ovarian , breast , and renal tumors ,710 its clinical application is limited because of severe systemic organ damage associated with significant side effects .6 its in vivo toxicity has been reported to be correlated with low solubility and instability in the aqueous environment .11 drug encapsulation via an optimal delivery system is an integral part of drug design to overcome the issues of systemic toxicity as well as to improve the efficiency of drug delivery . a number of studies have focused on the design of carriers for delivery to provide optimal incorporation of drugs .1214 to the best of our knowledge , effective encapsulation of hydrophobic drugs into a carrier for the treatment of neuroblastoma has not yet been reported . with evolution in nanotechnology , the design of a drug delivery system with more controllable physical properties has shown promising results in enhancing antitumor activity in target tumor tissue .15 tumor vasculature is characterized uniquely with leaky blood vessels , which allow nanoparticles greater than 100 nm in diameter to pass through .16 thus , larger nanoparticles of 100200 nm in diameter are ideal for delivery into tumor tissue and consequently can reduce renal clearance and uptake by the reticuloendothelial system .17 this phenomenon is called the enhanced permeability retention effect .15 for our delivery system , we used lipid nanoparticles consisting of cetyl alcohol and brij 78 to incorporate gp , because they have been shown to have excellent biocompatibility in blood .18 the formulation strategy was to incorporate a microemulsion into a lipid nanoparticle carrier in distilled water as opposed to the organic solvents used in the synthesis of most other formulations . the solvent was carefully chosen in order to address the common problem of additional toxicity associated with use of an organic solvent . in our previous study , surface modification of lipid nanoparticleswas shown to reduce the toxicity of gp , both in vitro and in vivo .19 in this work , we investigated the treatment efficiency of a lipophilic carrier by physical characterization , tumor accumulation , systemic distribution , and antitumor activity . to examine further the efficiency of a lipophilic carrier platform for delivery , we encapsulated camptothecin into the lipophilic carrier and investigated the activity and therapeutic effect of lipophilic - encapsulated camptothecin . gold ( iii ) porphyrin 1a was manufactured and kindly provided by the department of chemistry at hong kong university . the gp and camptothecin nanoparticles were prepared as previously described using an oil / water ( o / w ) microemulsion .19 briefly , the drug was melted into the oil phase of cetyl alcohol at 60c . brij 78 , a surfactant , was added to the oil phase and stirred for 5 minutes . methoxypoly ( ethylene glycol ) ( mpeg 7502000 da , 5 mol % ) was added to the nanoparticle template and mixed well by stirring . the particle size and surface charge of the nanoparticles was measured using a zetasizer nanoseries ( malvern , westborough , ma ) . then , 10 l of each sample was added to 1 ml of 1:100 ( v / v ) phosphate - buffered saline ( ph 7.4 ) in distilled water for the zeta potential study , as previously described .21 drug entrapment efficiencies were determined by separating free gp from the gp nanoparticles ( gpnp ) using a centrisart i centrifugal ultrafiltration unit ( supleco , bellefonte , pa ) with a filter membrane ( molecular weight cutoff 10 kda ) as described elsewhere ,22 and then measuring the gp in nanoparticle - containing supernatants using inductively coupled plasma - mass spectroscopy . about 1 ml of the formulation solution was put in the outside chamber and in the recovery chamber at the top . after separation by centrifugation at 4000 rpm for 30 minutes , gpnp remained in the outer chamber while free gp was in the recovery chamber . to ensure mass balance , gp loading and entrapment efficiency were calculated as follows : a murine glioblastoma ( d54 ) or neuroblastoma ( n2a ) cell line was seeded in a 96 - well plate at a density of 810 cells / well and cultured in dulbecco s modified eagle medium supplemented with 10 % fetal bovine serum and 1 % penicillin / streptomycin at 37c . an mtt assay was performed after incubation of the lipophilic nanoparticle - encapsulated drugs for 24 and 72 hours . normal fibroblasts was seeded at a density of 8000 cells / well in a 96 - well plate . the mtt assay was performed according to the manufacturer s protocol after incubation of the lipophilic nanoparticle - encapsulated drugs for 4 hours . briefly , 10 l of mtt substrate was added into each well and incubated for 4 hours at 37c , after which 100 l of solubilization buffer was added to each well and incubated overnight . the absorbance measurement was performed at 540 nm with the reference filter at 650 nm using an absorbance microplate reader ( biorad , hercules , ca ) . six - to eight - week - old male a / j mice weighing 202 g were obtained and housed in the laboratory animal unit , university of hong kong . the experimental protocol was approved by the committee on the use of live animals for teaching and research , university of hong kong ( culatr 1901 - 09 ) . n2a tumor - bearing mice were created by subcutaneous injection of 200 l of a mouse neuroblastoma cell line ( n2a ) at a density of 1.510 / ml suspended in phosphate - buffered saline into the right flank of the mouse . at 811 days after inoculation , tumor mass became visible and measurable at the injection site . tumor growth was evaluated by measuring the tumor volume using morphometric analysis with calipers every other day until 21 days . chemotherapy using 35 mg / kg of free gp , gpnp , or gpnp surface - coated with peg ( gpnp - peg ) was administered intraperitoneally after the tumor became visible and the dose was chosen according to our previous report .19 intraperitoneal administration was selected because this route has been demonstrated to be an effective and well tolerated systemic route as compared with intravenous administration to treat neuroblastoma .2326 tumor volume was calculated as height weight length . percentage survival was determined by the number of mice surviving at the designated time points . the liver , kidneys , and tumor tissue were harvested from each mouse , which was either untreated or had received 3 mg / kg ( 0.06 mg / 20 g ) of free gp or gpnp conjugated with or without peg at 6 and 24 hours . the harvested tissues were acid - digested as previously described .27 biodistribution analysis was conducted by measuring the gold isotope concentration ( ppb ) with inductively coupled plasma - mass spectroscopy in the bioengineering department at the university of science and technology , hong kong . a tunel assay was performed on 5 mm tumor paraffin sections using a commercially available kit ( roche applied science , gilroy , ca ) according to the manufacturer s instructions . briefly , the tissue was fixed in 4 % paraformaldehyde , dehydrated , paraffin - embedded , and sectioned . the section was then deparaffinized , rehydrated , and pretreated with 0.02 mg / ml of proteinase k in 0.1 mm tris - hcl ph8 buffer for 10 minutes . the tunel assay was performed by incubating fluorescein - conjugated terminal deoxynucleotidyl transferase in enzyme solution for 2 hours . the statistical analyses were performed using student s paired t - test ; a p value 0.05 was considered to be statistically significant . gold ( iii ) porphyrin 1a was manufactured and kindly provided by the department of chemistry at hong kong university . the gp and camptothecin nanoparticles were prepared as previously described using an oil / water ( o / w ) microemulsion .19 briefly , the drug was melted into the oil phase of cetyl alcohol at 60c . brij 78 , a surfactant , was added to the oil phase and stirred for 5 minutes . methoxypoly ( ethylene glycol ) ( mpeg 7502000 da , 5 mol % ) was added to the nanoparticle template and mixed well by stirring . the particle size and surface charge of the nanoparticles was measured using a zetasizer nanoseries ( malvern , westborough , ma ) . then , 10 l of each sample was added to 1 ml of 1:100 ( v / v ) phosphate - buffered saline ( ph 7.4 ) in distilled water for the zeta potential study , as previously described .21 drug entrapment efficiencies were determined by separating free gp from the gp nanoparticles ( gpnp ) using a centrisart i centrifugal ultrafiltration unit ( supleco , bellefonte , pa ) with a filter membrane ( molecular weight cutoff 10 kda ) as described elsewhere ,22 and then measuring the gp in nanoparticle - containing supernatants using inductively coupled plasma - mass spectroscopy . about 1 ml of the formulation solution was put in the outside chamber and in the recovery chamber at the top . after separation by centrifugation at 4000 rpm for 30 minutes , gpnp remained in the outer chamber while free gp was in the recovery chamber . to ensure mass balance , a murine glioblastoma ( d54 ) or neuroblastoma ( n2a ) cell line was seeded in a 96 - well plate at a density of 810 cells / well and cultured in dulbecco s modified eagle medium supplemented with 10 % fetal bovine serum and 1 % penicillin / streptomycin at 37c . an mtt assay was performed after incubation of the lipophilic nanoparticle - encapsulated drugs for 24 and 72 hours . normal fibroblasts was seeded at a density of 8000 cells / well in a 96 - well plate . the mtt assay was performed according to the manufacturer s protocol after incubation of the lipophilic nanoparticle - encapsulated drugs for 4 hours . briefly , 10 l of mtt substrate was added into each well and incubated for 4 hours at 37c , after which 100 l of solubilization buffer was added to each well and incubated overnight . the absorbance measurement was performed at 540 nm with the reference filter at 650 nm using an absorbance microplate reader ( biorad , hercules , ca ) . six - to eight - week - old male a / j mice weighing 202 g were obtained and housed in the laboratory animal unit , university of hong kong . the experimental protocol was approved by the committee on the use of live animals for teaching and research , university of hong kong ( culatr 1901 - 09 ) . n2a tumor - bearing mice were created by subcutaneous injection of 200 l of a mouse neuroblastoma cell line ( n2a ) at a density of 1.510 / ml suspended in phosphate - buffered saline into the right flank of the mouse . at 811 days after inoculation , tumor mass became visible and measurable at the injection site . tumor growth was evaluated by measuring the tumor volume using morphometric analysis with calipers every other day until 21 days . chemotherapy using 35 mg / kg of free gp , gpnp , or gpnp surface - coated with peg ( gpnp - peg ) was administered intraperitoneally after the tumor became visible and the dose was chosen according to our previous report .19 intraperitoneal administration was selected because this route has been demonstrated to be an effective and well tolerated systemic route as compared with intravenous administration to treat neuroblastoma .2326 tumor volume was calculated as height weight length . percentage survival was determined by the number of mice surviving at the designated time points . the liver , kidneys , and tumor tissue were harvested from each mouse , which was either untreated or had received 3 mg / kg ( 0.06 mg / 20 g ) of free gp or gpnp conjugated with or without peg at 6 and 24 hours . the harvested tissues were acid - digested as previously described .27 biodistribution analysis was conducted by measuring the gold isotope concentration ( ppb ) with inductively coupled plasma - mass spectroscopy in the bioengineering department at the university of science and technology , hong kong . a tunel assay was performed on 5 mm tumor paraffin sections using a commercially available kit ( roche applied science , gilroy , ca ) according to the manufacturer s instructions . briefly , the tissue was fixed in 4 % paraformaldehyde , dehydrated , paraffin - embedded , and sectioned . the section was then deparaffinized , rehydrated , and pretreated with 0.02 mg / ml of proteinase k in 0.1 mm tris - hcl ph8 buffer for 10 minutes . the tunel assay was performed by incubating fluorescein - conjugated terminal deoxynucleotidyl transferase in enzyme solution for 2 hours . the statistical analyses were performed using student s paired t - test ; a p value 0.05 was considered to be statistically significant . this lipophilic formulation had been developed earlier in our laboratory to incorporate lipophilic gp , and we showed that gpnp had a significant reduction in side effects when compared with free gp in a neuroblastoma model .19 nonetheless , prolonged administration of this early formulation still resulted in systemic toxicity due to accumulation in the liver . in this study , we surface - coated gpnp with peg to investigate if this modification could enhance drug delivery into tumor tissue and also reduce systemic uptake . the lipophilic nanoparticles with or without surface modification were first characterized ( table 1 ) . the zeta potential of gp , gpnp , and gpnp - peg ranged from 4.13 mv to 12.49 mv , suggesting a slight change in value but within a low negative range of net surface charge after peg modification , possibly due to nanoparticle encapsulation . the low negative value of the surface charge would mean that the favorable binding affinity for cells remained unchanged after encapsulation .28 direct light scattering measurements in table 1 showed that encapsulation increased the size of gpnp compared with gp . the addition of peg further increased the size of the lipophilic nanoparticles from 101.9 nm to 164.4 nm without a significant change in zeta potential or morphology . this would benefit delivery into tumor tissue via the enhanced permeability retention effect . because the pore sizes of the liver fenestrae are around 100 nm and the gap sizes of the tumor vessels are approximately 400nm ,2931 we hypothesized that gpnp - peg could evade uptake by the liver , with enhanced tumor uptake . accumulation of free gp in the liver was 336 ppb au / g tissue at 6 hours , and decreased to 112 ppb au / g tissue at 24 hours , while both the kidney and tumor tissue showed minimal uptake ( 30 ppb au / g tissue ) at 6 and 24 hours , respectively . the unconjugated gpnp showed comparable uptake in the liver and kidney ( 18 ppb au / g tissue and 52 ppb au / g tissue , respectively ) and relatively high tumor uptake at 6 hours . at 24 hours , uptake of unconjugated gpnp by the liver increased but was not significantly different from that in tumor tissue . on the other hand , gpnp - peg showed only minimal liver and kidney uptake ( 644 ppb au / g tissue ) , whilst uptake in tumor tissue was significantly higher ( 468 ppb au / g tissue and 392 ppb au / g tissue , respectively , p 0.05 ) at 6 and 24 hours . this finding would explain the reduced systemic toxicity after encapsulation into a peg surface - coated lipophilic carrier . another requirement of a carrier system in cancer therapy is the ability to facilitate the antitumor activity of the active drug . our in vitro study investigated the activity of the encapsulated drug against tumor cells . here , mtt assay showed that greater cell death was seen in the n2a neuroblastoma cell line using encapsulated gp in a dose - dependent manner ( figure 2a ) this would suggest that the lipophilic carrier facilitated antitumor activity against n2a . in order to confirm if our carrier template could enhance antitumor activity of other drugs , we tested camptothecin , another potent hydrophobic drug , using the same carrier system , whereby the peg - coated lipophilic carrier also enhanced antitumor activity . the ic50 of n2a for gpnp was 0.002 mm as compared with 0.005 mm of gp , and was 0.0025 mm for camptothecin - np or camptothecin - np - peg and 0.03 mm for free camptothecin . this result indicated that lipophilic carrier enhanced drug efficacy by 210-fold . on the other hand , because insertion of long - chained peg provided steric hindrance to prevent cellular and serum protein interaction , we investigated whether the composition of peg would interfere with the antitumor activity of the encapsulated drug . indeed , less antitumor activity was found when the nanoparticle carrier was coated with higher molecular weight peg ( peg 2000 ) , as compared with lower molecular weight peg ( peg 750 ) , as shown in figure 2b . we next investigated the in vivo therapeutic effect of gpnp - peg using a neuroblastoma model . as shown in figure 3 , gpnp - peg doses of 3 , 4 and 5 mg / kg all had a significant antitumor effect by inhibiting the growth of n2a cells when compared with the control ( p 0.05 ) . the antitumor effect decreased after the first 7 days but could be sustained by repeated doses . because evasion of cell death is an indicator of drug resistance ,32 we further studied tumor cell apoptosis using the tunel assay after treatment with the lipophilic nanoparticle carrier . figure 4 demonstrates that apoptotic activity was significantly higher in the gpnp - peg - treated neuroblastoma line than in the untreated neuroblastoma line . similar findings was also recorded when camptothecin - peg was given . taken together , positive tumor inhibition as well as apoptosis indicates that our nanoparticle carrier system was effective against neuroblastoma . nonetheless , a logical extension of our carrier system would be to show its usefulness against other aggressive cancers . here we have shown that our lipophilic carrier enhanced the efficacy of gp and camptothecin against d54 , an aggressive glioblastoma cell line ( figure 5 ) . this would suggest that our lipophilic nanoparticle system is adaptable , and therefore promising as a new therapeutic approach against a range of cancers . to summarize , drug encapsulation into a pegylated lipid nanoparticle carrier may further improve drug accumulation inside tumor tissue with low accumulation in the liver and provide effective antitumor activity in vitro and in vivo . our gpnp - peg formulation offers a new strategy for the development of a safe and effective carrier for drug treatment of cancer .\noutput:\n" }, { "from": "agent", "value": "backgrounddevelopment of anticancer drugs is challenging . indeed , much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity . we have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin . in this study , we investigated the delivery and treatment efficiency of peg surface - modified lipid nanoparticles as a carrier platform.methodswe encapsulated antitumor drugs into peg - modified lipid nanoparticles and these were characterized by size , zeta potential , and encapsulation efficiency . the delivery efficiency into tumor tissue was evaluated using a biodistribution study . to evaluate antitumor efficacy , gold porphyrin or camptothecin ( a dna topoisomerase i inhibitor ) were encapsulated and compared using an in vivo neuroblastoma ( n2a ) model.resultswe showed that drug encapsulation into peg - modified lipid nanoparticles enhanced the preferential uptake in tumor tissue . furthermore , higher tumor killing efficiency was observed in response to treatment with peg - modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin . the in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity . surface modification of lipophilic nanoparticles with peg increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity.conclusionthis specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: smile is a new method for the refractive correction of myopia and myopic astigmatism . in this procedure , an intrastromal lenticule is created between two photodisruption planes and mechanically removed via a 3 - 4 mm arcuate side cut . however , the visual recovery after lenticule extraction in smile is slower than after lasik . as the procedure is relatively new , the corneal wound healing response is not well documented , and the reason for delayed recovery is not clear . a transiently enhanced visibility of the interface in some lenticule extraction eyes during the first postoperative week has been reported , and it is speculated that this type of interface scatter after cutting of the intrastromal lenticule is to blame for the slightly reduced visual acuity in the early postoperative period when compared with lasik . however , an objective grading of haze in the smile group or a comparison of interface haze with the lasik group has not been performed . in vivoconfocal microscopy ( ivcm ) can be used to measure endothelial cell density to analyze corneal and intracorneal thicknesses and to assess cellular morphology and histopathologic changes . another important feature of ivcm is the ability to objectively quantify corneal backscatter , which is used to define stromal reaction , keratocyte activation , and objective haze grading in refractive and lamellar corneal surgery . in this study we used corneal backscatter analysis , backscattered light intensity ( li ) depth graphics ( z - scan ) , and subjective evaluation of ivcm images to detect differences between fellow eyes that underwent either smile or femto - lasik . this prospective study was approved by the ethics committee of the beyoglu eye research and training hospital and adheres to the principles of the declaration of helsinki . the study enrolled patients older than 18 years old with myopia or myopic astigmatism with a spherical equivalent refraction of 10 d , mesopic ( 4 lux ) , pupil size 6.5 mm , and calculated residual stromal bed thickness of 300 m . other inclusion criteria were best corrected visual acuity of at least 20/25 in both eyes , no ocular disease other than the refractive error , a normal topographic pattern and regular retinoscopic reflex , corneal pachymetry of 500 m at the thinnest point , and stable refraction for at least 2 years . all visual acuity measurements were completed using an illuminated etdrs chart ( optec 3500 vision tester , stereo optical co. , usa ) . objective cycloplegic refraction was performed with an autorefractometer ( kr - 1 auto kerato - refractometer , topcon , japan ) and retinoscopy in all patients . corneal topography , dynamic infrared pupillography , ocular wavefront analysis , and corneal wavefront analysis were performed with a sirius corneal topography and abberometry system ( costruzioni strumenti oftalmici , italy ) . horizontal corneal diameter was measured with an iolmaster 500 ( carl zeiss meditec , germany ) . optical coherence tomography was performed at the 1 - month followup to evaluate flap and cap thicknesses . one eye of each patient was assigned to the smile group and the fellow eye to the femto - lasik group using a random number table . the random numbers were placed in sealed envelopes that were shuffled and then sequentially numbered . if the random number in the envelope was odd , then the right eye was allocated to the smile group , and if the number was even , the left eye was allocated to the smile group . the same surgeon ( a. demriok ) the flap of the fellow eye was created before transporting the patient to the excimer laser . a visumax ( carl zeiss meditec , germany ) femtosecond laser platform was used for all eye surgeries . the spot distance was 3 m for lamellar cuts and 2 m for side cuts . the minimum lenticule side cut thickness was set to 15 m . the lenticule side cut angle was 120 , and the optical zone was 6.5 mm . the optical zone diameter was equal to the lenticule diameter in patients with purely spherical refractive error . however , if the patient had astigmatism , the software added a transition zone to convert the oval lenticule into a circle . as a result , the lenticule diameter was 6.5 - 6.6 mm depending on the presence or absence of astigmatism . the cap diameter was 7.5 mm with a 50 superior side cut and a side cut angle of 90 . a small - sized ( size s ) patient interface was used in all patients . when the lenticule and side cut had been created , the surgeon positioned the eye under the operating microscope of the laser platform using the joystick . under the operating microscope , a blunt spatula was inserted into the anterior lamellar photodisruption plane to perform dissection of any remaining attachments . after the lenticule was completely dissected from the overlying and underlying stroma , it was extracted through the side cut with forceps . after one drop of topical anesthetic was applied to both eyes and sterile draping was placed , an eyelid speculum was inserted . flaps were created by a visumax femtosecond laser platform ( carl zeiss meditec , germany ) . spot distance was 3 m for the lamellar flap cut and 2 m for the flap side cut . the flap side cut was 90 , and the flap diameter was set to 8.5 mm in all patients . a medium - sized ( size m ) patient interface was used in all patients . after the flap was created , the patient was transported to a schwind amaris 750s ( schwind eye - tech solutions , germany ) excimer laser platform . the flap was lifted with a blunt spatula ( katena , usa ) , and excimer laser photoablation was performed . the residual stromal bed was washed with balanced salt solution , and the flap was repositioned . confocal microscopy ( confoscan 4 , nidek , italy ) was performed at week 1 and months 1 , 3 , and 6 . the same experienced technician ( a. agca ) , who had no involvement in the operative procedures , performed all the examinations . the device was equipped with a standard 40 water - immersion front lens and a z - ring . one drop of viscotears ( novartis pharma ag , basel , switzerland ) was applied as an immersion substance between the 40 objective lens and the z - ring before each examination . a sterile small wire - lid speculum was inserted into the patient 's eye after topical anesthesia to improve examination quality . the technician asked the patient to look at the internal fixation light and manually centered on the endothelium before activating the microscope 's autoalignment . the procedure was repeated if there were any concerns about the quality or centration of the images or the stability of centration and quality throughout the image acquisition period . the backscattered li measurements were standardized by using amco clear turbidity standard ( gfs chemicals inc . , the relation between turbidity and image intensity can be used to express image intensity in sus , provided that 1 su is equal to the image intensity measured in a 1 - ntu suspension . , we examined ac - 4000 ( amco clear in a maximum concentration equivalent to 4000 ntu ) through a transparent rectangular 10 mm sample cell ( lpz045 ; hach lange , tiel , the netherlands ) and then , after gradual dilution , ac - 2000 , ac - 1000 , and ac - 500 . showed that the relation between image intensity and turbidity depends on the imaging depth and that a linear relationship with turbidity only exists at a depth image intensity of 200 m . thus , the image intensities at a depth of 200 m were plotted against the turbidity values , and the linear function defining the relation between them was used as the standardization function . this calculation was performed only once ( at the beginning of the study ) to define a standardization function that could be used to convert the confoscan 4 raw image intensity data to su . to ensure standardization of backscatter measurements over a long time period , a polymethylmethacrylate slab ( pmma , opal 040 perspex gs ; lucite international ltd . , uk ) was used every week . during pre - and postoperative visits , backscattered li was measured at the flap / cap interface , at the flap / cap - stromal bed interface , and at the stromal bed . in postoperative visits , the peak backscattered li in the anterior stroma and its corresponding corneal depth were also recorded . the border of the anterior stroma was determined as described by hillenaar et al . . in addition , the reflective particles at the flap / cap interface were counted manually . a backscattered li value was recorded 30 m below bowman 's membrane as this location approximately represents the middle portion of the flap or cap stroma in a 120 m flap or cap . the image with the clearest view of the refractive particles was selected to represent the flap / cap - stromal bed interface . accordingly , if it was difficult to choose between two images , the one that was nearest to 120 m from the last focused corneal epithelium image was chosen . corneal stroma 150 m below the superficial epithelium was chosen to represent the stromal bed , just below the stromal interface . the preoperative data were compared using student 's t - test ( table 1 ) . the preoperative and postoperative data were analyzed using two - way repeated measure anova with post hoc multiple comparisons . ibm spss 20.0 ( ibm corporation , usa ) software was used to analyze the data . fourteen patients ( 47 % ) were male and 16 patients ( 53 % ) were female . there were no statistically significant differences in preoperative characteristics of the eyes in the smile and femto - lasik groups ( table 1 , t - test , p 0.05 ) . the mean flap / cap thicknesses at month 1 visit were 1249.51 m in the femto - lasik group and 12210.16 m ( p 0.05 ) in the smile group . the mean thicknesses of the removed tissue ( the maximum thickness of the extracted lenticule in the smile group and the maximum ablation depth in the femto - lasik group ) were 8028.8 m and 7427.1 m in the smile and femto - lasik groups , respectively ( p 0.05 ) . the maximum value of the backscattered li increased in both groups postoperatively ( table 2 ) . the increase was higher in the smile group , and the difference between the groups was statistically significant at week 1 ( p 0.001 ) , month 1 ( p = 0.009 ) , and month 3 visits ( p = 0.008 ) . the difference in the amount of increase was not significant at month 6 visit ( p = 0.245 ) . table 3 shows the depth of the maximum backscattered li throughout the follow - up period . at the postoperative week 1 and month 1 visits , there was no statistically significant difference between the smile and femto - lasik groups in terms of the maximum backscattered li depths . however , at months 3 and 6 visits , the corneal depth at the maximum backscattered li was more anterior in the smile group ( month 3 , p = 0.02 ; month 6 , p = 0.01 ) than in the femto - lasik group . table 4 shows the backscattered li 30 m below bowman 's membrane ( cap and flap tissues in the smile and femto - lasik groups , resp . ) . li in the flap or cap stroma increased postoperatively in both groups ; however , the increase was higher in the smile group , and the difference was statistically significant at week 1 ( p 0.001 ) , month 1 ( p = 0.007 ) , and month 3 ( p = 0.003 ) visits . although the mean value was still higher in the smile group at the 6 - month visit , the difference was not statistically significant ( p = 0.065 ) . a similar pattern was observed for the backscattered li values at the intended flap ( table 5 ) . the increase was higher in the smile group and the difference was statistically significant at week 1 ( p 0.001 ) , month 1 ( p = 0.012 ) , and month 3 visits ( p = 0.006 ) but not at month 6 visit ( p = 0.051 ) . table 6 shows backscattered li values at the corneal stroma below the interface level ( 150 m ) . backscattered li at this depth increased in both groups postoperatively and the increase was higher in the smile group . however , the difference was only statistically significant at week 1 ( p 0.001 ) and month 1 visits ( p = 0.012 ) . subjective evaluation of backscattered li versus depth graphics ( z - scan ) revealed increased corneal backscatter in a wider area in smile eyes . a network of activated keratocytes and increased reflectivity from the extracellular matrix was easily identified in smile eyes , and in some patients , this area occupied the anterior one - third of the corneal stroma in the first postoperative week ( figure 1 ( b ) ) . in contrast , increased backscatter in fellow eyes that underwent femto - lasik was limited to close proximity of the flap interface ( figure 1 ( d ) ) . when reporting on corneal backscatter , image intensity in gray levels should be adjusted to absolute scatter units . mclaren et al . reported mean values for the mean image intensity in each five percentiles of depth . hillenaar et al . developed an algorithm that semiautomatically calculates the mean corneal backscatter of the whole stroma as well as the mean backscatter in the anterior , middle , and posterior third of the stroma . although we standardized our measurements according to hillenaar et al . , we were not interested in the mean values for thicker corneal sections obtained by averaging values from different depths ; instead , we were interested in detecting even a localized small difference between the groups that may not have affected the mean backscattered li in thicker corneal sections . thus , we measured backscattered li in three specific locations around the flap / cap interface where we most expected to find a difference ; in addition , we measured the maximum li in the anterior stroma and its location . there have been no previous studies comparing ivcm in smile and femto - lasik eyes , and we were uncertain which postoperative period we should concentrate on in order to detect any possible differences . as a result , we performed ivcm as early as 1 week after the surgery and performed it quite frequently ( four times in 6 months ) . only 0.14 % of the corneal surface is imaged in ivcm , and a tracking system is not present in confocal microscopy devices . as a result , however , centralization of the scan on the corneal apex can be verified by obtaining a uniform image of the corneal endothelium . in our opinion , corneal haze in this group of patients could be monitored with sufficient repeatability only if the central cornea was imaged in all cases . further positional repeatability is practically impossible with current confocal microscopy technology . in some studies on lenticule extraction , the very slight clinical haze at the interface is not even mentioned . the status of the interface may not have been recorded by some authors because it may not have been considered to be related to visual symptoms ; others may have not reported it , as the design of their studies lacked an objective instrument to detect and measure the interface haze . in the few studies where it was reported , there is no detailed information or measurement of interface haze after lenticule extraction and there is no comparison of it with a lasik interface . they reported that slit - lamp examination showed a transiently enhanced visibility of the interface in some flex eyes during the first postoperative week ; however , they provided no further data ( e.g. , number of eyes with enhanced visibility , duration of haze ) . also reported a transient haze in some flex eyes ; however , they did not give a measure of it , nor did they compare it with femto - lasik . in this studytypical differences were observed in the objective corneal backscatter analysis of corneas between smile and femto - lasik eyes . eyes that underwent smile and femto - lasik both showed increased postoperative backscattered li ; however , maximum backscattered li and backscattered li from three different depths in the anterior stroma were higher in smile eyes . in fact , the difference in the early postoperative period was so dramatic that , even without measuring the actual intensity levels or performing a statistical analysis , we could easily identify that there was an obvious difference between the eyes ( figures 1 ( a ) and 1 ( c ) ) . subjective evaluation of confocal microscopy images revealed that increased reflectivity in the smile eyes was due to the extracellular matrix and activated keratocytes ( figure 1 ( a ) ) . the difference was not likely to be due to individual immunological differences because smile and femto - lasik were compared on fellow eyes operated on in the same day . in addition , the amount of preoperative refractive error , the thickness of the tissue removed from the stroma , and the depth from which the removal ( ablation or extraction depending on the surgical method ) took place were similar between the groups , and the patients were given the same postoperative drug regimen . thus , the groups were perfectly matched , and the only difference was the surgical procedure . we found that the difference between the groups in terms of backscattered li was the highest at week 1 and reduced gradually thereafter . interestingly , the location of the peak backscattered li was more anterior in the smile group at 3 and 6 months postoperatively ( table 3 ) . at month6 visit , the location of the peak backscattered li was at , or slightly above , the interface in the smile group ( 10627 m ) and at the level of , or slightly below , the interface ( 14227 m ) in the femto - lasik group . the only confocal microscopy study comparing lenticule extraction and femto - lasik was carried out in a limited number of rabbit eyes by riau et al . . they performed a semiquantitative analysis of the reflectivity level of the flap interface by measuring the mean gray value of the reflective particles using imagej software ( national institutes of health , usa ) . the reflectivity level was not standardized in their study . as a result , although it is possible to make a comparison between the two groups in that particular study , the values can not be compared with any other study group examined with a different confocal microscope . contrary to our findings , they reported that the relative reflectivity of the flap interface was significantly higher in femto - lasik eyes . they concluded that refractive lenticule extraction may result in less inflammation and less extracellular matrix deposition compared to lasik , especially at high refractive correction . their study included 36 eyes evenly divided between the flex and femto - lasik groups . instead , each group was divided into three subgroups , with six eyes in each subgroup ( subgroups with 3.00 , 6.00 , and 9.00 d corrections ) . each subgroup of the flex eyes was compared with its corresponding femto - lasik subgroup ( the difference between the surgical procedures was statistically significant in two of the three subgroups ) . as a result , the statistics and study conclusions were based on the means of six eyes for each subgroup ; results on such a small number of eyes may be misleading . lasik leads to a variably thick , hypocellular , primitive stromal interface scar . by using confocal microscopy , the interface wound can be identified in 100 % of cases because the scar always contains numerous brightly reflective interface particles . these reflective particles were found to consist primarily of organic cellular constituents in histologic studies . reported more intense and abundant reflective particles in those corneas that underwent femto - lasik compared with those that underwent flex . however , the number of these reflective particles did not differ between groups in the present study . the more superficial lamellar cut made in the smile surgery is similar to the flap cut that is created in femto - lasik . thus , the difference between the surgical procedures is the result of the addition of a second lamellar cut at a deeper level or the increased number of surgical steps required for blunt separation of the lenticule floor and roof in the smile group . in femto - lasik , only one lamellar cut is performed with a femtosecond laser to create the flap , and the incidence of deep lamellar keratitis was found to be consistently higher after femto - lasik when compared with lasik using a mechanical keratome . thus , the application of a femtosecond laser on the corneal stroma may have unique immune consequences . in smile , two lamellar cuts are performed , and when the lenticule is extracted , these two surfaces come face to face at the cap - stromal bed interface , where our measurements were recorded . in addition , the total energy applied to the corneal stroma in smile is higher than that applied to the stroma in femto - lasik performed with the same platform . the surgical maneuvers used in the smile procedure are far more challenging than those used in flex and femto - lasik procedures , so varying inflammatory responses could equally as well be related to the surgical maneuvers as to the effects of the laser treatment . a study comparing flex and smile procedures would help to reveal whether increased surgical maneuvers increase postoperative corneal backscatter . reported that refractive predictability and corneal aberrations following flex seemed better than or equal to those following femto - lasik at 3 months , whereas visual recovery after flex was slower . r. shah and s. shah also reported that although the efficacy and safety of refractive lenticule extraction ( flex and smile ) are comparable to those of lasik , visual recovery is slower , and changing the scanning trajectory of the femtosecond laser had a positive effect on visual outcome . another possible factor that delays visual recovery may be the different patterns of stromal response to lenticule extraction and femto - lasik . in fact , it should not be surprising to find different patterns of stromal response to lenticule extraction and femto - lasik because they are different surgical procedures . in conclusion , we report for the first time that smile eyes have increased corneal backscatter for at least 3 months after surgery at the level where the lenticule is extracted compared with femto - lasik eyes . this increased corneal backscatter in the early postoperative period does not necessarily result in decreased vision , increased incidence of complications , or increased inflammation , but it obviously reflects a different healing response after smile . whether this difference hashowever it is speculated that suboptimal cutting of the stromal fibers by the femtosecond laser may be the reason for this type of interface scatter , which results in slightly reduced visual acuity in the early postoperative period . if this is correct , incorporating ivcm evaluation of the interface into future studies on laser energy , spot size , and spacing settings may help to further optimize these factors and minimize a delay in recovery .\noutput:\n" }, { "from": "agent", "value": "purpose . to evaluate and compare corneal backscatter from anterior stroma between small incision lenticule extraction ( smile ) and femtosecond laser - assisted lasik ( femto - lasik ) . methods . a cohort of 60 eyes of 30 patients was randomized to receive smile in one eye and femto - lasik in the fellow eye . in vivo confocal microscopy was performed at 1 week and 1 , 3 , and 6 months after surgery . the main outcome measurements were maximum backscattered intensity and the depth from which it was measured , the backscattered light intensity 30 m below bowman 's membrane at the flap interface and 150 m below the superficial epithelium , and the number of refractive particles at the flap interface . results . the mean backscattered light intensity ( li ) at all measured depths and the maximum backscattered li were higher in the smile group than the femto - lasik group at all postoperative visits . li differences at 1 week and 1 - and 3 - month visits were statistically significant ( p < 0,05 ) . li differences at 6 months were not statistically significant . there was no difference in the number of refractive particles at the flap interface between the groups at any visit . conclusions . smile results in increased backscattered li in the anterior stroma when compared with femto - lasik were evaluated ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the main causes of snhl are advanced age , the use of ototoxic medications , noise exposure , hereditary , and autoimmune diseases . it has recently been reported that various other factors such as family history , smoking , alcohol consumption , head trauma , diseases such as diabetes , high blood pressure , and some renal pathologies also lead to changes in hearing . polycystic ovary syndrome ( pcos ) is a common endocrine disease affecting at least 10 % of females of reproductive age . it is described by hyperandrogenism , menstrual irregularity , anovulation , infertility , and obesity . in addition , pcos is often accompanied by hyperinsulinemia , insulin resistance , dyslipidemia , and low - grade chronic inflammation that predispose to endothelial damage . also , high - frequency hearing is often affected sooner in diseases that cause endothelial damage . high - frequency ( 40008000 hz ) hearing loss was first described in pcos patients by oghan and coksuer . kucur et al . also identified eh frequency ( 800014000 ) hearing loss in pcos patients . however , these studies did not include any information about the association between hearing thresholds and the known parameters of pcos such as ir , lh / fsh ratio , hirsutism score , and free testosterone index ( fti ) . the aim of our study was to investigate the association between pcos and hearing thresholds . in addition , the relationship among insulin resistance ( ir ) , lh / fsh ratio , hirsutism score , and fti with hearing thresholds were investigated . this prospective study enrolled 80 consecutive cases that applied to the endocrinology and gynecology polyclinics of our hospital that met the inclusion criteria . forty cases ( mean age , 24.336.38 years ; range 1646 years ) that were diagnosed with pcos composed the pcos group . diagnosis of pcos was according to rotterdam eshre / asrm - sponsored pcos consensus workshop group . forty age and body mass index ( bmi ) matched female volunteers ( mean age , 26.386.75 years ; range 1642 years ) composed the control group . the study design was confirmed by the local ethics committee ( approval number : 1126.12.2012 ) and informed consent was obtained from all of the women that participated in the study . for all participants , anamnesis was obtained , and otoscopic examination and pure - tone audiometric tests were performed . the exclusion criteria were : hyperprolactinemia , congenital adrenal hyperplasia , androgen - secreting tumors , thyroid disorders , cushing syndrome , vertigo , tinnitus , middle ear diseases , major neurological and psychiatric disease , diabetes mellitus , chronic kidney failure , chronic liver failure , hypertension or hyperlipidemia and similar chronic diseases , history of previous ear surgery , family history of hearing loss , history of acoustic trauma , conductive hearing loss , subject to ototoxic substances , autoimmune diseases , cancer , exposure to radiation in the head or neck , pregnancy , smoking , alcohol use , ongoing infection or inflammation , and history of using any medication . all patients had routine audiometric tests performed by the same expert audiometrist blinded to the study . the pure - tone audiometry ( pta ) test was performed in a soundproof environment using an interacoustic clinical audiometer ( model ac40 ; denmark ) . pta - low ( 250 , 500 , 1000 , and 2000 hz ) , pta - high ( 4000 , 6000 , and 8000 hz ) and pta - extended high ( 9000 , 10000 , 11200 , 12500 , 14000 , 16000 , 18000 , and 20000 hz ) frequencies were tested . hearing threshold levels were measured in decibels ( db ) . in each case , the threshold level was calculated for both ears and at every frequency . the threshold levels at 250 hz , 500 hz , 1000 hz , and 2000 hz were identified as low - frequency audiometry , the thresholds at 4000 hz , 6000 hz , and 8000 hz as high - frequency audiometry and the thresholds at 9000 hz , 10000 hz , 11200 hz , 12500 hz , 14000 hz , 16000 hz , 18000 hz , and 20000 hz as extended - high ( eh ) frequency audiometry and the mean value was calculated . the mean hearing thresholds of the pcos group and control group at pta - low , pta - high , and pta - eh frequencies were compared . the physical examination of each of the women was performed by the same endocrinology specialist . bmi was calculated by dividing the weight by the square of height ( kg / m ) . the degree of hirsutism was determined using the ferriman - gallwey scoring ( fgs ) system . blood samples were obtained during the follicular phase of the menstrual cycle after 12 hours fasting . the fasting plasma glucose levels ( fpg ) were evaluated using roche hitachi pp modular analyzer ( roche - hitachi , tokyo , japan ) by enzymatic colorimetric assay . follicle - stimulating hormone ( fsh ) , luteinizing hormone ( lh ) , total testosterone ( tt ) , sex hormone - binding globulin ( shbg ) , and insulin measurements were done using the chemiluminescent immunoassay method with an immulite 2000 ( diagnostic products , los angeles , ca , usa ) analyzer . insulin resistance was measured using the homa - ir ( homeostasis model assessment for insulin resistance ) index . the free testosterone index ( fti ) was calculated according to the formula 100 serum testosterone ( nmol / l ) / shbg ( nmol / l ) . the descriptive statistics of the variables studied were given as mean , standard deviation , and minimum and maximum values . the student t - test was used to compare data between the control group and pcos group . the statistical significance level was taken as 5 % , and spss ( version 21 ) was utilized for all statistical calculations . this prospective study enrolled 80 consecutive cases that applied to the endocrinology and gynecology polyclinics of our hospital that met the inclusion criteria . forty cases ( mean age , 24.336.38 years ; range 1646 years ) that were diagnosed with pcos composed the pcos group . diagnosis of pcos was according to rotterdam eshre / asrm - sponsored pcos consensus workshop group . forty age and body mass index ( bmi ) matched female volunteers ( mean age , 26.386.75 years ; range 1642 years ) composed the control group . the study design was confirmed by the local ethics committee ( approval number : 1126.12.2012 ) and informed consent was obtained from all of the women that participated in the study . for all participants , anamnesis was obtained , and otoscopic examination and pure - tone audiometric tests were performed . the exclusion criteria were : hyperprolactinemia , congenital adrenal hyperplasia , androgen - secreting tumors , thyroid disorders , cushing syndrome , vertigo , tinnitus , middle ear diseases , major neurological and psychiatric disease , diabetes mellitus , chronic kidney failure , chronic liver failure , hypertension or hyperlipidemia and similar chronic diseases , history of previous ear surgery , family history of hearing loss , history of acoustic trauma , conductive hearing loss , subject to ototoxic substances , autoimmune diseases , cancer , exposure to radiation in the head or neck , pregnancy , smoking , alcohol use , ongoing infection or inflammation , and history of using any medication . all patients had routine audiometric tests performed by the same expert audiometrist blinded to the study . the pure - tone audiometry ( pta ) test was performed in a soundproof environment using an interacoustic clinical audiometer ( model ac40 ; denmark ) . pta - low ( 250 , 500 , 1000 , and 2000 hz ) , pta - high ( 4000 , 6000 , and 8000 hz ) and pta - extended high ( 9000 , 10000 , 11200 , 12500 , 14000 , 16000 , 18000 , and 20000 hz ) frequencies were tested . hearing threshold levels were measured in decibels ( db ) . in each case , the threshold level was calculated for both ears and at every frequency . the threshold levels at 250 hz , 500 hz , 1000 hz , and 2000 hz were identified as low - frequency audiometry , the thresholds at 4000 hz , 6000 hz , and 8000 hz as high - frequency audiometry and the thresholds at 9000 hz , 10000 hz , 11200 hz , 12500 hz , 14000 hz , 16000 hz , 18000 hz , and 20000 hz as extended - high ( eh ) frequency audiometry and the mean value was calculated . the mean hearing thresholds of the pcos group and control group at pta - low , pta - high , and pta - eh frequencies were compared . the physical examination of each of the women was performed by the same endocrinology specialist . bmi was calculated by dividing the weight by the square of height ( kg / m ) . the degree of hirsutism was determined using the ferriman - gallwey scoring ( fgs ) system . blood samples were obtained during the follicular phase of the menstrual cycle after 12 hours fasting . the fasting plasma glucose levels ( fpg ) were evaluated using roche hitachi pp modular analyzer ( roche - hitachi , tokyo , japan ) by enzymatic colorimetric assay . follicle - stimulating hormone ( fsh ) , luteinizing hormone ( lh ) , total testosterone ( tt ) , sex hormone - binding globulin ( shbg ) , and insulin measurements were done using the chemiluminescent immunoassay method with an immulite 2000 ( diagnostic products , los angeles , ca , usa ) analyzer . insulin resistance was measured using the homa - ir ( homeostasis model assessment for insulin resistance ) index . the free testosterone index ( fti ) was calculated according to the formula 100 serum testosterone ( nmol / l ) / shbg ( nmol / l ) . the descriptive statistics of the variables studied were given as mean , standard deviation , and minimum and maximum values . the student t - test was used to compare data between the control group and pcos group . the statistical significance level was taken as 5 % , and spss ( version 21 ) was utilized for all statistical calculations . the demographic data and laboratory findings of the study groups are presented in table 1 . significantly higher fgs , fpg , insulin , homa - ir , tt , fti , and lh / fsh measurements were identified in the pcos group than in the control group ( p = 0.001 , 0.009 , 0.013 , 0.005 , 0.001 , 0.001 , and 0.003 , respectively ) . the comparison of the low , high , and eh frequency hearing thresholds of the pcos and control groups is presented in table 2 . there was no statistically significant difference between the mean hearing thresholds of the groups at low or high frequencies . on the other hand , the mean hearing thresholds at eh frequencies were statistically significantly higher in the pcos group than in the control group ( p = 0.001 for the right ear and p = 0.015 for the left ear ) . the correlation analysis of the pcos group showed a positive correlation between the eh frequency hearing threshold levels and the fti values ( r = 0.380 , p = 0.016 for the right ear and r = 0.360 , p = 0.022 for the left ear ; figure 1a , 1b ) . also , a significant positive correlation was identified between the hearing thresholds at eh frequencies and the fgs value ( r = 0.344 , p = 0.030 for the right ear and r = 0.432 , p = 0.005 for the left ear ; figure 2a , 2b ) . but there was no significant correlation between the eh frequency and bmi , fpg , insulin , homa - ir , lh / fsh ( p 0.005 ) in the pcos group . comparison of the pcos and control groups in terms of the average hearing thresholds at each frequency in pta - eh measurements are shown in table 3 . hearing thresholds at each frequency in pta - eh were statistically significantly higher in the pcos group than in the control group except for left ear 20000 hz . there are various previous studies reporting that pcos and hearing loss are associated at high ( 40008000 hz ) and eh ( 800014000 hz ) frequencies . these studies do not provide any information about the presence of a relationship between hearing loss and known parameters of pcos such as ir , elevated lh / fsh ratio , hirsutism score , and elevated fti . to our knowledge , our study is the first study to investigate the association of hearing thresholds with parameters such as ir , lh / fsh ratio , hirsutism score , and fti in pcos cases . in histological examination , hwang et al . detected the presence of microvascular structures with leaner walls in the stria vascularis of the basal end of the cochlea in obese rats . they also reported that markers such as tumor necrosis factor alpha , hypoxia - induced factor 1 , caspase 3 , poly ( adp - ribose ) polymerase - 1 , nuclear factor kappa b , and apoptosis inducing factor are present in the basal end of the cochlea at high concentrations . various methods have been used to measure hearing thresholds . in our study , the hearing threshold levels at eh frequencies ( 900020000 hz ) were statistically significantly higher in the pcos group when compared to the control group . however , at low ( 2502000 hz ) and high ( 40008000 hz ) frequencies , there was no significant difference between the hearing thresholds of the pcos group and the control group . our findings support other studies that also reported findings suggesting that eh frequencies which represent the basal end of the cochlea are often influenced sooner in disorders that cause endothelial and vascular damage . in one other study , it was reported that chronic inflammation in pcos could induce of hearing loss , particularly at eh frequencies . as exposure to the multifactorial agents of pcos continues over time , it was determined that hyperandrogenism was associated with elevated blood pressure , low hdl cholesterol , dysglycemia , insulin resistance , and abdominal obesity . endothelial damage and increased risk for cardiovascular disease in pcos patients have also been reported . some of the biochemical and hormonal changes that occur in pcos have been identified as responsible for atherosclerosis and endothelial dysfunction . in light of all this information , it can be suggested that the hyperandrogenism in pcos impairs microcirculation especially in the basal end of the cochlea through microangiopathy and leads to an elevation in hearing thresholds at eh frequencies . in our study , we detected the presence of a positive correlation between the fti and fgs values and hearing thresholds at eh frequencies in the pcos group . however , there was no significant correlation between bmi , fpg levels , insulin levels , ir , or lh / fsh ratio and hearing thresholds at eh frequencies . these results support the view that the elevation of testosterone levels ( the fundamental cause of hirsutism in pcos ) may play a significant role in the pathophysiology of elevated hearing thresholds . first , it is a cross - sectional study and therefore is incapable of assessing the changes that may occur in hearing levels over time ; new longitudinal studies are required to investigate the causal role of pcos in hearing loss . new studies conducted with larger case populations are needed to elucidate the influence of pcos and various risk factors on auditory functions . at pta - eh frequencies , we detected significantly higher hearing thresholds in pcos patients than in controls . we also determined that elevated fti and fpg levels were positively correlated with elevated hearing thresholds . these findings support the position that one of the most important factors playing a role in the elevation of hearing thresholds in pcos is hyperandrogenism , which is a fundamental component of pcos . a positive correlation was identified between elevated hearing thresholds and hirsutism scores ( fgss ) , which can easily be calculated during physical examination . we believe that pcos - related hyperandrogenism plays an important role in sensorineural hearing loss and that this effect can be avoided by managing identified risk factors . also , early hearing screening may help diagnose hl early , especially in pcos cases with significant hyperandrogenism and hirsutism .\noutput:\n" }, { "from": "agent", "value": "backgroundthe purpose of our study was to investigate the association between polycystic ovary syndrome ( pcos ) and hearing thresholds.material / methodsforty women diagnosed with pcos ( mean age , 24.336.38 years ) and 40 healthy women controls ( mean age , 26.386.75 years ) were included in prospective study . each case was tested with low ( 250 , 500 , 1000 , and 2000 hz ) , high ( 4000 , 6000 , and 8000 hz ) and extended high ( eh ) ( 900020000 hz ) frequency audiometry . the fasting plasma glucose , insulin , fsh , lh , total testosterone , and sex hormone - binding globulin were measured in all patients.resultsthe mean hearing thresholds at eh frequencies were statistically significantly higher in the pcos group than in the control group ( p = 0.001 right ear and p = 0.015 left ear ) . there were significant positive correlations among free testosterone index ( fti ) values and hirsutism scores with eh frequency hearing thresholds.conclusionsat pure - tone audiometry ( pta ) eh frequencies , we detected significantly higher hearing thresholds in pcos patients than in controls . we also determined that elevated fti and hirsutism score were positively correlated with elevated hearing thresholds in eh frequencies . these findings support that hyperandrogenism can play a role in the elevation of hearing thresholds in pcos ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: cerebral palsy ( cp ) is the term for a range of movement difficulties caused when the parts of the brain controlling the movements do not work properly1 . nutritional problems observed in children with cp have an important place in the care of these children . if these nutritional problems are not treated , they lead to inadequate nutrition and growth - development retardation and affect morbidity and mortality unfavorably5 , 6 . nutrition and gastrointestinal system ( gis ) problems in patients with cp depend on the interaction of several factors . most of these patients can not walk , reach their meals , or move food to their mouth due to motor impairment therefore , they depend on other people in their nutritional activities6 . it is related to oral phase dysfunction in addition to insufficient lip closure generally and to tongue movements impaired due to diminished oral and perioral sensory perception , upside down posture , and diminished swallowing frequency and dysphagia . drooling is a stressful situation for children as well as their parents and caretakers . among the reported side effectsare social rejection risk ; continuously moist and wet outfits ; unpleasant odor ; chapped or softened facial skin ; perioral and oral mouth infections , generally candida albicans , dehydration ; impaired chewing function ; dependency in talking ; book harming ; impaired communication skills ; and social isolation7 . inability to swallow saliva , it was observed that drooling of cp individuals with spastic quadriplegia was greater in cp individuals with than other functional capacities , and the prevalence of drooling was higher at younger ages9 . based on this information , the primary purpose of the study was to evaluate drooling frequency and severity in children with quadriparetic cerebral palsy , to lead development of suitable treatment strategies , and to investigate the relationship of drooling frequency and severity with nutrition and head control . we believe that this study will shed light to necessity of rehabilitation programs composed of oral stimulation , exercises for improving oral motor abilities , speech and language therapy , appropriate feeding positions , family education for better sitting and feeding of the child , diet and feeding solutions . fifty - six quadriparetic individuals were included in the present study , which investigated the effects of drooling on nutrition in individuals with quadriparetic cp . parents of individuals included in the study were informed about the study , and the required permit was obtained from the abant izzet baysal university clinical research ethics committee ( 23625 - 050.01.04 - 194 ) . individuals diagnosed with quadriparetic spastic type cerebral palsy who were between the ages 215 were included in the study after obtaining approval from their parents , and individuals who had a diagnosis other than quadriparetic cerebral palsy or withdrew from the study on their own or due to the decision of their parents or caretakers were not included in the study . ten individuals were not included in the study because they did not fulfill the age criterion among the inclusion criteria . of the 56 individuals , 10 individuals ( 17.9 % ) , 12 individuals ( 21.4 % ) , and 34 individuals ( 60.7 % ) were classified as levels iii , iv and v , respectively , according to the gross motor function classification system . drooling control was evaluated by using the scale developed by thomas - stonell and greenberg ( drooling severity and frequency scale , dfss ) . individuals were divided into two groups : those who did not drool ( group 2 , n = 27 ) and those who drooled ( group 1 , n = 29 ) . the subjects included in the study were evaluated according to an evaluation form . for determining characteristics of the subjects in the evaluation form , birth date , gender , height and body weight were recorded . the episodes of the subjects were considered under these headings : birth weight ( grams ( gr ) ) and gestational age ( weeks ) , and diagnosed gastrointestinal system problemquestions were asked about the eating period of the subjects ( 20 min , 2040 min , or 40 min and above ) , meal interval ( 2 hours , 3 hours , 4 hours , or more than 4 hours ) , kind of food that could be consumed from a diet list ( liquid , solid , mash ) , presence of gastronomy , independent eating skill ( independent , semi - independent , fully dependent ) , and materials used in consuming meals ( nursing bottle , glass , spoon , finger , straw ) . moreover , appetite status of the children was as also queried ( good , inconsistent , and weak ) . skill to hold the head in an upright position for 10 seconds ( sec ) in a supported sitting position was evaluated10 . head control was determined as yes or no . drooling severity and frequency was determined based on the method of observation determined in meetings with the parents or caretakers and related physiotherapists . drooling status of the individuals during the last two weeks was determined numerically by using the scale developed by thomas - stonell and greenberg ( dfss ) 7 . according to the scale developed by thomas - stonell and greenberg , drooling severity was evaluated as follows : 1 dry ( no drooling ) ; 2 , mild ( moist lips ) ; 3 , moderate ( wet lips and chin ) ; 4 , severe ( moist outfits ) ; and 5 , profuse ( wet outfits , hands , and objects ) . drooling frequency was evaluated as follows : 1 , none ; 2 , sometimes ( not every day ) ; 3 , sometimes ( part of the day ) ; and 4 , continuously . individuals who had a score of 1 for drooling severity formed the not drooling group ( group 2 ) , and individuals who had scores of 2 , 3 , 4 or 5 for drooling severity formed the drooling group ( group 1 ) . the heights of the subjects were measured and recorded in meters , their body weights were measured and recorded in kilograms , and their body mass indexes ( kg / m ) was estimated by dividing their body weights ( in kilograms ) by the square of their heights ( in meters ) . furthermore , body mass indexes ( bmis ) were determined numerically based on age . bmis based on age were categorized as suggested by the world health organization ( who ) : below the 5th percentile , inadequate nutrition ; 6th to 15th percentile , weak ; 16th to 85th percentile , , 86th to 95th percentile , increased risk for overweight ; and over the 95th percentile , overweight ( obese ) . a group was formed by combining the individuals from the 86th to 95th percentiles , increased risk for overweight , and individuals from the over 95th percentile , overweight ( obese ) . as a result , individuals from below the 5th percentile made up the inadequate nutrition group , individuals from the 16th to 85th percentile made up the normal nutritiongroup , and individuals from the 86th percentile and above made up the overweight - obese group . growth curves made over normal limits were used in kilogram index based on age and children remaining under 3 percentile were named as low weight . weight indexes based on age were grouped according to the distribution interval in the population and indicated numerically . statistical analyses were performed by using the spss statistics software ( version 11.5 , spss inc . , the student s t test was used , and in the analysis of categorical variables , ( fisher s exact ) test was used . statistically significant differences were found between the groups in terms of weight ( p = 0.017 ) and bmi ( p = 0.018 ) values ( table 1table 1 . physical characteristics of the individualsphysicalcharacteristicsgroup 1 ( n = 29 ) xsdgroup 2 ( n = 27 ) xsdage ( years ) 7.863.898.594.09 weight ( kg ) 18.108.4424.5310.89 height ( cm ) 115.4817.38115.8123.56 bmi ( kg / m ) 13.774.1417.156.00 ) . a statistically significant difference was found between the groups in terms of age values ( p = 0.032 ) ( table 2table 2 . birth weights and gestational ages of the individualsgroup 1 ( n = 29 ) xsdgroup 2 ( n = 27 ) xsdbirth weight ( g ) 2772.8975.82497.2901.8 gestational age ( weeks ) 36.794.4633.965.10 ) . the drooling severity and frequency scores of drooling individuals were 3.060.79 and 3.000.84 , respectively . presence / absence of gastrointestinal system problems , nutrition periods , meal intervals , presence / absence of feeding with a tube , and a comparison of solid and mashed food eating skills are shown in table 3table 3 . comparison of the presence / absence of gastrointestinal system problems , eating periods , meal intervals , presence / absence of feeding with a tube , and solid and mash food eating skills of the individualsgroup 1n ( % ) group 2n ( % ) totaln ( % ) gastrointestinal system problemyes10 ( 17.9 % ) 10 ( 17.9 % ) 20 ( 35.7 % ) no19 ( 33.9 % ) 17 ( 30.4 % ) 36 ( 64.3 % ) eating period20 min15 ( 26.8 % ) 14 ( 25.0 % ) 29 ( 51.8 % ) 3040 min8 ( 14.3 % ) 11 ( 19.6 % ) 19 ( 33.9 % ) 45 min and above6 ( 10.7 % ) 2 ( 3.6 % ) 8 ( 14.3 % ) meal interval2 h10 ( 17.9 % ) 5 ( 8.9 % ) 15 ( 26.8 % ) 3 h10 ( 17.9 % ) 8 ( 14.3 % ) 18 ( 32.1 % ) 4 h7 ( 12.5 % ) 12 ( 21.4 % ) 19 ( 33.9 % ) over 4 h2 ( 3.6 % ) 2 ( 3.6 % ) 4 ( 7.1 % ) feeding with tubeyes1 ( 1.8 % ) 2 ( 3.6 % ) 3 ( 5.4 % ) no28 ( 50 % ) 25 ( 44.6 % ) 53 ( 94.6 % ) feeding with mashyes27 ( 48.2 % ) 25 ( 44.6 % ) 52 ( 92.9 % ) no2 ( 3.6 % ) 2 ( 3.6 % ) 4 ( 7.1 % ) feeding with solid foodyes14 ( 25 % ) 18 ( 32.1 % ) 32 ( 57.1 % ) no15 ( 26.8 % ) 9 ( 16.1 % ) 24 ( 42.9 % ) . a significant difference was found between the groups in terms of meal eating skill ( p = 0.001 ) . it was observed that the not drooling group was more independent ( table 4table 4 . comparison of eating , use of a nursing bottle , drinking from a glass , eating with a spoon , and eating with the hands skills of individualsgroup 1n ( % ) group 2n ( % ) totaln ( % ) eating skillindependent0 ( 0 % ) 6 ( 10.7 % ) 6 ( 10.7 % ) semi - dependent4 ( 7.1 % ) 9 ( 16.1 % ) 13 ( 23.2 % ) fully dependent25 ( 44.6 % ) 12 ( 21.4 % ) 37 ( 66.1 % ) use of a nursing bottleyes11 ( 19.6 % ) 9 ( 16.1 % ) 20 ( 35.7 % ) no18 ( 32.1 % ) 18 ( 32.1 % ) 36 ( 64.3 % ) drinking from a glassyes21 ( 37.5 % ) 21 ( 37.5 % ) 42 ( 75 % ) no8 ( 14.3 % ) 6 ( 10.7 % ) 14 ( 25 % ) eating with a spoonyes28 ( 50 % ) 22 ( 39.3 % ) 50 ( 89.3 % ) no1 ( 1.8 % ) 5 ( 8.9 % ) 6 ( 10.7 % ) eating with the handsyes8 ( 14.3 % ) 11 ( 19.6 % ) 19 ( 33.9 % ) no21 ( 37.5 % ) 16 ( 28.6 % ) 37 ( 66.1 % ) ) . there was no significant difference between the groups in terms of chewing and drinking with a straw skill ( table 5table 5 . comparison of chewing and drinking with a straw skills among groupsgroup 1n ( % ) group 2n ( % ) total n ( % ) chewingyes17 ( 30.4 % ) 19 ( 33.9 % ) 36 ( 64.3 % ) no12 ( 21.4 % ) 8 ( 14.3 % ) 20 ( 35.7 % ) drinking with a strawyes8 ( 14.3 % ) 12 ( 21.4 % ) 20 ( 35.7 % ) no21 ( 37.5 % ) 15 ( 26.8 % ) 36 ( 64.3 % ) ) . a significant difference was found between head control ( p = 0.038 ) and drooling . the drooling severity was higher in individuals having no head control ( table 6table 6 . comparison of head control of the individualsgroup 1n ( % ) group 2n ( % ) totaln ( % ) head controlyes15 ( 26.8 % ) 21 ( 37.5 % ) 36 ( 64.3 % ) no14 ( 25 % ) 6 ( 10.7 % ) 20 ( 35.7 % ) ) . there was no significant difference between the groups in terms of bmi index values based on age ( p = 0.169 ) ( table 7table 7 . comparisons of bmi values based on age between the groupsgroup 1n ( % ) group 2n ( % ) totaln ( % ) bmi based on age05 ( inadequate nourishment ) 20 ( 35.7 % ) 8 ( 14.3 % ) 28 ( 50 % ) 615 ( poor nourishment ) --- 1685 ( normal nourishment ) 7 ( 12.5 % ) 11 ( 19.6 % ) 18 ( 32.1 % ) 8695 ( increased risk for overweight ) 2 ( 3.6 % ) 3 ( 5.4 % ) 5 ( 8.9 % ) 95 and above ( obese ) 0 ( 0 % ) 5 ( 8.9 % ) 5 ( 8.9 % ) ) . the bmi indexes of individuals who did not drool were found to be greater based on age . in other words , the nutrition levels of individuals who had saliva control were better . there was quadratic regression between the bmi index and drooling severity based on age . until the drooling severity score reached 2 ( mild ) , there was negative linear regression with bmi based on age , and after the drooling severity score reached 2 , regression did not change significantly . weight indexes in individuals who had no head control based on age were found to be lower . in other words , the growth levels of individuals who had no head control were lower . the overweight and obese groups were combined . as a result , inadequate nutrition , normal nutrition , and overweight / obese groups were formed . there were significant differences between the inadequate nutrition , normal nutrition , and overweight / obese groups ( p = 0.008 ) ( table 8table 8 . comparison of bmivalues between groups based on ages of the individualsgroup 1n ( % ) group 2n ( % ) totaln ( % ) inadequate nourishment ( 5 ) 20 ( 35.7 % ) 8 ( 14.3 % ) 28 ( 50 % ) normal ( 1685 ) 7 ( 12.5 % ) 11 ( 19.6 % ) 18 ( 32.1 % ) overweight / obese ( 86 ) 2 ( 3.6 % ) 8 ( 14.3 % ) 10 ( 17.9 % ) ) . there were significant differences between the groups having low weights and the groups that did not have low weights according to weight index based on age ( p = 0.002 ) ( table 9table 9 . grouping and comparison of the weight percentile values of the individuals based on agegroup 1n ( % ) group 2n ( % ) totaln ( % ) 3 ( low weight ) 17 ( 30.4 % ) 5 ( 8.9 % ) 22 ( 39.3 % ) 312 ( 21.4 % ) 22 ( 39.3 % ) 34 ( 60.7 % ) ) . in the present study , there was a significant difference between the drooling and not drooling groups in terms of eating skills . it was observed that as the eating skill diminished , drooling prevalence increased . it was found that 44.6 % of individuals having saliva control were able to eat mash and that 48.2 % of individuals who drooled were able to eat mash . there were no significant differences between the groups in terms of meal content ( solid , mash , liquid ) , nutrition periods , and presence / absence of feeding with a tube . in other wordswe think that the factors determining diet content are oral health ( teeth situation , etc . ) and oral motor dysfunction . for drinking with a straw , it is necessary to reach to the straw and then it is necessary to grab it without biting and to draw fluid into the mouth . individuals with middle and severe nutrition disorder have problems drawing liquid into the mouth with a straw and with grabbing a straw with their lips . ylmaz et al. 10 found that the drinking with a straw skill of younger individuals was worse than that of older individuals because of lack of experience . reid et al. 11 reported that there was no drooling in 80.1 % of individuals with cp who could use straw and that the other 19.9 % drooled . in our study , it was found that 35.7 % of the subjects could drink with a straw . drooling was found in 14.3 % of these subjects , and whereas the other 21.4 % did not drool . we think that in our study , having considerably high drinking skills with a straw was related to the mental situation of the individuals . we think that having a good mental situation , good oral muscle strength , and good coordination affects drinking with a straw positively in individuals . siktberg and bantz13 reported that physical growth and nutrition level of children with swallowing impairment were affected by social interaction . nutrition has significant social effect not only for sustaining life but also for the establishment of intrafamilial relationships and out of home independence14 . in an epidemiologic study by erasmus et al. 15 conducted in northern ireland during 19922009 at a cp center , dysphagianutrition and swallowing problems caused malnutrition and dehydration and may affect physical and cognitive growth and development of children13 . arvedson16 reported that the prevelance of nutrition impairment was greater in spastic quadriplegic children ( 5075 % ) . early detection of dysphagia and diagnosis by an interdisciplinary team may correct the nutritional situation and physical , cognitive , and psychological growth and development of children and their interaction with other children and their families13 . growth analyses and follow - up with developmental evaluations are important for determining nutrition and swallowing impairments16 . in the present study , we wanted to draw attention to nutrition problems and the nutrition behavior of quadriparetic cp children . snider et al. 14 reported that prevalence studies indicating nutrition difficulties of cp children are scarce . in study by erkinet al. 17 , nutrition problems were detected in 86 % of quadriplegic cp children and 37 % of hemiplegic or diplegic children . liquid and food loss is prevalent during swallowing in individuals who have severe nutritional dysfunction10 . hou et al. 18 reported that oral motor dysfunction and nutritional problems in children with cp were seen at early ages and that they affected growth and the nutrition level . it was reported that 27 % of cp children who had a swallowing problem experienced a suction problem in the past . no relationship was found between the severity of swallowing difficulty and suction skill in the present study . in full - term newborn children , complex delayed swallowing problems have been observed19 . in our study , there was no significant difference between drooling and suction functions in the postnatal term . reid et al. 11 observed that 77.5 % of children with cp experiencing difficulty in eating did not drool and that the other 22.5 % did drool . in the present study , 66.7 % of the children with a drooling problem experienced difficulty in eating solid food , and 39.3 % of children without a drooling did not experience difficulty in eating solid food . when mash food eating skills were evaluated , it was seen that 65.7 % of children who did not drool could eat mash and that 34.5 % of children who drooled could eat mash . drooling was found in 97.6 % of children who fed with a tube , and no drooling was found in 2.4 % of the children . food content affects growth and nutrition impairment and oral health , especially at early ages20 , 21 . santos et al. 20 reported that there was significant difference between tooth health and diet content . in our study , the health of the subjects teeth was not evaluated , and therefore it could not be determined , whether oral motor dysfunction or tooth problems influenced preferences regarding diet content . by conducting a multidisciplinary study with dentists , the conditions of the teeth of the individuals could be evaluated , and it could be determined whether the health of the teeth plays a role in determination of diet content . in the present study , the incidence of assisted nutrition ( by a caretaker ) with a spoon was found to be 89.3 % . when the functional levels of individuals with quadriparetic cp are considered , it is clear that acquiring the skill to eat independently with a spoon is rather difficult . there was no significant difference between the drooling and not drooling groups in nursing bottle usage , drinking from a glass , eat with a spoon and eating with the hands skills . we think that the reason for it is the sufficiency of functional levels and mental status of the individuals . san et al. 22 reported in a study that evaluated children with cp that 79.3 % of them could not eat with spoon , 83.45 % could not bite , 66.33 % could not chew , 91.61 % could not drink , and 74.73 % could not swallow . santos et al. 20 reported difficulty in eating with a spoon , biting , chewing , drinking from a glass , drinking with a straw , and swallowing skills . gisel and patrick23 found that the chewing and swallowing periods were longer in individuals with severe cp . lack of facial tone and head control affect drooling17 . in children who bend forward , drooling is greater24 . head posture and position affect chair sitting manner and drooling11 , 24 , 25 . lack of postural control increases nutrition and swallowing disorders26 . in a study conducted by yilmaz et al. 10 , head control was evaluated by physiotherapists , and individuals who could hold their head in a sitting position for less than 10 sec were categorized as having weak head holding skill . in another study , it was established that 4.4 % of the children with cp did not have head control but had saliva control , and drooling was found in 95.6 % of the children11 . in the present study , drooling was found in 25 % of the subjects , whereas no drooling was found in the other 10.7 % . less drooling was found as the head control of the subjects improved . there was a significant difference between head control and drooling . as we stated previously , head control affects drooling control . in treatment programs applied for drooling control development , attentionmust be paid to ensure that the head position is in a neutral position27 . in quadriparetic children , allowing them to lie down all day long combined with swallowing impairment , it could lead to aspiration and lung infection . this is a life - threatening situation in individuals with cp , and it illusrates the importance of drooling control . right postural arrangement plays a vital role in the normal nutrition and swallowing process26 . it was previously observed that positional programs result in recovery of eating and swallowing skills14 . head control is affected by body arrangement , and the body depends on pelvis stability . along with techniques such as therapeutic sitting and oral control , right postural arrangement corrects oral functions and enables food intake safely26 . it is considered that investigations are needed regarding development of head control within the physiotherapy programs and this will contribute to the development of saliva control and nutrition and swallowing functions . in children who are not able to develop head control , it is important that proper sitting and eating positions are developed by training their family members . in individuals with drooling , weight and bmi were found to be lower , the incidence of low weight , was higher , and bmi based on age decreased as drooling severity increased . it was determined that saliva control affected nutrition level , and when the eating skills of the groups with and without drooling control were compared , it was observed that the individuals having saliva control were more independent . the limitations of the study are as follows : the epilepsy episodes of the subjects of the study were not questioned . furthermore , tooth problems are vital factors influencing the nutrition levels and diet content of individuals . in the present study , finally , only the individuals with quadriparetic cerebral palsy were included in our study .\noutput:\n" }, { "from": "agent", "value": "[ purpose ] the aim of the present study was to investigate the relationship of drooling , nutrition , and head control in individuals with quadriparetic cerebral palsy . [ subjects and methods ] fifty - six individuals between the ages 2 and 15 diagnosed with spastic quadriparetic cerebral palsy and their families / caretakers were included in the study . drooling severity and frequency of individuals was evaluated by using the scale developed by thomas - stonell and greenberg ( drooling severity and frequency scale ) . individuals having a drooling severity value of 1 were included in the not drooling group ( group 2 ) ( n = 27 ) . individuals having a drooling severity of 2 , 3 , 4 , or 5 were included in the drooling group ( group 1 ) ( n = 29 ) . the evaluations were applied to both groups . [ results ] there were significant differences between the two groups in terms of gestational age , nutrition behavior , eating abilities , head control , gagging , nutritional status ( inadequate nutrition , normal nutrition , over weight - obese ) , and low weight . it was established that as head control increased , drooling severity diminished , and as drooling severity increased , bmi index decreased . independence of eating ability was found to be greater in the group having better drooling control . [ conclusion ] in the present study , it was determined that drooling control affected nutritional functions and that drooling control was affected by head control ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: homologs inherit similarities from their common ancestor , while structural analogs converge to similar structures due to a limited number of energetically favorable ways to pack secondary structural elements ( sses ) ( 1,2 ) . homology is inferred from sequence , structure and functional similarities , and several databases exist to catalog homologous proteins , e.g. pfam ( 3 ) , scop ( 4 ) and cath ( 5 ) . in contrast , analogy is more difficult to assess , and currently , no database exists that is devoted to structural analogs . traditionally , studies aimed at discriminating homologs and analogs from their structures use domains classified in the same scop superfamily as homologs and domains classified in the same scop fold but different superfamilies as analogs ( 68 ) . however , scop authors do not explicitly state that members of different superfamilies are necessarily analogous . domains are grouped in scop superfamilies when convincing evidence for their homology exists . when additional evidence comes to light , for instance , through newly determined structures , many studies argue for homology between certain scop superfamilies or even folds ( 1013 ) . hence , using domains in the same scop fold but different superfamilies as structural analogs is problematic because some domains in this category may be homologous . in an attempt to assemble a reliable set of structural analogs , we construct the malisam ( manual alignments for structurally analogous motifs ) database . by definitionthus , to identify structural analogs convincingly , we need to minimize the possibility of homology . to this end , we explore three situations where we are more confident that the structural similarities have arisen in the absence of evolutionary relationships . in the first situation , a hybrid motif , formed by an insertion together with part of the evolutionary core of one domain family , may fortuitously match the core motif in another evolutionarily unrelated domain family . second , an interface motif , formed by part of each domain or subunit contacting along a domain domain or subunit subunit interface , may happen to be structurally similar to the core motif of another unrelated domain family . and third , an artificial protein , obtained through selection from random peptides or sequence design experiments not biased by sequences of a particular homologous family , is a bona fide analog to a structurally similar , natural protein . to determine if a structural motif is a hybrid motif , an interface motif , or a core motif , we use the descriptions of the involved fold , superfamily or family in the scop database , in particular , scop definitions of fold cores ( 4 ) . currently , malisam does not include examples of structural analogy between stand - alone , compact domains because , for stand - alone domains , we can not argue for analogy convincingly by ruling out homology , especially when the domains share stronger structural similarity . it is our hope that , by studying the reliable analogs in malisam , researchers can gain a better understanding of structural analogy and develop better approaches to discriminating between remote homologs and analogs . in this work , a structural motif refers to a set of sses with a specific spatial arrangement ( architecture ) and sequential connectivity ( topology ) , allowing for circular permutations ( 14 ) . two structural motifs are regarded as analogs if they come from evolutionarily distinct domain families , but share the same architecture and topology , allowing for circular permutations . a domain refers to a possible evolutionary unit with a well - defined hydrophobic core . domain . for instance , scop has a whole multi - domain protein class , in which , by definition , a scopin addition , our domains frequently correspond to duplicated structural repeats in scop , when such repeats constitute evolutionary units and form a well - defined hydrophobic core within each repeat with fewer interactions between repeats . the 130 pairs of analogous motifs in malisam are organized in the following three categories corresponding to the three situations discussed in introduction section . in evolution , a domain family usually preserves a common core structure while accumulating insertions and deletions in the periphery ( 15 ) . a core motif is composed entirely of sses belonging to the evolutionary core of a domain family , while a hybrid motif is composed of both core elements and peripheral insertions . a hybrid motif in one family may happen to be structurally similar to the core motif in another evolutionarily unrelated family . for instance , a hybrid - grasp motif found in formate dehydrogenase is formed by part of the ferredoxin core and a large c - terminal extension . this hybrid - grasp motif is analogous to the core - grasp motif in protein l ( 16 ) . this structural phenomenon is a special case of a general property called gregariousness ( 17 ) , i.e. proteins displaying partial structural similarity to many , frequently unrelated proteins . consider two ancient domain families with evolutionary cores denoted as ab and bc , respectively . as represented by b and b , these two families show partial similarity between their cores . although most members in the first family have structure ab , some members carry an additional part c and have structure abc . the bc motif in these proteins is structurally similar to the core motif bc in the second family . to justify analogy between bc and bc , it is necessary to demonstrate that c is an insertion rather than a deletion , i.e. the first family evolved from ab to abc instead of from abc to ab . if c is not present in the majority of the family members and is restricted to a particular phylogenetic or functional group within the family , it is most likely that proteins with structure ab are ancient and proteins with structure abc are comparatively new . in other words , ab is the ancient core of the family , and c is a recent insertion . thus , though ab and bc show partial structural similarity , they are not homologous , both being ancient and having different cores . since ab and abcare homologous , abc and bc can not be homologous . therefore , the hybrid motif bc and the core motif bc are structural analogs . figure 1 illustrates an analogous pair comprised of a hybrid motif and a core motif . glyoxalase / bleomycin resistance protein / dihydroxybiphenyl dioxygenase consists of four - strands and one - helix with the sequential connection of . one representative of this superfamily , the first domain in the antibiotic resistance protein fosa from pseudomonas aeruginosa ( 18 ) , is diagramed in figure 1a . in this domain ( termedstructural repeat having glyoxalase fold in scop ) , the motif is a core motif , and no other sses are present . figure 1b depicts another domain that contains a motif , namely , the first domain in the oligopeptide - binding protein oppa from salmonella typhimurium ( 19 ) , which belongs to the scop superfamily periplasmic - binding protein - like ii . the core of this superfamily includes five - strands and their connecting helices , as illustrated in figure 1c by a more typical member in this superfamily , the first domain in lysine / arginine / ornithine - binding protein ( lao ) from s. typhimurium ( 20 ) . although fosa and oppa are classified in different scop superfamilies , folds and even classes , the two motifs boxed in figure 1a and b are similar in both architecture and topology . a comparison of figure 1b and c suggests that the - hairpin highlighted in red , which is present in oppa but absent in lao , is an insertion . indeed , a manual inspection of the structures in this superfamily shows that the - hairpin is present in only 4 out of the superfamily 's 32 proteins . moreover , these four proteins form a more closely related subgroup as indicated by their higher sequence identities to one another than to other proteins in this superfamily . all these observations suggest that the - hairpin does not belong to the ancient core of this superfamily and is instead an insertion that appeared later in evolution . thus , the motif in oppa ( figure 1b ) has a hybrid origin : the red - hairpin is an insertion while the remaining two strands and one helix are core elements . therefore , the hybrid motif in oppa and the core motif in fosa ( figure 1a ) define a pair of analogs . figure 1 . an analogous pair composed of a hybrid motif and a core motif . ( a ) the first domain in fosfomycin resistance protein a ( fosa ) from p. aeruginosa ( pdb code 1nki ) . the core region is colored from deep blue ( n - terminus ) to pale blue ( c - terminus ) . ( b ) the first domain in oligopeptide - binding protein ( oppa ) from s. typhimurium ( pdb code 1b05 ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) , and the inserted - hairpin is colored in red . ( c ) the first domain of lysine / arginine / ornithine - binding protein ( lao ) from s. typhimurium ( pdb code 1lst ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . ( a ) the first domain in fosfomycin resistance protein a ( fosa ) from p. aeruginosa ( pdb code 1nki ) . the core region is colored from deep blue ( n - terminus ) to pale blue ( c - terminus ) . ( b ) the first domain in oligopeptide - binding protein ( oppa ) from s. typhimurium ( pdb code 1b05 ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) , and the inserted - hairpin is colored in red . ( c ) the first domain of lysine / arginine / ornithine - binding protein ( lao ) from s. typhimurium ( pdb code 1lst ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . we use the following procedure to find analogous pairs consisting of a hybrid motif and a core motif . first , we represent the most commonly found structure motifs ( 21,22 ) or their circularly permuted forms by matrices and use these matrices as queries in prosmos ( 23 ) searches to find scop domains that contain the query motif . we inspect one randomly selected representative domain from each superfamily to determine whether the query motif occurring in this superfamily is a hybrid or not , according to scop description of the core of this superfamily . sses that do not belong to the core are considered to be insertions , and a hybrid motif should contain both core elements and inserted elements . the coordinates of a hybrid motif are extracted from the original pdb file and used as a query in dali ( 24 ) searches against a culled pdb database , in which any two proteins share 50 % sequence identity . the hits are sorted by dali z score and inspected manually to select the most similar core motif ( s ) to the query . the hybrid motif and the selected core motif are then added to the database as a pair of analogs . currently , there are 91 pairs of such analogs in malisam . an interface motif is formed by part of each domain or subunit contacting along a domain domain or subunit subunit interface . in compact multi - domain proteins or obligate multi - chain complexes , where domains or subunits are closely associated , an interface motif may be well defined enough to mimic the structure and topology of a core motif , which is composed entirely of sses belonging to the evolutionary core of a domain family . for the interface motif and the core motif to be a pair of analogs , they should come from evolutionarily unrelated domain families . particularly , the interface motif should not cover the complete core of any of the contributing domains or subunits because in that case , the core motif might be a duplicated or elaborated version of that completely covered domain or subunit . figure 2 shows an analogous pair comprised of an interface motif and a core motif . the actin filament capping protein capz ( figure 2a ) is a heterodimer of two homologous subunits and ( 25 ) . scop divides each subunit into three domains , with the n - terminal domain being a 3 - helical bundle ( diagramed in ribbons in figure 2a ) . the two 3 - helical bundle domains from the two subunits make many hydrophobic contacts at the dimer interface , forming a 4 - helical bundle ( framed in red ) . this 4 - helical bundle defines an interface motif , consisting of part of the 3 - helical bundle from the subunit followed by part of the 3 - helical bundle from the subunit . figure 2b depicts one monomer in the conserved hypothetical protein xcc0516 homopentamer from xanthomonas campestris ( 26 ) . this 4 - helical bundle in xcc0516 comprises the whole polypeptide chain and is a core motif . the interface 4 - helical bundle in capz ( boxed in red in figure 2a ) shares the same overall structure and topology with the upper portion of the core 4 - helical bundle in xcc0516 ( boxed in red in figure 2b ) . yet the interface motif comes from a 3 - helical bundle domain family , while the core motif comes from an evolutionarily unrelated 4 - helical bundle domain family . therefore , the interface motif in capz and the core motif in xcc0516 can be regarded as a pair of analogs . ( a ) the actin filament capping protein capz from gallus gallus ( pdb code 1izn ) . the three domains in each subunit are represented as a ribbon diagram , a pentagon and a rectangle , respectively . ( b ) the conserved hypothetical protein xcc0516 from x. campestris ( pdb code 2gsc ) . the polypeptide chain is colored in rainbow from n - terminus ( blue ) to c - terminus ( orange ) . the part that is aligned to the hybrid 4 - helical bundle motif in capz is in red frame . the disordered region between the 2nd and the 3rd helices is represented by a dotted curve . the helices in the red frames in ( a ) and ( b ) are diagramed as cylinders in the same colors above or below their corresponding sequences . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . ( a ) the actin filament capping protein capz from gallus gallus ( pdb code 1izn ) . the three domains in each subunit are represented as a ribbon diagram , a pentagon and a rectangle , respectively . ( b ) the conserved hypothetical protein xcc0516 from x. campestris ( pdb code 2gsc ) . the polypeptide chain is colored in rainbow from n - terminus ( blue ) to c - terminus ( orange ) . the part that is aligned to the hybrid 4 - helical bundle motif in capz is in red frame . the disordered region between the 2nd and the 3rd helices is represented by a dotted curve . the helices in the red frames in ( a ) and ( b ) are diagramed as cylinders in the same colors above or below their corresponding sequences . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . the same procedure described above to find hybrid motifs is used to identify interface motifs . in addition , we manually inspected the scop entries in the multi - domain proteins class or with duplication in their annotations in a search for interface motifs . the coordinates of an interface motif are extracted from the original pdb file and used as a query in dali ( 24 ) searches against the aforementioned , culled pdb database to find the most similar core motif ( s ) for it . note that , before running dali , the coordinates file of a subunit subunit interface motif is preprocessed so that it contains only one chain . currently , malisam stores 33 pairs of analogs that are composed of an interface motif and a core motif . an artificial protein and a natural proteinwe analyze the entries in the scop class designed proteins and select the ones with de novo sequences and reasonably complex structures to serve as queries in dali searches against the aforementioned representative pdb database . we pay attention to whether an artificial protein is designed without a sequence bias towards a particular homologous family , e.g. the artificially designed ww domain ( pdb 1e0 m ) will not work as an analog to natural ww domains , because it is based largely on the consensus sequence of ww domain family . by inspecting topdali hits , we select the most similar natural proteins for an artificial protein query . currently , malisam contains six pairs of analogs that consist of an artificial protein and a natural protein , but we expect this number to increase due to active research in the field of protein sequence design . each analogous pair is aligned manually by visual inspection and automatically by three programs [ dali ( 28 ) , tm - align ( 29 ) and fast ( 30 ) ] . in constructing the manual alignment for a pair , we first superimpose the two motifs in the insight ii software according to their corresponding sses , then transform the structural superposition into sequence alignment following these general rules : ( i ) corresponding sses are aligned and loops are frequently ignored ; ( ii ) h - bonding networks in - sheets are followed , i.e. if two residues are aligned , their respective h - bond partners are also aligned and ( iii ) gap openings are avoided as much as possible . different aligners , manual or automatic , may give different structural alignments for the same pair of structures . for example , since - strands are repeats of two - residue units , one can superimpose two - strands in several ways or registers by shifting one strand relative to the other by two residues at a time . such kind of ambiguity in structural alignments has been discussed in the literature ( 31,32 ) . to quantify the similarity between a manual alignment and an automatic alignment , we compute an agreement by dividing the number of positions aligned the same way in the two alignments by the total number of aligned positions in the manual alignment . the distribution of these agreements is shown in figure 3 . out of the three programs usedfrequently , the disagreements between different aligners result from the aforementioned register or shifting problem . the horizontal axis corresponds to the ranges of the agreement bins , and the vertical axis corresponds to the number of pairs that fall into each bin . the horizontal axis corresponds to the ranges of the agreement bins , and the vertical axis corresponds to the number of pairs that fall into each bin . to characterize a manual or automatic alignment between two analogous motifs , we compute six alignment - based scores , namely , aligned length , sequence identity , c rmsd , gdt_ts ( 33 ) , compass - like score and consensus . sequence identity and compass - like score measure how similar the two motifs are in sequence by comparing two single sequences or two multiple sequence alignments , respectively . in calculating the compass - like score , two sequence profiles , one for each motif , are generated by running psi - blast ( 34 ) , aligned according to the manual or automatic structure alignment , and then compared and scored by the scoring function used in the compass program ( 35 ) . in calculating the consensus score , we compare the four alignments generated by the four aligners ( manual , dali , tm - align and fast ) , assuming that similarities captured by different aligners are more likely to be correct . for each aligner , the consensus score equals the percent of its alignment that is agreed by at least one of the other three aligners . ( 36 ) or by clicking a score name on a pair - specific page at the malisam website . table 1 shows the mean and the standard error of each score and each aligner over the 130 pairs in malisam . manual alignments are typically shorter than dali and tm alignments , but longer than fast alignments . also , manual alignments have the best average rmsd , gdt_ts and consensus score , implying their higher overall quality than the automatic alignments . table 1 . mean and standard error of various scores for each alignerdalitm - alignfastmanualaligned length ( a.a. ) 60.961.0461.121.2350.831.0256.691.00 sequence identity ( % ) 8.210.328.060.318.610.358.540.36 rmsd ( ) 3.110.053.060.053.230.222.920.06gdt_ts ( % ) 59.050.5960.240.6357.180.9460.530.73 compass - like11 .460.7412.080.7610.450.7610.750.72 consensus ( % ) 67.022.4847.412.9066.842.7673.932.37 the mean and the standard error for each score and each aligner . for rmsd , a smaller value indicates higher similarity ; for all other scores , a larger value means higher similarity . mean and standard error of various scores for each aligner the mean and the standard error for each score and each aligner . for rmsd , a smaller value indicates higher similarity ; for all other scores , a larger value means higher similarity . in evolution , a domain family usually preserves a common core structure while accumulating insertions and deletions in the periphery ( 15 ) . a core motif is composed entirely of sses belonging to the evolutionary core of a domain family , while a hybrid motif is composed of both core elements and peripheral insertions . a hybrid motif in one family may happen to be structurally similar to the core motif in another evolutionarily unrelated family . for instance , a hybrid - grasp motif found in formate dehydrogenase is formed by part of the ferredoxin core and a large c - terminal extension . this hybrid - grasp motif is analogous to the core - grasp motif in protein l ( 16 ) . this structural phenomenon is a special case of a general property called gregariousness ( 17 ) , i.e. proteins displaying partial structural similarity to many , frequently unrelated proteins . consider two ancient domain families with evolutionary cores denoted as ab and bc , respectively . as represented by b and b , these two families show partial similarity between their cores . although most members in the first family have structure ab , some members carry an additional part c and have structure abc . the bc motif in these proteins is structurally similar to the core motif bc in the second family . to justify analogy between bc and bc , it is necessary to demonstrate that c is an insertion rather than a deletion , i.e. the first family evolved from ab to abc instead of from abc to ab . if c is not present in the majority of the family members and is restricted to a particular phylogenetic or functional group within the family , it is most likely that proteins with structure ab are ancient and proteins with structure abc are comparatively new . in other words , ab is the ancient core of the family , and c is a recent insertion . thus , though ab and bc show partial structural similarity , they are not homologous , both being ancient and having different cores . since ab and abc are homologous , abc and bc can not be homologous . therefore , the hybrid motif bc and the core motif bc are structural analogs . figure 1 illustrates an analogous pair comprised of a hybrid motif and a core motif . glyoxalase / bleomycin resistance protein / dihydroxybiphenyl dioxygenase consists of four - strands and one - helix with the sequential connection of . one representative of this superfamily , the first domain in the antibiotic resistance protein fosa from pseudomonas aeruginosa ( 18 ) , is diagramed in figure 1a . in this domain ( termedstructural repeat having glyoxalase fold in scop ) , the motif is a core motif , and no other sses are present . figure 1b depicts another domain that contains a motif , namely , the first domain in the oligopeptide - binding protein oppa from salmonella typhimurium ( 19 ) , which belongs to the scop superfamily periplasmic - binding protein - like ii . the core of this superfamily includes five - strands and their connecting helices , as illustrated in figure 1c by a more typical member in this superfamily , the first domain in lysine / arginine / ornithine - binding protein ( lao ) from s. typhimurium ( 20 ) . although fosa and oppa are classified in different scop superfamilies , folds and even classes , the two motifs boxed in figure 1a and b are similar in both architecture and topology . a comparison of figure 1b and c suggests that the - hairpin highlighted in red , which is present in oppa but absent in lao , is an insertion . indeed , a manual inspection of the structures in this superfamily shows that the - hairpin is present in only 4 out of the superfamily 's 32 proteins . moreover , these four proteins form a more closely related subgroup as indicated by their higher sequence identities to one another than to other proteins in this superfamily . all these observations suggest that the - hairpin does not belong to the ancient core of this superfamily and is instead an insertion that appeared later in evolution . thus , the motif in oppa ( figure 1b ) has a hybrid origin : the red - hairpin is an insertion while the remaining two strands and one helix are core elements . therefore , the hybrid motif in oppa and the core motif in fosa ( figure 1a ) define a pair of analogs . ( a ) the first domain in fosfomycin resistance protein a ( fosa ) from p. aeruginosa ( pdb code 1nki ) . the core region is colored from deep blue ( n - terminus ) to pale blue ( c - terminus ) . ( b ) the first domain in oligopeptide - binding protein ( oppa ) from s. typhimurium ( pdb code 1b05 ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) , and the inserted - hairpin is colored in red . the hybrid motif is framed in yellow . ( c ) the first domain of lysine / arginine / ornithine - binding protein ( lao ) from s. typhimurium ( pdb code 1lst ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . ( a ) the first domain in fosfomycin resistance protein a ( fosa ) from p. aeruginosa ( pdb code 1nki ) . the core region is colored from deep blue ( n - terminus ) to pale blue ( c - terminus ) . ( b ) the first domain in oligopeptide - binding protein ( oppa ) from s. typhimurium ( pdb code 1b05 ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) , and the inserted - hairpin is colored in red . ( c ) the first domain of lysine / arginine / ornithine - binding protein ( lao ) from s. typhimurium ( pdb code 1lst ) . the core region is colored from deep green ( n - terminus ) to pale green ( c - terminus ) . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . we use the following procedure to find analogous pairs consisting of a hybrid motif and a core motif . first , we represent the most commonly found structure motifs ( 21,22 ) or their circularly permuted forms by matrices and use these matrices as queries in prosmos ( 23 ) searches to find scop domains that contain the query motif . we inspect one randomly selected representative domain from each superfamily to determine whether the query motif occurring in this superfamily is a hybrid or not , according to scop description of the core of this superfamily . sses that do not belong to the core are considered to be insertions , and a hybrid motif should contain both core elements and inserted elements . the coordinates of a hybrid motif are extracted from the original pdb file and used as a query in dali ( 24 ) searches against a culled pdb database , in which any two proteins share 50 % sequence identity . the hits are sorted by dali z score and inspected manually to select the most similar core motif ( s ) to the query . the hybrid motif and the selected core motif are then added to the database as a pair of analogs . an interface motif is formed by part of each domain or subunit contacting along a domain domain or subunit subunit interface . in compact multi - domain proteins or obligate multi - chain complexes , where domains or subunits are closely associated , an interface motif may be well defined enough to mimic the structure and topology of a core motif , which is composed entirely of sses belonging to the evolutionary core of a domain family . for the interface motif and the core motif to be a pair of analogs , they should come from evolutionarily unrelated domain families . particularly , the interface motif should not cover the complete core of any of the contributing domains or subunits because in that case , the core motif might be a duplicated or elaborated version of that completely covered domain or subunit . figure 2 shows an analogous pair comprised of an interface motif and a core motif . the actin filament capping protein capz ( figure 2a ) is a heterodimer of two homologous subunits and ( 25 ) . scop divides each subunit into three domains , with the n - terminal domain being a 3 - helical bundle ( diagramed in ribbons in figure 2a ) . the two 3 - helical bundle domains from the two subunits make many hydrophobic contacts at the dimer interface , forming a 4 - helical bundle ( framed in red ) . this 4 - helical bundle defines an interface motif , consisting of part of the 3 - helical bundle from the subunit followed by part of the 3 - helical bundle from the subunit . figure 2b depicts one monomer in the conserved hypothetical protein xcc0516 homopentamer from xanthomonas campestris ( 26 ) . this 4 - helical bundle in xcc0516 comprises the whole polypeptide chain and is a core motif . the interface 4 - helical bundle in capz ( boxed in red in figure 2a ) shares the same overall structure and topology with the upper portion of the core 4 - helical bundle in xcc0516 ( boxed in red in figure 2b ) . yet the interface motif comes from a 3 - helical bundle domain family , while the core motif comes from an evolutionarily unrelated 4 - helical bundle domain family . therefore , the interface motif in capz and the core motif in xcc0516 can be regarded as a pair of analogs . figure 2 . an analogous pair composed of an interface motif and a core motif . ( a ) the actin filament capping protein capz from gallus gallus ( pdb code 1izn ) . the three domains in each subunit are represented as a ribbon diagram , a pentagon and a rectangle , respectively . ( b ) the conserved hypothetical protein xcc0516 from x. campestris ( pdb code 2gsc ) . the polypeptide chain is colored in rainbow from n - terminus ( blue ) to c - terminus ( orange ) . the part that is aligned to the hybrid 4 - helical bundle motif in capz is in red frame . the disordered region between the 2nd and the 3rd helices is represented by a dotted curve . the helices in the red frames in ( a ) and ( b ) are diagramed as cylinders in the same colors above or below their corresponding sequences . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . ( a ) the actin filament capping protein capz from gallus gallus ( pdb code 1izn ) . the three domains in each subunit are represented as a ribbon diagram , a pentagon and a rectangle , respectively . ( b ) the conserved hypothetical protein xcc0516 from x. campestris ( pdb code 2gsc ) . the polypeptide chain is colored in rainbow from n - terminus ( blue ) to c - terminus ( orange ) . the part that is aligned to the hybrid 4 - helical bundle motif in capz is in red frame . the disordered region between the 2nd and the 3rd helices is represented by a dotted curve . the helices in the red frames in ( a ) and ( b ) are diagramed as cylinders in the same colors above or below their corresponding sequences . the pdb code , chain identifier and starting and ending residue numbers are given for each sequence . the same procedure described above to find hybrid motifs is used to identify interface motifs . in addition , we manually inspected the scop entries in the multi - domain proteins class or with duplication in their annotations in a search for interface motifs . the coordinates of an interface motif are extracted from the original pdb file and used as a query in dali ( 24 ) searches against the aforementioned , culled pdb database to find the most similar core motif ( s ) for it . note that , before running dali , the coordinates file of a subunit subunit interface motif is preprocessed so that it contains only one chain . currently , malisam stores 33 pairs of analogs that are composed of an interface motif and a core motif . an artificial protein and a natural protein are a pair of analogs if they are structurally similar . we analyze the entries in the scop class designed proteins and select the ones with de novo sequences and reasonably complex structures to serve as queries in dali searches against the aforementioned representative pdb database . we pay attention to whether an artificial protein is designed without a sequence bias towards a particular homologous family , e.g. the artificially designed ww domain ( pdb 1e0 m ) will not work as an analog to natural ww domains , because it is based largely on the consensus sequence of ww domain family . by inspecting top dali hitscurrently , malisam contains six pairs of analogs that consist of an artificial protein and a natural protein , but we expect this number to increase due to active research in the field of protein sequence design . each analogous pair is aligned manually by visual inspection and automatically by three programs [ dali ( 28 ) , tm - align ( 29 ) and fast ( 30 ) ] . in constructing the manual alignment for a pair , we first superimpose the two motifs in the insight ii software according to their corresponding sses , then transform the structural superposition into sequence alignment following these general rules : ( i ) corresponding sses are aligned and loops are frequently ignored ; ( ii ) h - bonding networks in - sheets are followed , i.e. if two residues are aligned , their respective h - bond partners are also aligned and ( iii ) gap openings are avoided as much as possible . different aligners , manual or automatic , may give different structural alignments for the same pair of structures . for example , since - strands are repeats of two - residue units , one can superimpose two - strands in several ways or registers by shifting one strand relative to the other by two residues at a time . such kind of ambiguity in structural alignments has been discussed in the literature ( 31,32 ) . to quantify the similarity between a manual alignment and an automatic alignment , we compute an agreement by dividing the number of positions aligned the same way in the two alignments by the total number of aligned positions in the manual alignment . the distribution of these agreements is shown in figure 3 . out of the three programs usedfrequently , the disagreements between different aligners result from the aforementioned register or shifting problem . the horizontal axis corresponds to the ranges of the agreement bins , and the vertical axis corresponds to the number of pairs that fall into each bin . the horizontal axis corresponds to the ranges of the agreement bins , and the vertical axis corresponds to the number of pairs that fall into each bin . to characterize a manual or automatic alignment between two analogous motifs , we compute six alignment - based scores , namely , aligned length , sequence identity , c rmsd , gdt_ts ( 33 ) , compass - like score and consensus . sequence identity and compass - like score measure how similar the two motifs are in sequence by comparing two single sequences or two multiple sequence alignments , respectively . in calculating the compass - like score , two sequence profiles , one for each motif , are generated by running psi - blast ( 34 ) , aligned according to the manual or automatic structure alignment , and then compared and scored by the scoring function used in the compass program ( 35 ) . in calculating the consensus score , we compare the four alignments generated by the four aligners ( manual , dali , tm - align and fast ) , assuming that similarities captured by different aligners are more likely to be correct . for each aligner , the consensus score equals the percent of its alignment that is agreed by at least one of the other three aligners . ( 36 ) or by clicking a score name on a pair - specific page at the malisam website . table 1 shows the mean and the standard error of each score and each aligner over the 130 pairs in malisam . manual alignments are typically shorter than dali and tm alignments , but longer than fast alignments . also , manual alignments have the best average rmsd , gdt_ts and consensus score , implying their higher overall quality than the automatic alignments . table 1 . mean and standard error of various scores for each alignerdalitm - alignfastmanualaligned length ( a.a. ) 60.961.0461.121.2350.831.0256.691.00 sequence identity ( % ) 8.210.328.060.318.610.358.540.36 rmsd ( ) 3.110.053.060.053.230.222.920.06gdt_ts ( % ) 59.050.5960.240.6357.180.9460.530.73 compass - like11 .460.7412.080.7610.450.7610.750.72 consensus ( % ) 67.022.4847.412.9066.842.7673.932.37 the mean and the standard error for each score and each aligner . for rmsd , a smaller value indicates higher similarity ; for all other scores , a larger value means higher similarity . mean and standard error of various scores for each aligner the mean and the standard error for each score and each aligner . for rmsd , a smaller value indicates higher similarity ; for all other scores , a larger value means higher similarity . clicking a pair name redirects the browser to that pair 's specific page ( figure 4 ) , which contains a summary table , a short justification for analogy , a table of alignment - based scores and structure - based sequence alignments . the summary table provides basic information about the two motifs in that pair : pdb code , chain identifier , residue ranges and scop code and classification . the structural superposition reconstructed from a manual or automatic alignment can be viewed in pymol ( http://pymol.sourceforge.net/ ) by selecting the aligned motifs in pymol link or can be downloaded by selecting the pdb format superposition link . a compressed file of the entire database with alignments of all pairs can be downloaded from ftp://iole.swmed.edu/pub/cheng/analogs/analogs.tar . the malisam database is a compilation of manual as well as automatic alignments between structurally analogous motifs . to the best of our knowledge , malisam may be used in protein - folding studies , for the similarities between analogs result from folding and packing constraints rather than evolutionary relatedness . a reliable set of structural analogs provided in malisamcould be used in the training of remote homology detection methods , since these methods frequently involve discrimination between homologs and structural analogs . additionally , malisam manual alignments should be useful for the development of better automatic structure alignment techniques .\noutput:\n" }, { "from": "agent", "value": "malisam ( manual alignments for structurally analogous motifs ) represents the first database containing pairs of structural analogs and their alignments . to find reliable analogs , we developed an approach based on three ideas . first , an insertion together with a part of the evolutionary core of one domain family ( a hybrid motif ) is analogous to a similar motif contained within the core of another domain family . second , a motif at an interface , formed by secondary structural elements ( sses ) contributed by two or more domains or subunits contacting along that interface , is analogous to a similar motif present in the core of a single domain . third , an artificial protein obtained through selection from random peptides or in sequence design experiments not biased by sequences of a particular homologous family , is analogous to a structurally similar natural protein . each analogous pair is superimposed and aligned manually , as well as by several commonly used programs . applications of this database may range from protein evolution studies , e.g. development of remote homology inference tools and discriminators between homologs and analogs , to protein - folding research , since in the absence of evolutionary reasons , similarity between proteins is caused by structural and folding constraints . the database is publicly available at http://prodata.swmed.edu/malisam ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: epidemiological data have for some time now supported a link between parkinson 's disease ( pd ) and cumulative lifetime pesticide exposure ( tanner et al . , 2011 , wang et al .2013 ) , and it has been suggested that the pro - oxidant pesticide , paraquat , could be especially relevant for some of the neuropsychiatric symptoms of the disease ( kim et al . , 2013 ) . besides its effect on the nigrostriatal system , exposure to paraquat in rodents has produced other neurotoxic biological characteristics associated with pd including microglia activation , lewy - body like aggregates containing - synuclein , pro - inflammatory cytokine expression , and oxidative stress via mitochondria complex inhibition or microglia activation ( litteljohn et al . upon entry into the brain , paraquat is distributed across areas including the prefrontal cortex , hippocampus , olfactory bulbs , and the substantia nigra pars compacta ( snc ) ( peng et al . , 2007 ) . the pesticide was also found to induce several pd - like non - motor behavioural deficits , including olfactory dysfunction ( czerniczyniec et al . , 2011 ) , campos et al . , 2013 ) , and memory impairment ( chen et al . , 2010 ) . nonetheless , it has yet to be determined whether paraquat can induce anhedonic - like behaviour in rodents , and the need for understanding the pesticide 's effects on extra - nigrostriatal brain regions should be broadened . in addition to biological insults , it is conceivable that psychologically relevant stressors could affect the primary motor symptoms and neurodegenerative process ( urakami et al . , 1988 , metz , 2007 , kibel and drenjancevi - peri , 2008 , smith et al . , 2008 ) , as well as non - motor or co - morbid neuropsychiatric manifestations in pd patients . for instance , major life events influenced the development of depression among pd patients ( rod et al . , 2013 ) , and psychological therapies have proven to be effective in reducing depression and anxiety symptoms in pd patients ( yang et al . , 2012 , whitworth et al . , 2013 ) . in the present investigation we sought to assess the individual and combined effects of the pd - linked pesticide , paraquat , and a psychologically relevant chronic intermittent immobilization / social defeat stressor ( cis ) challenge . we were particularly interested in further characterizing the influence of paraquat upon extra - nigrostriatal brain regions and ascertaining whether the disparate classes of stressors ( chemical vs. psychological ) would interact to influence hedonic behaviour . it was also of interest to determine whether any such effects would be accompanied by changes in stressor hormone levels ( corticosterone ) , central neurotransmitter activity and immune messengers ( circulating cytokines ) . specifically , it was hypothesized that chronic systemic paraquat administration and concurrent cis exposure would provoke physiological and behavioural changes consistent with a depressive - like phenotype , as expected in a sizable portion of pd patients . male c57bl6 / j mice were obtained at 67 weeks of age from the jackson laboratory ( bar harbor , me , usa ) and acclimated to our vivarium for 2 weeks . animals were singly housed in standard polypropylene cages ( 272114 cm ) and maintained on a 12 - h light / dark cycle with lights on at 08:00 h. a diet of ralston purina ( st . louis , mo ) mouse chow and water was provided ad libitum , and room temperature was maintained at 21 c . one week prior to the commencement of the study , mice were randomly assigned to one of four experimental conditions ( no stress / saline ; no stress / paraquat ; stress / saline ; stress / paraquat ) and sucrose preference training initiated ( n = 1012 ) . a further 8 mice comprised the testing - nave negative control : except for behavioural testing ( see below ) , these animals received identical treatment to the no stress / saline mice . all animals were rapidly decapitated 2 h following the final paraquat or saline injection . in order to minimize the effects of diurnal variations , tests and proceduresall experimental procedures were approved by the carleton university committee for animal care and complied with the guidelines set out by the canadian council for the use and care of animals in research . all mice received intraperitoneal injection with 10 mg / kg paraquat ( 1,1 - dimethyl -4,4-bipyridinium dichloride ; sigma aldrich , st louis , mo , usa ) or physiological saline ( sigma aldrich ) . injections were administered twice a week for 6 weeks ( 13 injections in total ) on a regular interval basis . this paraquat dose is routinely used in our lab and has been shown to reliably induce nigrostriatal damage ( 2535 % neuron loss ) ( mangano and hayley , 2009 , mangano et al . , 2011 ) . during the30 min immediately preceding each injection , half of the animals were either socially defeated or physically restrained in semicircular plexiglas tubes ( 412 cm ) with tails taped to prevent turning . the social defeat paradigm involved introducing experimental mice into the home - cage of a significantly larger and more aggressive mouse ( retired cd1 breeders from charles river , qc , can ) . a mesh wire divider was inserted into the cage upon the first display of submissive behaviour ( upright posture with belly exposed ) or if excessive fighting occurred ( continuous biting ) ; this had the effect of physically separating the mice while still allowing for interactions between them ( audet et al . , 2011 ) . stressor application followed a fixed alternating schedule such that each mouse in the stressor groups received one session per week of restraint and one of social defeat . on the day of sacrifice all animals in the stressor conditions received 30 min restraint immediately prior to the final paraquat or saline injection . due to the nature of the stressor paradigm , the stressed animals were housed in holding rooms separate from , but otherwise identical to , their non - stressed counterparts . following rapid decapitation , brains were excised and sectioned into sequential coronal slices using razor blades and a chilled stainless steel microdissecting matrix with adjacent slots spaced 0.5 mm apart . hollow biopsy needles were used to collect the dorsal striatum , paraventricular nucleus of the hypothalamus ( pvn ) , locus coruleus ( lc ) and nucleus accumbens . all tissue samples were taken with reference to the mouse brain atlas of franklin and paxinos ( 1997 ) . samples were maintained in a homogenizing solution containing 14.17 g monochloroacetic acid , 0.0186 g disodium ethylenediamine tetraacetate ( edta ) , 5.0 ml methanol , and 500 ml h2o ; and stored at 80 c until determination of central monoamine and metabolite levels using high performance liquid chromatography ( hplc ) . at the time of decapitation , trunk blood from all of the animals , including those in the behavioural testing - naive control group , was collected in tubes containing 10 g edta . samples were centrifuged ( 3000 g for 8 min ) and the plasma removed and stored in aliquots at 80 c for later corticosterone determination with commercially available radioimmunoassay kits ( icn biomedicals , ca , usa ) . samples were assayed in duplicate within a single run to control for inter - assay variability ; the intra - assay variability was less than 10 % . circulating levels of 11 different cytokines were determined by multiplex analysis using the luminex 100 suspension - based bead array system ( luminex corp . , austin , tx ) and a custom multiple cytokine detection kit ( milliplex map mouse cytokine / chemokine kit , millipore , cat . the assay was performed according to the kit manufacturer 's instructions ( see www.millipore.com/userguides ) and , unless otherwise indicated , all reagents were provided in the multiplex kit . eight samples from each of the four treatment groups were run in duplicate ; the remaining samples were singly run . where applicable , results of duplicate sample determinations were averaged prior to the data being analysed . in cases where cytokine levels were so low as to be undetectable , regional brain levels of monoamines and their primary metabolites ( see table 1 ) were determined by hplc in keeping with previously reported methods ( litteljohn et al . tissue punches were homogenized by ultrasonic disruption ( sonic dismembrator model 100 , fisher scientific ) in the homogenizing solution in which they were initially frozen ( with dhba as an internal standard ) . the level of protein was determined with the pierce bca protein assay kit ( thermo scientific 23225 ) . homogenized samples were centrifuged ( 12,000 rpm for 3 min at 4 c ) , after which 50 l of supernatant was injected , at a flow rate of 1 ml / min , into the automated hplc system ( agilent 1100 ) with electrochemical detector ( decade ii sdc , antec ) and zorbax eclipse xdb - c8 columns ( agilent : 4.6 mm inner diameter , 150 mm length , 5 m particle size ; thermostated at 40 c ) ; the oxidation potential was maintained at 0.60 v. the mobile phase comprised : 90 mm sodium phosphate monobasic , 1.7 mm 1 - octanesulfonic acid , 50 mm edta , 10 % acetonitrile , 50 mm citric acid ( monohydrate ) , 5 mm kcl , and hplc - grade water . monoamine and metabolite concentrations were expressed relative to the protein content of the samples , and final results presented as ng / mg protein ( litteljohn et al . , 2014 ) . baseline sucrose preference training was undertaken during the seven days leading up to the start of the experiment . briefly , singly housed mice were presented with two identical 15 ml ball - bearing sipper tubes ( introduced into the home - cage through spaces in the cage lid ) , one of which contained regular tap water and the other a 1 % palatable sucrose solution . animals were permitted ad - lib access to both of the bottles , which were weighed at the same time each morning and the amount consumed from each recorded . sucrose preference was calculated according to the formula : sucrose preference = [ sucrose intake / ( sucrose intake + water intake ) ] 100 . in this way , 24 - h baseline sucrose preference levels were established for the animals prior to initiating any of the experimental treatments . only those mice demonstrating a steady baseline sucrose preference ( average sucrose preference over the final 2 baseline training days 75 % ) were used in the study ; all but 1 mouse met or surpassed the pre - determined cut - off value . each week commencing at 60 min after the second of the two weekly injections / stressors , animals were permitted free access for 3 consecutive days to the water and sucrose solutions . to avoid capturing any acute toxic effects of the pesticide , recovery day data ( corresponding to the 24 - h period commencing the morning after the most recent treatment application ) were collected and analysed . although we considered the repeated sucrose - testing paradigm to be non - invasive and minimally stressful , an additional cohort of animals was included to explicitly assess the degree of stress associated with the testing regimen . to this end , blood samples from the testing - nave control mice were assayed for corticosterone concentration , and the data included in the between - groups analysis . it was decided a priori that a statistically significant difference in plasma corticosterone levels between the two non - stressed , saline - treated control groups ( assessed via the two - sample t - test , p 0.05 ) would be considered evidence of a testing - related stressor - like effect and , as such , would warrant inclusion of testing - nave samples in ( or at the minimum alter the interpretation of the results from ) the subsequent cytokine and monoamine assessments . data were analysed by 2 ( injection ; saline v. paraquat ) 2 ( stress ; no stress v. stress ) anovas followed by fisher 's planned comparisons ( p 0.05 ) where appropriate . where applicable , repeated measures anovas were conducted with time as the 3rd independent variable . in instances where it was of interest to assessthe linear relationship between outcome variables ( e.g. , cytokine network analysis ) , this was done via pearson product moment correlations ( r ) and , in certain cases , coefficients of determination ( r ) . as numerous correlations were conducted , the level of statistical significance was set to 0.025 , per the method of poulter et al . in addition , we ran analyses to determine whether the frequency of significant cytokine correlations differed between the treatment groups ( p 0.05 ) . during the course of tissue dissection and hplc analysesfor the sucrose preference test , data points exceeding 2 standard deviations were deemed outlier values and omitted from the analyses . data were evaluated using a statview ( version 6.0 ) statistical software package and visualized with graphpad prism 6 ( la jolla , ca ) . as shown in fig . 1a , paraquat increased the circulating concentrations of the haematopoietic colony - stimulating factor , gm - csf ( f1 , 35 = 4.75 , p 0.05 ) . none of the other assayed cytokine species were significantly affected by the pesticide treatment ( with respect to absolute protein levels ; data not shown ) . as it relates to the cis treatment , il - 6 levels were significantly elevated overall following stressor exposure ( f1 , 34 = 5.62 , p 0.05 ) , though the magnitude of this effect was quite small and the absolute levels of this cytokine rather low across all groups ( fig . in contrast , plasma levels of the il - 12 subunit , il - 12 ( p40 ) , were reduced in mice receiving the stressor treatment , irrespective of pesticide exposure ( f1 , 32 = 4.24 , p 0.05 ) . fig .1 b shows the cross - correlations between the different cytokines among non - stressed ( top panel ) and stressed mice ( bottom panel ) as a function of saline ( left matrices ) and paraquat treatment ( right matrices ) . precise correlation values are presented within the individual squares of each matrix and the squares are colour - coded so as to better reflect the patterns of correlations : green and blue indicate significant positive and negative correlations , respectively ( p 0.025 ) , while grey denotes a lack of statistical significance . among the saline - treated animals , very few correlations were found to be statistically significant and their frequency ( 3 positive correlations in the non - stressed group , 1 positive and 1 negative correlation in the stressed condition ) was unaffected by the stressor treatment ( = 0.21 , df = 1 , p = 0.65 ) . yet , it should be noted that the stressor did abolish the few significant correlations that were observed among the non - stressed saline controls , and seemed to selectively influence correlations involving gm - csf ( fig . following paraquat treatment , the frequency of significant cytokine correlations among the non - stressed mice increased from 3 ( of a possible 66 correlations ) to 17 ( = 9.96 , df = 1 , p 0.01 ) , and all of these associations were positive and ranged in strength from weak ( 0.4 r 0.5 ) to very strong ( r 0.9 ) . as can be seen in fig . 1b , almost half ( 8 out of 17 ) of the significant correlations in the no stress / paraquat condition involved il - 10 and gm - csf , and these cytokines themselves demonstrated a moderate linear relationship ( r = 0.59 ) . perhaps even more striking was the marked difference in the profile of significant paraquat - associated cytokine correlations among the non - stressed vs. stressed mice . whereas in the former group , paraquat clearly enhanced the rigidity of the peripheral cytokine network , no such effect was apparent in the latter group ( relative to the stressor alone - treated mice ) ( fig . in fact , the stressor reduced the frequency of significant paraquat - associated cytokine correlations from 17 to 2 ( = 12.05 , df = 1 , p 0.001 ) . there was no difference in plasma corticosterone content between the non - stressed , saline - treated control mice that underwent behavioural testing and the testing - nave negative controls ( t14 = 0.68 , p 0.50 : 6.570.66 v 5.761.06 ) . accordingly , pooled data from these two groups were used for the between - groups corticosterone analysis ( n = 16 ) . the 2 - way anova indicated that plasma corticosterone concentrations were modestly but significantly increased following treatment with either paraquat or the stressor ( fs1 , 43 = 4.26 and 4.52 , respectively , p 0.05 ) . as depicted in fig . 2a , while the interaction effect of paraquat with stress was not statistically significant ( p 0.10 ) , levels of the stress hormone appeared to be highest among mice receiving the combination treatment . in addition to augmenting plasma corticosterone , paraquat increased ne concentrations within the locus coeruleus ( lc ) ( f1 , 33 = 6.62 , p 0.05 ) and pvn ( f1 , 27 = 33.31 , p in contrast , within these brain regions , paraquat did not significantly alter the levels of the primary ne metabolite , mhpg . while the pvn concentrations of 5 - ht , 5 - hiaa and da were likewise unchanged following the pesticide treatment , accumulation of the da metabolites , dopac and hva , was significantly enhanced overall among the paraquat - treated animals ( fs1 , 27 = 7.37 and 13.3 , p 0.05 : 7.631.17 v 13.562.42 and 10.741.15 v 15.381.27 , respectively ) . the chronic intermittent stressor had comparatively less influence than paraquat on lc and pvn monoaminergic activity . still , within the pvn , levels of both 5 - ht ( f1 , 27 = 9.34 , p 0.01 ; see fig .2 a ) and hva ( f1 , 27 = 10.18 , p 0.01 : 11.141.20 v 15.291.22 ) were significantly elevated overall among animals undergoing the stressor treatment . within the reward - relevant nucleus accumbens , da levels varied as a function of the significant interaction between pesticide and stress ( f1 , 38 = 6.53 , p 0.05 ) . as shown in fig . 3 and confirmed by the follow - up comparisons , while accumbal da concentrations were diminished ( to a similar level ) by treatment with either paraquat or cis ( p 0.05 ) , combining the two insults did not lead to a further decrement in parent amine levels . separate anovas also revealed significant pesticide stress interaction effects for dopac and hva levels ( fs1 , 38 = 10.17 and 8.77 , respectively , p 0.01 ) . whereas in the former case , pesticide exposure normalized the stressor - induced elevation of dopac , in the latter case paraquat interacted with the stressor treatment to enhance accumbal hva accumulation ( p 0.01 compared to all other groups ) ( fig . 3 ) . the overall effect ( s ) of the experimental treatments on da utilization in the nucleus accumbens can perhaps best be appreciated by examining the rate of da turnover ( i.e. , the ratio of da metabolites to da ) ; not surprisingly , this was also noted to vary as a function of a significant paraquat stress interaction ( f1 , 38 = 7.72 , p 0.01 ) . the post - hoc analyses confirmed that the pesticide and stressor each provoked a significant increase in the da metabolite - to - parent amine ratio ( p 0.01 relative to the non - stressed , saline - treated controls ) . within the dorsal striatum , there were no significant effects of paraquat or the cis treatment on da concentrations ( fig . however , higher hva levels were observed among mice receiving the pesticide treatment ( f1 , 37 = 7.04 , p 0.05 ) , and a significant pesticide stress interaction was revealed for striatal dopac ( f1 , 37 = 7.30 , p 0.05 ) . specifically , mice that received either the paraquat alone or stressor alone treatments displayed diminished dopac concentrations relative to the non - stressed , saline - treated animals ( p 0.05 ) . contrastingly , dopac levels in the paraquat - plus - stressor - treated mice were unchanged compared to controls ( fig . 4 ) . the pattern of paraquat - and - stressor - associated dopaminergic changes suggested that the combination treatment had the effect of increasing da turnover within the dorsal striatum , similar to what was previously seen in immobilization - plus - mptp - treated mice ( urakami et al . , 1988 ) . this was borne out by the anova , which revealed a significant pesticide stress interaction effect on da turnover ( f1 , 37 = 5.70 , p 0.05 ) . as shown in fig . 4 and confirmed by the post - hoc tests , only those animals co - treated with paraquat and stress displayed enhanced da turnover in the striatum ( p 0.05 ) . although there was no significant main effect for the stressor treatment nor were there any significant interactions between any of the variables , the repeated measures anova indicated that paraquat itself had the overall effect of reducing animals ' preference for a palatable sucrose - containing solution ( f1 , 33 = 5.55 , p 0.05 ) . despite the lack of significant interaction effects of paraquat with stress or time , from fig .5 ( top ) it is clear that the paraquat effect developed gradually over time and that the pesticide had its most pronounced effect in mice that were also exposed to the stressor . indeed , the multiple comparisons indicated that the paraquat - plus - stressor - treated animals were the only ones to exhibit significant decrements in sucrose preference and this occurred at weeks 4 , 5 and 6 ( p 0.05 relative to saline - treated controls ) . assessment of difference between baseline and weeks 6 , indicated that the stress alone group was identical to controls and the paraquat alone treatment caused only a 1.5 % sucrose reduction , however , the paraquat + stress treatment promoted a modest but statistically significant 9 % reduction in sucrose preference at week 6 relative to baseline . as shown in fig . 5 ( bottom ) , mice receiving either paraquat or the stressor gained slightly but significantly less weight overall than saline - treated controls . specifically , there were significant paraquat time and stress time interactions ( fs5 , 230 = 4.58 and 11.83 respectively , p 0.01 ) . parallelling the time - dependent sucrose effects , the comparisons revealed diminished weight at weeks 46 in paraquat or stressor treated mice . however , in contrast to the sucrose variations , no further weight loss was noted among animals in the paraquat - plus - stressor condition , relative to either of the treatments administered alone . additionally , neither of the treatments was observed to provoke any overt sickness behaviour ( piloerection , lethargy , ptosis ) . not only does co - morbid depressive illness pose a major threat to quality of life among pd patients , there is evidence to suggest that depression can actually influence the severity and clinical management of pd motor symptoms and perhaps even affect the progression of the underlying neurodegenerative process ( backer , 2000 , smith et al . , 2002 , metz et al . , 2005 , the current findings are consistent with a growing number of reports suggesting that environmental toxicants , and pesticides in particular , may play a role in the development of not only motor impairment , but also non - motor symptoms that are often evident in pd ( mcdowell and chesselet , 2012 , freire and koifman , 2012 ) . indeed , in the case of paraquat alone , a number of groups have found evidence of both cognitive and anxiety - like symptoms in infrahuman chronic exposure models , and it appears likely that oxidative , inflammatory and potentially even neuroplastic changes occurring in the hippocampus and , to a lesser extent the prefrontal cortex , are implicated in this regard ( litteljohn et al . , 2009 , chen et al . , 2010 , , 2011 , mangano et al . , 2011 , mitra et al . , 2011 , songin et al . although scant data are available regarding the potential emotional or affective behavioural effects of paraquat , a very recent study found that , in rats , chronic low - dose exposure to paraquat ( delivered via osmotic minipumps ) induced behavioural signs of learned helplessness in a forced swim test ( campos et al . , 2013 ) ( 2013 ) study did not uncover any signs of anhedonia ( or cognitive dysfunction for that matter ) among the paraquat - treated rats . seeing as how in the present study the paraquat - induced sucrose preference deficits were only observed in the cis co - treated animals , it may be the case that exposure to paraquat alone is insufficient to cause such deficits , and that another overlapping insult , such as intermittent exposure to psychologically - relevant stress , is needed to fullythe fact that animals receiving the paraquat or stressor treatments gained significantly less weight over time compared to control mice raises the possibility that the sucrose deficits might be related to generalized toxicity or non - specific stressor effects . yet , it is important to note that , unlike the weight loss , the sucrose reduction was only evident in mice that received the combination of stressor + paraquat treatments . it also warrants reiterating that the sucrose preference test data were collected between 24 and 48 h after pesticide and / or stressor application ( i.e. , on the recovery day ) , thus limiting any potential confounds related to the possible acuteof course , it should be noted that the observed effects were modest and the fact that the stressor alone had little effect on sucrose is an important caveat in this study . indeed , we are not able to say that the stressor and paraquat treatment really had any synergistic or additive effects , but rather simply that the combination was required to observe any significant effect at all . what are the biological mechanisms responsible for this behavioural phenomenon ? in the present investigation we examined four distinct but not mutually exclusive possibilities , namely treatment - induced alterations of : 1 ) hpa activity ( i.e. , the classical stress response ) , 2 ) concentrations and network activity of circulating cytokines ( i.e. , the peripheral immunological response ) , 3 ) dopaminergic neurotransmission at the nucleus accumbens ( i.e. , mesolimbic reward circuitry ) , and 4 ) striatal da activity ( i.e. , nigrostriatal motor pathway ) . . it will be recalled that only in the paraquat - plus - stressor group was striatal da utilization significantly increased . it is thus tempting to speculate that the combination - treated mice were , in fact , hitharder than the paraquat alone - treated animals , and a prospective compensatory response ( kuter et al . , 2007 , biju and de la fuente - fernndez , 2009 ) proved sufficient to stave off striatal da depletion . while much evidence points to the critical involvement of nucleus accumbens da dysfunction in the development of anhedonic - like symptoms ( remy et al . , 2005 ) , there 's certainly precedent for suggesting that alterations of striatal ( caudate / putamen ) da signalling could also play a role . ( 2008 ) , reported that striatal and pfc alterations of da , as well as 5 - ht and ne , are the likely cause of emotional and cognitive disturbances induced by 6 - ohda administration in rats . these findings were largely recapitulated in a 2010 study by santiago and colleagues , which also implicated deficits in hippocampal 5 - ht signalling . while not explicitly addressed in the present investigation , findings from our laboratory have indicated that paraquat also influence monoamine activity ( 5 - ht , ne and da ) in the hippocampus and prefrontal cortex ( reviewed in litteljohn et al . , 2011b ) . recent work has established a connection between circulating pro - inflammatory cytokines and depressive - like symptoms in pd patients ( menza et al . , 2010 , lindqvist et al . , 2012 ) . in the present study , however , neither paraquat nor the cis treatment provoked many significant changes in absolute cytokine concentrations . yet , the pesticide did increase circulating levels of the haematopoietic colony - stimulating factor , gm - csf . since we and others have already demonstrated the capacity of this trophic cytokine to protect against the neurodegeneration caused by paraquat and other environmental insults ( nakagawa et al . choudhury et al . , 2011 , mangano et al . , 2011 ) , it seems reasonable to suggest that the presently observed gm - csf increase represents a compensatory homoeostatic response to xenobiotic challenge . despite the paucity of cytokine changes , we did find that paraquat imposed a distinct rigidity on the circulating cytokine network that was abolished by co - administration of the stressor regimen . particularly intriguingwere the positive correlations between pro - inflammatory cytokines ( ifn - , tnf - , il - 17 , mip - 1 ) and the pro - trophic cytokine , gm - csf , and the anti - inflammatory cytokine , il - 10 . in effect , our data hint at a heightened coordination of peripheral cytokine network action among mice exposed only to paraquat , and a capacity of psychological stress to disrupt such network responding . valence to the observed cytokine changes is not straightforward ( litteljohn and hayley , 2012 ) . nonetheless , it is our contention that increasing the rigidity of the cytokine network likely constitutes an adaptive response to xenobiotic insult , serving to better position the organism to combat further challenges . our findings indicate that paraquat affects hpa activity , peripheral cytokines , and mesolimbic and nigrostriatal da turnover , some of which might be relevant for the development of depressive - like behaviours . moreover , it appears that psychological stressors are capable of modulating some of the brain and behaviour effects of paraquat . these data could have implications for how chronic stress is perceived and managed in a neurological context or among individuals with a known history of environmental toxicant exposure .\noutput:\n" }, { "from": "agent", "value": "a number of epidemiological and experimental studies have implicated the non - selective herbicide , paraquat , in the development of sporadic parkinson 's disease ( pd ) . while preclinical research has focused mainly on elucidating the nigrostriatal effects of paraquat , relatively little data are available concerning non - motor brain systems and inflammatory immune processes ( which have been implicated in pd ) . hence , in the present study , we sought to take a multi - system approach to characterize the influence of paraquat upon extra - nigrostriatal brain regions , as well ascertain whether the impact of the pesticide might be enhanced in the context of chronic intermittent stressor exposure . our findings support the contention that paraquat itself acted as a systemic stressor , with the pesticide increasing plasma corticosterone , as well as altering neurochemical activity in the locus coeruleus , paraventricular nucleus of the hypothalamus , nucleus accumbens , dorsal striatum , and central amygdala . however , with the important exception striatal dopamine turnover , the stressor treatment did not further augment these effects . additionally , paraquat altered inter - cytokine correlations and , to a lesser extent , circulating cytokine levels , and concomitant stress exposure modulated some of these effects . finally , paraquat provoked significant ( albeit modest ) reductions of sucrose preference and weight gain , hinting at possible anhendonic - like or sickness responses . these data suggest that , in addition to being a well known oxidative stress generator , paraquat can act as a systemic stressor affecting hormonal and neurochemical activity , but largely not interacting with a concomitant stressor regimen ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: opioids have been used to minimize these responses to short - term stimuli such as eti . however , opioid administration is not recommended in ga in parturients for cesarean section , because of its depressant effects on the newborn . hemodynamic alterations due to stress and pain as a result of eti may decrease uteroplacental blood flow and lead to adverse neonatal outcomes . many drugs have been employed to blunt the eti response like lignocaine and opioid , nonnarcotic analgesics and gabapentin . paracetamol has a well - established safety and analgesic profile and is a safe drug during pregnancy . the main mechanism of action is inhibition of cyclo - oxygenase enzyme which is responsible for the production of prostaglandins , an important mediator of inflammation , pain and fever . the peak analgesic effect is obtained in 1 h and the duration of action is 4 - 6 h. the purpose of the study was to observe the efficacy of intravenous paracetamol in preventing hemodynamic changes due to pain in cesarean sections at intubation , as well as its effect on neonatal apgar score . this study was conducted after obtaining the institutional ethical review committee approval and an informed patient consent . the study did not include american society of anesthesiologists - iii and above patients , emergency surgeries , patients allergic to paracetamol , anticipated difficult intubation with mallampatti grade - iii and above , preeclampsia and eclampsia . patients with known hypertension , peripheral vascular disease , ischemic heart disease , cardiac arrhythmias or having cardiac pacemaker , patients taking any hr modifying drugs , monoamine - oxidase inhibitors , or any drug affecting autonomic nervous system were also excluded . random allocation of patients in two groups was done by the hospital pharmacy as per computer generated table . the placebo group ( n = 55 ) received normal saline and paracetamol group ( n = 55 ) received 1 g intravenous paracetamol . the placebo or paracetamol solutions were given to the patient in a 100 ml piggy bag which was labeled as study drug . the drug was given 1 h before the surgery by a registered ward nurse who was not involved in the or management of the patient . in the operating room , patient was placed in a supine position with 15 left tilt . ringers lactate was given at the rate of 200 ml / h to all patients as soon as a patient entered the or . two baseline readings of hr , systolic bp ( sbp ) , diastolic bp ( dbp ) and mean bp ( mbp ) were recorded before induction . general anesthesia was induced with rapid sequence induction by using the calculated dose of propofol ( 2 mg / kg ) and succinylcholine ( 1.5 mg / kg ) . macintosh laryngoscope blade size three with an endotracheal tube of size 7.0 mm internal diameter was inserted . final hr , sbp , dbp and map readings were taken as soon as intubation started . pethidine ( 1 mg / kg ) , atracurium ( 0.5 mg / kg ) and syntocinon 40 units ( 10 units stat and 30 units in 500 ml fluid at 100 ml / h ) were given after the cord was clamped . hypotension ( bp 20 % of baseline ) was treated by giving iv fluid boluses ( 32 ml / kg ) . all variables ( hr , sbp , dbp and map ) and their management were noted in data collection sheets at baseline and the final outcome was measured at intubation . to see any detrimental effect on neonate , all neonates were assessed and apgar score was measured at 1 and 5 min after the birth . all statistical analysis was performed using statistical packages for social science version 19 ( spss inc . , data were expressed as mean ( standard deviation ) for quantitative variables like age , weight , sbp , dbp , hr . independent sample t - test and mann - whitney tests were applied to compare the mean / median difference between groups for age , weight . the paired t - test was used to compare within - subject effect for hr and bp . all statistical analysis was performed using statistical packages for social science version 19 ( spss inc . , data were expressed as mean ( standard deviation ) for quantitative variables like age , weight , sbp , dbp , hr . independent sample t - test and mann - whitney tests were applied to compare the mean / median difference between groups for age , weight . the paired t - test was used to compare within - subject effect for hr and bp . mean age and weight were not significantly different between the groups [ table 1 ] . comparison of demographic variables between groups comparison of mean hr , dbp , sbp and map at baseline and at intubation is presented in table 2 . average hr , sbp , dbp and map were increased significantly from baseline in both groups , but significant differences were not observed in inter - group comparison as shown in table 2 . comparison of mean hemodynamic parameters between groups mean percent increase in hr , sbp , dbp and map from baseline were not significantly different in the two groups [ figure 1 ] . group a : normal saline ; group b : paracetamol there was no significant difference between groups in altering hemodynamic during intubation when the age was divided into 30 or less and more than 30 years ( p = 0.57 ) . hemodynamic stability at intubation is important in all surgeries , under ga especially in cesarean sections where two lives are involved . there are many published controlled trials for the pharmacological modifications of the sympathetic response to laryngoscopy , tracheal intubation , and surgical stimulation , including opioids , tenoxicam , ketorolac , lidocaine , and paracetamol . however , opioids can readily cross the placenta and lead to adverse neonatal outcomes such as serious respiratory depression and bradycardia if given before clamping . nonsteroidal antiinflammatory drugs also can not be used due to their effect on maternal and fetal hemorrhage and premature closure of fetal ductus arteriosus . it belongs to aniline analgesic class of drugs and is an active metabolite of phenacetin . the main mechanism of action is inhibition of cyclo - oxygenase enzyme , which is responsible for the production of prostaglandins , an important mediator of inflammation and pain . oral paracetamol is widely used as an over - the - counter nonopioid analgesic and antipyretic with few contraindications and lack significant drug interactions . park et al . in his study compared the effects of remifentanil at 0.5 or 1.0 g / kg on maternal hemodynamic responses to laryngoscopy and tracheal intubation in pregnant patients undergoing cesarean delivery under general anesthesia . sbp was increased by tracheal intubation in both groups . the peak systolic arterial pressure after intubation was greater in the r0 .5 group than in the r1 .0 group , whereas it did not exceed baseline values in either group . hr increased significantly above baseline in both groups with no significant differences between the groups . neonatal apgar scores and umbilical arterial and venous ph and blood gas values were comparable between the groups . a double - blind randomized placebo - controlled study showed less mean hr change in the paracetamol group when compared to control group ( 76.113.1 ( 95 % confidence interval ( ci ) : 69.9 - 82.23 ) vs. 80.615 ( 95 % ci : 73.6 - 87.62 ) ) . another randomized controlled trial showed that intraoperative hemodynamics in cesarean sections were not statistically significant between clonidine versus control groups ( 9.1 % vs. 12.7 % respectively ; p 0.05 ) . the rationale of this study was to observe the efficacy of intravenous paracetamol in preventing hemodynamic changes due to pain in cesarean sections at intubation as well as its effect on neonatal apgar score . as the literature shows that paracetamol has been used safely in labor as well as before induction to observe its analgesic effects postoperativelytherefore , this study was designed to evaluate the efficacy of intravenous paracetamol in the prevention of hemodynamic changes due to pain on eti . significant difference was not observed between the groups . none of the patients in any intervention group had any untoward effects related to paracetamol . although paracetamol proves to be a safe drug for both mother and neonate , but it probably has no role in preventing hemodynamic alterations due to intubation . its combination with other nonnarcotic analgesics may be an area , which needs further research . administration of intravenous paracetamol 1 h before cesarean section has no significant effect in preventing hemodynamic changes at the time of eti . there were no immediate side - effects of paracetamol on patient or neonate in both the groups .\noutput:\n" }, { "from": "agent", "value": "background and aims : profound hemodynamic alterations due to stress and pain during endotracheal intubation may cause deleterious effects . the purpose of this study was to evaluate the effect of intravenous ( iv ) paracetamol on hemodynamic changes due to endotracheal intubation during cesarean section under general anesthesia.material and methods : random allocation of one hundred and ten patients in two groups ( group a - placebo and group b - paracetamol ) , was achieved as per computer generated table . the placebo ( normal saline ) and paracetamol solutions looked identical as both were available in 100 ml piggy bags and were labeled as study drug . infusion of the drug was given 1 h before surgery . two baseline readings of heart rate , systolic blood pressure ( bp ) , diastolic bp and mean bp were recorded before induction , and these readings were repeated during intubation . detrimental effect on neonate was evaluated by apgar score measured at 1 and 5 min after birth.results : there were no significant demographic differences found between the two groups . hemodyamic changes during intubation also did not differ between the two groups.conclusion : administration of iv paracetamol 1 h before cesarean section has no significant effect in preventing hemodynamic changes at the time of endotracheal intubation ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: as in many fields of neuropsychology , the study of multisensory processing dysfunctions in brain - lesioned patients has been of invaluable help in better understanding the mechanisms and functional roles of multisensory perception and integration in human cognition . in particular , crossmodalextinction has constituted a very useful model for investigating how multiple representations of the space that surrounds us are built in our brains through the integration of sensory information perceived in different modalities ( ldavas and farn , 2004 ; farn et al . , 2007 ) . extinction is a neuropsychological syndrome closely related to spatial neglect , both arising in a vast majority of cases following damage to the right hemisphere , most typically in the posterior parietal region ( becker and karnath , 2007 ) . while neglect patients fail to consciously perceive sensory events located in the contralesional side of space ( i.e. , most commonly the left hemispace ; driver and vuilleumier , 2001 ; kerkhoff , 2001 ) extinction patients have difficulties in consciously perceiving a contralesional stimulus only when it is delivered simultaneously with an ipsilesional stimulation ( bender , 1952 ) . this deficit specific to conditions of double simultaneous stimulation ( dss ) , together with a ( at least almost ) normal detection of contralesional stimuli presented in isolation , is the hallmark of extinction . besides the widely recognized spatial nature of these two syndromes , extinction and neglect patients also exhibit deficits in the temporal processing of contralesional stimuli ( husain et al . , 1997 ; rorden et al . ,1997 ) . in particular , extinction patients exhibit an abnormally long attentional dwell - time ( i.e. , the period during which the perception of a first attended stimulus interferes with that of a subsequent one ) in the contralesional visual hemifield , and this might contribute to the competitive bias in favor of ipsilesional stimuli in these patients ( di pellegrino et al . , 1998 ) . however , the temporal order of ipsi - and contralesional stimuli seems not to influence extinction rate , which remains maximal for simultaneous stimuli ( di pellegrino et al . neglect and extinction can affect all sensory modalities , either separately , across patients , or jointly , in the same individual ( brozzoli et al . , 2006 ) . extinction was first reported in humans in the tactile modality by oppenheim ( 1885 ; cited in benton , 1956 ) . the phenomenon has subsequently been described for visual ( poppelreuter , 1917 ; cited in bender and teuber , 1946 ; critchley , 1953 ; heilman et al . , 1993 ) and auditory ( bender , 1952 ; heilman et al . , 1970 ; de renzi et al . , 1984 ; jacquin - courtois et al , 1988a , b ) and gustatory ( bender and feldman , 1952 ) extinction have also been reported , although it is unclear whether they reflected true olfactory or gustatory extinction , or were rather due to somatosensory deficits ( kobal et al . , 1989 ; berlucchi et al . , 2004 ) . the first observation of extinction in animals also dates back to 1885 . in parallel to oppenheim 's discovery in humans , loeb reported that dogs with damage to one hemisphere favored pieces of meat situated on the side of the lesion only upon simultaneous presentation of two pieces of meat ( benton , 1956 ) . since then , a few studies have sought to develop a model of neglect or extinction in non - human primates , using lesions of parietal , frontal , or superior temporal cortices to induce behaviors similar to those observed in patients . authors have investigated the impact of these lesions on the perception of visual ( faugier - grimaud et al . , 1994 ; heilman et al . , 1995 ) or tactile ( ettlinger and kalsbeck , 1962 ) stimuli , or both ( but as separate modalities ; matelli et al . , 1982 ; rizzolatti et al . , 1983 ) for example , lynch and mclaren ( 1989 ) demonstrated visual extinction in five monkeys with unilateral parietal damage trained to detect single or double small visual targets presented at various eccentricities . although still able to direct saccades toward a single contralesional stimulus , all five monkeys were unable to detect the same target when presented simultaneously with an ipsilesional one . for about a century after its discovery , extinction was thought to occur only within sensory modalities , despite anecdotal reports of crossmodal extinction ( bender , 1952 ) . as a unimodal phenomenon , it provided insights into the neural bases of unisensory competition ( kinsbourne , 1977 ; duncan , 1996 ; riddoch et al . , 2009 ) . however , when its multisensory dimension became clear , extinction could then be used as a model to study the multisensory neural representation of space . the present review focuses on this most recent development in extinction research and the considerable insight it brought into human spatial cognition , before proposing new developments in healthy individuals and non - human primates as the support for future research on extinction . the first sections provide a brief outline of the original demonstration of the existence of multisensory ( or crossmodal ) extinction , its role in the investigation of multisensory spatial representation , and an overview of the current theoretical accounts of extinction . in the second part of this paper , we propose two future developments for extinction research that we believe are key to deepen our understanding of the cerebral mechanisms of extinction and multisensory processing . the first one is the exploration of physiological extinction phenomena in healthy humans , their behavioral mechanisms and their neural underpinnings , thanks to functional neuroimaging and brain stimulation methods . the second one is the refinement of the existing non - human primate model of extinction by using the same behavioral approach as in humans to strengthen the validity for inter - species comparisons , also building on the unique opportunity provided by animal research of combining focal lesions techniques to functional neuroimaging methods . posner 's seminal work on selective spatial attention in the 1980s ( posner et al . , 1982 , 1984 , 1987a , b ) motivated the first attempts to systematically investigate whether stimuli presented in different sensory modalities could compete for common , supramodal attentional resources . the first evidence of multisensory competition for attentional resources was brought by farah et al . ( 1989 ) , who used a modified version of posner 's task ( posner et al . , 1982 ) . in this study , a lateralized auditory cue , either valid or invalid , preceded the presentation of a visual target either to the left or to the right of a central fixation point , and participants had to respond as soon as possible to the visual target by pressing the corresponding button . patients with right parietal lesions were slower at detecting contralesional left visual targets when previously invalidly cued to the right side of space , suggesting a deficit in disengaging spatial attention from the wrongly cued ipsilesional location to subsequently relocate it to the contralesional visual target . ( 1989 ) interpreted these results as evidence for the existence of a supramodal system controlling the allocation of spatial attention . however , auditory cues did not interfere with the perception of visual stimuli to the point of hampering their detection . while these lengthened reaction times indeed reflected interferences between the processing of auditory cues and visual target stimuli , they remained much less spectacular than the outright omissions of stimulations observed in extinction patients during dss . ( 1992 ) investigated more explicitly the possible existence of crossmodal , visuotactile extinction in patients suffering from right parieto - frontal lesions and exhibiting unimodal visual and tactile extinction . to this end , they used the classical confrontation test , which consists in having the patient face the experimenter and apply stimuli either to the left or right side of space , or both simultaneously . typically , the patient is asked to verbally report which side ( s ) the stimulation was applied to , and the experimenter compares performance on single stimulus detection with responses to dss . as detailed previously , the hallmark of extinction is a ( relatively ) normal detection of single stimulations together with a deficit in detecting contralesional stimuli on dss trials . in inhoffet al. s ( 1992 ) study , visual stimuli corresponded to wiggling either index finger or both at the patient 's eye level , while tactile stimulations were applied by lightly touching the dorsum of the hand ( s ) while the patient had the eyes closed . the three patients tested showed pronounced extinction within the visual and tactile modalities , but no sign of visuotactile extinction , which led inhoff et al . ( 1992 ) to conclude that processing of sensory inputs from both modalities is controlled by separate spatial attention systems , and that parieto - frontal brain structures may not contribute to the elaboration of a supramodal representation of space . these findings were subsequently challenged by abundant neurophysiological data collected in the monkey that demonstrated the existence of multimodal neurons in areas commonly associated with spatial attention and extinction , such as parietal cortex ( duhamel et al . , 1998 ) and basal ganglia ( graziano and gross , 1993 ) , as well as ventral premotor cortex ( rizzolatti et al . , 1981 ; graziano et al . , 1994 ) . these neurons respond to stimuli delivered in different sensory modalities ( e.g. , vision and touch ) and have been suggested to constitute the substrate for crossmodal integration and multisensory representation of space . the most widely studied cells are visuotactile neurons , which have a visual receptive field in register with their tactile receptive field , that is , they respond to visual stimuli applied on or in the space immediately surrounding a specific body part , thus providing multiple multisensory maps of space centered on different body parts . importantly , this implies that visuotactile interactions are strongest near the body , but fade as the visual stimulus moves away . in light of these findings , inhoff et al. s ( 1992 ) failure to demonstrate the existence of visuotactile extinction might just be due to the fact that their visual stimulations were delivered too far from the hand , at patients eye level , where they would interact much less , if at all , with the tactile stimuli . ( 1997 ) , independently and at about the same time , tested patients with right brain damage and suffering from unisensory extinction in the tactile or visual modality , or both . both investigations were based on a confrontation test similar to that used in inhoff et al. s ( 1992 ) investigation , except that visual stimuli were applied near the hand . in both studies , patients exhibited strong visuotactile extinction , with a visual stimulus applied near the ipsilesional hand hampering the detection of a tactile stimulation of the contralesional hand . the reverse pattern of extinction ( i.e. , a right tactile stimulus extinguishing a left visual stimulus applied near the hand ) was also present when investigated ( mattingley et al . importantly , the patient tested in di pellegrino et al. s ( 1997b ) study did not show visuotactile extinction when the ipsilesional visual stimulus was applied far from the hand , supporting the hypothesis that these multisensory interactions are supported by mechanisms similar to those described in the monkey ( rizzolatti et al . , 1981 ; graziano et al . however , the fact that crossmodal extinction was still present when the visual stimulus was applied at patients eye level in mattingley et al. s ( 1997 ) study suggests that these interactions , although strongest in near space , are not an all - or - nothing phenomenon . this is consistent with subsequent observations that , although usually milder , crossmodal extinction can still occur with ipsilesional stimuli delivered far from the hand ( ldavas et al . , 1998a ; farn and ldavas , 2000 ) , suggesting that the transition from near to far space is gradual rather than an abrupt boundary at arm 's length ( longo and lourenco , 2006 ) . since the demonstration of the existence of visuotactile extinction , many investigations have used extinction as a window on the mechanisms of normal multisensory processing in the human brain , showing for example that other sensory modalities can interact , such as touch and audition ( ldavas et al . , 2001 ; for a similar demonstration using alloesthesia , see ortigue et al . , 2005 ) . most importantly , as we will detail in the next section , the study of neglect and crossmodal extinction has proven an invaluable tool for the exploration of human spatial cognition . although our conscious experience of the space that surrounds us is that of a unitary entity , it is actually the product of the integration of multiple neural representations , subserved by distinct cerebral systems and involving the convergence of information perceived in different sensory modalities ( calvert et al . , 2004 ; the first evidence of separate representations of distinct sectors of space in humans has been brought by the demonstration that neglect can be restricted to personal space ( e.g. , bisiach et al . , 1986 ) or to the space within ( halligan and marshall , 1991 ; berti and frassinetti , 2000 ) or beyond ( vuilleumier et al . , this distinction between the representations of near and far space had been previously shown in monkeys following focal lesions to the postarcuate cortex ( area 6 ) , which induced tactile and visual neglect for the contralateral space immediately surrounding the body , and to the frontal eye field ( area 8 ) , which gave rise to visual neglect for far space , with a tendency to deviate the eyes and the head toward the side of the lesion and to decrease spontaneous eye movements contralateral to the lesion , as typically observed in human neglect ( rizzolatti et al . , 1983 ) . subsequently however , the study of patients with crossmodal extinction has provided a much more detailed picture of the modularity of the cerebral representation of space . indeed , the first report of spatially selective visuotactile extinction described above ( di pellegrino et al . , 1997b ) provided evidence that the space located within reaching distance , also often termed peripersonal space ( for a detailed discussion of these concepts of spatial representation , see cardinali et al . , 2009 ) , can be divided into two parts : a near sector , constituted of the space immediately surrounding body ( about 5 cm ) , where visuotactile integration is strongest ; and a far sector ( at approximately 35 cm from the body ) , where visuotactile interactions are weaker . in addition , these studies showed that the maps of near peripersonal space were centered on a specific body part , that is , in those cases , the hand . ( 1997b ) presented the visual stimulus at the same spatial location as in the regular confrontation test ( i.e. , next to where the patient 's hand used to be ) , while the patient held his hand behind his back . in this condition , the patient detected flawlessly the left tactile stimulus when it was delivered concurrently with the ipsilesional visual stimulus , showing that the visuotactile interaction evidenced in the normal confrontation test occurred in hand - centered space , and not in a retinal or other more general egocentric ( e.g. , head - or trunk - centered ) spatial frame of reference . this interpretation was further supported by the observation that , while a visual stimulus might prevent the detection of a contralesional tactile stimulus if it is applied near the ipsilesional hand in a patient with tactile extinction , it can on the contrary enhance the detection of the same contralesional tactile stimulus if it is instead applied near the contralesional hand during tactile dss ( ldavas et al . again , this modulation of tactile perception by visual stimuli was dramatically diminished if the visual stimulus was applied far from the hand . therefore , in the former case , the simultaneous activation of the visuotactile representations of the left and right hands by the tactile and visual stimulus , respectively , leads to the extinction of the weaker representation supported by the lesioned right hemisphere , that is , the one of the left hand . by contrast , in the latter case , when the visual stimulus is applied near the left hand , it enhances the activation of the weaker representation , thereby allowing the detection of a left tactile stimulus even when a concurrent tactile stimulus is delivered on the right hand . subsequently , similar paradigms have been used to reveal the existence of multisensory maps of near peripersonal space and their relation to other body parts . in particular , crossmodal extinction has been used to demonstrate interactions between vision and touch in a space centered on the face in humans ( ldavas et al . , 1998b ) . in this study , extinction patients received unilateral and bilateral tactile stimuli on the cheeks , together with a visual stimulus applied either on the ipsilesional or on the contralesional side . akin to what has been described for the hand , the visual stimulus extinguished the contralesional tactile stimulus when presented ipsilesionally , whereas it enhanced its detection when delivered near the contralesional cheek . again , visual stimuli presented far from the face modulated touch perception to a much lesser extent . further investigation strengthened the evidence of a modular organization of visuotactile near peripersonal space , by directly studying the effects of ipsilesional visual stimuli delivered to homologous or non - homologous body parts ( i.e. , the face or the hand ) to that receiving the contralesional tactile stimulus ( farn et al . , 2005a ) . visuotactile extinction observed in near peripersonal space was stronger when homologous body parts were stimulated , while it was weak and comparable in the homologous and non - homologous condition in far peripersonal space . near peripersonal space is thus not represented as a unitary entity , but rather consists of different modules , separately representing multisensory space , possibly centered on several body parts . finally , similar modulations of tactile extinction have been revealed through multisensory interactions between touch and audition ( ldavas et al . detection of contralesional single touches applied on the neck of tactile extinction patients was prevented by ipsilesional white noise stimuli delivered near the patients head . when the auditory stimulus was delivered far from the head , audiotactile extinction was dramatically reduced . interestingly , spatially selective interactions between audition and touch were strongest when the auditory stimuli came from the back , rather than from the front , of the patients head . additionally , the spatial specificity of the modulation of touch perception by audition was more pronounced for white noise bursts than pure tones . this suggests that different degrees of multisensory integration may occur depending on the complexity of the stimuli , and on the functional relevance of a given sensory modality for a particular sector of space ( farn and ldavas , 2002 ) . together , these phenomena of crossmodal extinction and facilitation show that multisensory maps of near peripersonal space are elaborated through the integration of multisensory information , presumably at the neuronal level , via multimodal cells similar to those described in the monkey ( rizzolatti et al . , 1981 ; graziano and gross , 1993 ; graziano et al . , 1994 , 1997 ; duhamel et al . , as we have already mentioned , those neurons have been found in several cortical regions in the monkey that are commonly associated to spatial attention and extinction ( vallar et al . , 1994 ; karnath et al . , 2003 ; corbetta et al . , 2005 ) , including parietal ( duhamel et al . , 1998 ) and ventral premotor ( rizzolatti et al . , 1981 ; graziano et al . , 1994 ) cortices . this interpretation is supported by the fact that crossmodal extinction in humans and the activity of multimodal neurons in monkeys are modulated by similar parameters . indeed , multimodal neurons , whether visuotactile ( rizzolatti et al . , 1981 ; graziano and gross , 1993 ; graziano et al . , 1994 ; duhamel et al . , 1998 ) or audiotactile ( graziano et al . , 1999 ) , progressively cease to fire when the non - corporeal stimulus ( i.e. , visual or auditory ) moves away from the relevant body part . furthermore , similarly to audiotactile extinction described in patients ( farn and ldavas , 2002 ) , the activity of monkey audiotactile neurons is also modulated by auditory complexity ( graziano et al . , 1999 ) . finally , tool use induces plastic modifications of the multisensory representation of near space in both monkeys and humans . in monkeys , visuotactile neurons that normally fire only when visual stimuli are applied near the hand show an enlarged visual receptive field after tool use , which encompasses the hand and the tool ( iriki et al . , visuotactile extinction increases strongly in the region of space that was previously beyond reach ( i.e. , far space ) but made accessible by the use of the tool ( for a similar effect in neglect patients , see berti and frassinetti , 2000 ; in healthy individuals , see maravita et al . , 2002 ; holmes et al . , 2004 ; for review , see maravita and iriki , 2004 ; farn et al . , 2007 ) . additionally , this remapping occurs only after active and functional use of the tool in both species ( iriki et al . , 1996 ; maravita et al . , 2002 ; in sum , the body of evidence reviewed here and collected through the study of crossmodal extinction supports the hypothesis of a cerebral representation of multisensory space organized in a modular fashion , supported by several neural systems devoted to the representation of different sectors of space , in different coordinates , and probably for different behavioral purposes ( stein and arigbede , 1972 ) . as stated earlier , extinction and neglect are often considered manifestations of the same underlying deficit , representing different levels of impairment along a continuum ( e.g. , heilman et al . , 1993 ) . as such , both disorders have usually been addressed jointly by several theories proposed to account for their behavioral manifestations . whether they postulate a deficit in the representation of the contralesional hemispace ( bisiach et al . , 1981 ) or in the ability to disengage attention from ipsilesional stimuli ( posner et al . , 1984 ) , a deviation ( jeannerod and biguer , 1987 ) or a distortion ( bisiach et al . , 1996 ) of spatial representation , most of these interpretations have been based on a dominant role of the right hemisphere in representing and orienting attention to both sides of space , while the left hemisphere would only be concerned with the right contralateral hemispace ( heilman et al . , 1993 , 1997 ) . while this assumption might explain the spatial bias exhibited by neglect patients who fail to attend to or act toward stimuli in the contralesional hemispace , it is hard to reconcile with the competitive nature of extinction . indeed , the hypothesis that the right lesion would leave intact only the attentional capacities of the left hemisphere leads to the prediction of an inability to detect single contralesional stimuli , rather than extinction arising from the competition between ipsi - and contralesional stimuli for attentional resources ( for a detailed discussion of this point , see di pellegrino and de renzi , 1995 ) . in fact , this view is hardly compatible with the competitive aspects of neglect itself , which has been shown to be reduced for example on a cancelation task when ipsilesional targets were progressively removed ( mark et al . , 1988 ) . this finding has been interpreted as evidence for a deficit in disengaging attention from ipsilesional stimuli , but might also be conceived of as suggesting competitive underlying mechanisms . an alternative model addresses explicitly the competitive dimension of extinction ( and neglect ) by proposing that these phenomena result from a breakdown in the dynamic balance that normally exists in the reciprocal inhibition between homologous areas of the two hemispheres that orient spatial attention in opposing , contralateral directions ( kinsbourne , 1977 , 1987 ) . according to this proposal , a lesion lateralized to one hemisphere induces not only its hypoactivity , but also hyperactivity in the other hemisphere due to the release of inhibition by the affected one . this imbalance generates a general bias toward the ipsilesional side of space , which results in a biased competition between simultaneous stimuli ( duncan , 1996 ; driver et al . , 1997 ) . the higher frequency of neglect and extinction following left than right brain damage would be explained by the fact that the rightward orienting bias generated by the left hemisphere is stronger than the opposing bias induced by the right hemisphere . this model provides a convincing explanation of why , in extinction , a contralesional stimulus is normally detected most of the time when delivered in isolation , but goes undetected when presented simultaneously with an ipsilesional stimulus ( bender , 1952 ) . because the deficit lies at the level of interhemispheric rivalry , in the former case , the lesioned hemisphere is still capable of processing ( almost normally ) the isolated contralesional stimulus . in the latter case , however , the concurrent activation of the intact hemisphere by the ipsilesional stimulus leads to enhanced inhibition of homologous areas on the side of the lesion , thereby preventing the conscious detection of the contralesional stimulus . strong support to this model comes from brain stimulation studies using repetitive transcranial magnetic stimulation ( rtms ) to temporarily decrease the activity of the intact hemisphere in brain - damaged patients suffering from tactile extinction ( oliveri et al . , 1999 ) andtransient deactivation of the healthy hemisphere temporarily decreased the manifestations of extinction or neglect , in accordance with the predictions drawn from kinsbourne 's theory . although the implications of this model have usually been discussed in the framework of unimodal extinction ( e.g. , di pellegrino and de renzi , 1995 ) , it is applicable to the case of crossmodal extinction as well , whether the competition is considered to happen at the level of the orientation of some supramodal attentional system , or at a more physiological level where multisensory representations of near peripersonal space interact directly through reciprocal transcallosal connections . the results of recent neuroimaging studies have led to a more complete picture of the pathophysiological mechanisms involved in neglect and extinction , and given further support to their competitive accounts . ( 2000 ) orienting of spatial visual attention toward a specific location involves a bilateral , dorsal frontoparietal network comprising the intra - parietal sulcus and superior parietal lobule , and the frontal eye field . another , more ventral network , constituted of the temporoparietal and inferior parietal region and the caudal part of the inferior frontal gyrus , redirects attention toward novel stimuli by sending signals to the dorsal network . this ventral network is lateralized to the right hemisphere , and corresponds to the location of lesions usually associated with neglect . further work in right brain - lesioned patients with neglect has shown that lesions in these patients not only directly affect the ventral attention network , but also indirectly modifies the activity within the structurally intact bilateral dorsal network ( corbetta et al . , 2005 ) . indeed , the disruption of the normal interaction between the ventral and dorsal systems resulted in these patients in abnormally unbalanced activity in the left and right dorsal parietal cortices , with increased activations in the contralesional left hemisphere and comparatively reduced activity on the right side . further , the hyperactivity of the left superior parietal lobe correlated with the patients bias toward the ipsilesional side of space . these findings thus provide strong support to the competitive accounts of neglect and extinction , and suggest that dorsal parietal cortex is the site of the interhemispheric activity imbalance responsible for neglect and extinction patients rightward spatial bias . in the framework offered by these models , indeed , the interhemispheric rivalry hypothesis suggests that even in a healthy brain , competition occurs between simultaneous stimuli . in line with this hypothesis , previous work has shown , using positron emission tomography ( pet ) , that simultaneous bilateral visual stimulation induces a reduction in response of the primary visual cortex when compared to the activation observed after contralateral single stimulation , thereby providing physiological support for the existence of interhemispheric rivalry occurring in the intact brain at early levels of processing ( fink et al . , 2000 ) . thus , it should be possible to elicit extinction in healthy subjects performing a detection task with simple - feature stimuli , provided that the system is placed in challenging enough conditions . however , in contrast with patients behavior , healthy individuals should exhibit no spatial bias in favor of one side or the other . indeed , while kinsbourne postulated that the higher occurrence of neglect and extinction following right brain damage was due to a stronger rightward attentional orienting bias generated by the left hemisphere , he suggested that , in the absence of lesion , the right brain 's opposing leftward bias holds the left hemisphere 's rightward bias in checkfurther , according to corbetta et al. s ( 2005 ) model , imbalance between the activity of left and right dorsal parietal cortices only occurs following lesion to the ventral attention network , lateralized to the right hemisphere . therefore , the competition should be balanced between the two hemispheres in subjects in a normal state of vigilance ( matthias et al . , 2009 ; the idea that extinction observed in brain - damaged patients may be a pathological exacerbation of limits to the physiological capacities of the brain is not new . bender himself , in his seminal monograph about disorders of perception ( bender , 1952 ) , anecdotally reported what resembles extinction - like phenomena in normal subjects during tactile dss on non - homologous body parts . subjects frequently missed the first of a series of dss when they were not aware of what body parts would be stimulated . this observation led bender to assume that more consistent patterns of extinction - like behavior might be observed in healthy individuals with the appropriate testing paradigm and devices . more recent works have investigated competitive phenomena in healthy subjects in the visual ( duncan , 1984 ; gorea and sagi , 2002 ) and tactile ( meador et al . , 2001 ; marcel et al . , 2004 ; serino et al . ,2008 ) domain , but the induction of extinction - like patterns of performance required the use of complex experimental displays and demands ( discrimination task , unbalanced stimuli , masking procedures , etc ) that are highly likely to rely on different processes than the mere detection of simultaneous simple - feature stimuli . other groups were able to elicit extinction - like behaviors in healthy individuals , but induced to this purpose temporary and reversible lesions using either tms or transcranial direct current stimulation ( tdcs ) to transiently impair sensory processing ( dambeck et al . , 2006 ; meister et al . , 2006 ; sparing et al . , 2009 ; for review , seeoliveri and caltagirone , 2006 ) . below , we will review recent data from our group and others showing that extinction - like phenomena can be elicited in healthy individuals without brain stimulation , using simple stimuli and tasks much more similar to the classical confrontation test , provided the appropriate experimental conditions are met , as bender had predicted . in accordance with the predictions drawn from the competitive accounts of extinction , our group sought to demonstrate the existence of tactile extinction in healthy individuals ( farn et al . , 2007 ) . the hypothesis was that the somatosensory system is intrinsically limited when simultaneous stimuli compete to reach consciousness , so that extinction should manifest itself physiologically , provided the stimuli are challenging enough to perceive . to address this last point , the intensity of stimuli was first titrated independently on each side in order for the subject to detect 90 % of left and right single stimulations , in order to avoid ceiling effects . during the experiment , neurologically healthy subjects performed a task as close as possible to the confrontation test , to investigate the same processes as those involved in pathological extinction . specifically , participants were asked to localize tactile stimuli delivered to either or both index fingers by verbally responding left , right , both , or none as fast as they could , while their hands were out of their sight . while subjects were able to report approximately 90 % of single stimulations , as expected from the titration procedure , the rate of correct detection dropped to 78 % for dss . this score was lower than the joint probability of detecting both stimuli , confirming that this drop in performance was due to a genuine extinction phenomenon . finally , in agreement with the prediction made by the hemispheric rivalry hypothesis , there was no spatial bias in the distribution of participants errors , meaning that they missed equally often left and right stimuli when a stimulus was extinguished on dss trials . this study is the first demonstration of the existence of tactile extinction - like phenomena in healthy individuals , using a very simple task , as close as possible to the classical confrontation test used with patients , as well as simple - feature stimuli . this allows us to confidently believe that we are studying the very same processes that are at play in clinical extinction . we are currently investigating whether the same procedure applied to visual stimuli results in patterns of performance reminiscent of extinction patients behavior . indeed , participants miss stimuli on dss trials while they perceive single stimulations almost perfectly and , again , do not seem to exhibit a spatial bias when failing to perceive one of two simultaneous stimuli . of particular relevance to the question addressed here are studies about the colavita effect , a phenomenon reflecting the fact that vision dominates over other sensory modalities in most experimental conditions . colavita ( 1974 ) originally designed an experiment in which visual , auditory , or audiovisual stimuli were randomly presented , asking participants to report what they had perceived . typically , on a certain number of bimodal trials , subjects missed the auditory stimulus and reported only the visual one , while they had no difficulties in reporting isolated stimuli . there has been lately a resurgence of interest in this phenomenon , and many studies have confirmed the existence of this effect under more controlled experimental conditions ( for review , see spence , 2009 ) . while this effect is somewhat reminiscent of the manifestations of crossmodal extinction , it lacks a spatial dimension for the parallel with extinction and interhemispheric competition to be solid . recently however , this effect of visual dominance has been extended to the perception of visuotactile stimuli ( hartcher - o'brien et al . , 2008 ) , showing that people tend to miss the tactile stimulus much more often than the visual one on dss trials with extinction . in this study , ( 2008 ) first tested their participants in a similar configuration to the audiovisual colavita experiments done before , that is , with one hand ( right ) located centrally in front of them . the tactile and visual stimuli were presented from the same spatial location , at the tip of the subject 's index finger . in a subsequent experiment , to establish a better correspondence with crossmodal extinction , these authors introduced a spatial dimension to their task , by placing each hand in its corresponding visual field and asking the subjects to fixate centrally . the visual and tactile stimuli could be delivered to either hand , resulting in bimodal trials that were either unilateral ( i.e. , both stimuli applied to the same hand ) or bilateral ( i.e. , each hand received one of the two stimuli ) . the latter condition corresponds to the typical experimental set up usually used to test for visuotactile extinction . the results show that , even when both stimuli do not come from the same spatial location but are rather delivered on homologous body parts placed in different hemispaces , the colavita visual dominance effect still holds , although in lesser proportions . following the approach we used to study physiological extinction in the tactile and visual modalities , we recently started to investigate visuotactile extinction - like effects in healthy participants . tactile stimuli are applied to the tip of either index finger , while visual stimuli are delivered in the space immediately surrounding either hand . a similar intensity titration is used independently for visual and tactile stimuli , on the left and right side , in order for the subject to detect approximately 90 % of the single stimuli of each of the four types ( 2 modalities 2 sides ) . then , during the experiment itself , unilateral visual or tactile stimuli as well as bilateral visuotactile stimulations are randomly delivered while participants are asked to report whether they detected a stimulus , regardless of its modality , on the left , right , or both sides . preliminary data indicate that visuotactile extinction - like effects can be elicited in healthy individuals using this protocol : participants fail to perceive one of the two stimuli on dss trials , while perceiving almost perfectly either visual or tactile stimuli delivered in isolation . here again , there seem not to be a spatial bias in the distribution of their errors . in sum , it is possible , using well - controlled experimental conditions , to induce extinction - like phenomena in healthy individuals , and thus to establish a physiological model of uni - and multisensory competition . such a model will allow testing hypotheses drawn from patients behavior about physiological processes directly , as well as overcoming the potential confounds inherently associated with the study of clinical extinction when it comes to the investigation of the anatomo - functional bases of multisensory perception of competing stimuli . indeed , although valuable contributions can be made by single case investigations using functional neuroimaging techniques ( e.g. , rees et al . , 2000 ; sarri et al . ,2006 ) as well as group studies using lesion overlapping methods ( e.g. , karnath et al . ,2003 ) , the neuropsychological approach is limited due to the heterogeneity of lesion sites , sizes , and etiology , and by the plasticity following permanent brain damage . the use of neuroimaging and neurophysiological techniques in neurologically healthy individuals will allow investigating the neural underpinnings of physiological extinction - like phenomena in different modalities without these limitations . after identification of these functional networks , brain stimulation methods such as tms and tdcs will permit to examine the behavioral disturbances caused by the selective disruption of specific nodes of these networks in the intact brain . this approach will also allow a better comprehension of the anatomo - functional and pathophysiological bases of clinical extinction by comparing these findings to the specific aspects of pathological sensory competition phenomena , such as the ipsilesional spatial bias and the prevalence of extinction after right - hemisphere damage . in sum , thanks to this physiological model of sensory competition , it will be possible to test the validity of current theoretical accounts of extinction , and to better understand how multisensory processes are organized in the intact brain . in addition to this human physiological model , a refined animal model of the cerebral bases of sensory competition would provide the unique opportunity to bridge the gap between investigations of multisensory processes at the level of single cells and of functional networks , and between studies of the functioning of intact and damaged systems . to this end , establishing a model of physiological extinction - like phenomena in monkeys following the same approach as used in neurologically healthy humans would constitute a very valuable tool in order to refine the framework provided by previous lesion studies in non - human primates . as suggested in the previous sections , the properties of multimodal neurons recorded in several brain structures including the parietal and premotor cortices in the monkey ( rizzolatti et al . , 1981 ; graziano and gross , 1993 ; graziano et al . , 1994 ; duhamel et al . , 1998 ) suggest that these neurons likely constitute crucial nodes in crossmodal interactions and the building of multisensory representations of space . however , typical lesion - based approaches in the monkey have so far been only partially satisfactory . cortical ablation studies in monkeys have shown that neglect and extinction can occur following lesions of either the periarcuate frontal ( rizzolatti et al . , 1983 ; heilman et al . , 1995 ) or the inferior parietal regions ( faugier - grimaud et al . , 1978 ; lynch and mclaren , 1989 ) a first limitation of these studies lies in the fact that the choice of the areas to be lesioned was based on a fair , but putative homology of functional anatomy between humans and monkeys . a second limitation comes from the rapid spontaneous recovery that follows permanent lesions that were used in most studies , leaving only little testing time , sometimes only a few days , which is insufficient to explore the many different aspects of neglect and spatial attention uncovered by neuropsychological investigations in humans ( matelli et al . , 1982 ; further , this rapid recovery raises questions about the validity of the comparison with human neglect , as it might reflect a true difference in the cerebral organization of attention and space representation mechanisms between the two species , or be related to secondary factors such as lesion location and size , or extent of white matter damage . the emergence of fmri in monkeys in the recent years provides an invaluable tool to bridge the gap between these findings in monkeys and the research conducted in humans . in particular , one promising perspective is to induce physiological extinction - like phenomena in monkeys within and between sensory modalities using very similar procedures as the one used in humans . the unique advantage of monkey fmri is that it can be combined with invasive techniques , in particular focal reversible lesions , and thus unequivocally demonstrate which neural network is actually crucial for managing the competition involved in tasks involving the perception of simultaneous sensory stimuli . by applying the very same task in healthy humans and in trained monkeys to identify the networks involved in competitive sensory perception using fmri , future work should allow establishing true homologies between humans and monkeys based on functional activations . functionally identified target regions could then be temporarily and reversibly shut down ( using muscimol , see e.g. , wardak et al . , 2004 , 2006 ) in order to investigate their causal role in producing behavioral extinction - like effects . in other words , the pitfalls of permanent ablations would be overcome , and the consistency of the results would be ascertained by multiple testing sessions . in addition , using fmri , one could study the impact of a circumscribed lesion on the activity of the remaining competitive sensory perception network and therefore shed light on the pathophysiology of neglect / extinction . in addition , such a model would undoubtedly provide extremely valuable insight into more theoretical aspects of spatial awareness . the study of pathological crossmodal extinction has allowed deepening significantly our knowledge about how multisensory processing contributes to human spatial cognition . it has revealed the modular organization of the neural representation of space , with the existence of multiple multisensory maps of different sectors of space likely centered on specific body parts , and allowed to suggest a parallel between behavioral findings in humans and multisensory processes described at the cellular level in non - human primates . it also laid the bases for the development of a model of multisensory competition in neurologically healthy humans . now , this physiological model can in turn motivate the parallel investigation of competitive multisensory processes in humans and monkeys using complementary techniques in order to complete the framework of the cerebral organization of the perception of multisensory competitive stimuli and of selective spatial attention , in human and non - human primates , from the cellular level to that of functional networks . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .\noutput:\n" }, { "from": "agent", "value": "the study of crossmodal extinction has brought a considerable contribution to our understanding of how the integration of stimuli perceived in multiple sensory modalities is used by the nervous system to build coherent representations of the space that directly surrounds us . indeed , by revealing interferences between stimuli in a disturbed system , extinction provides an invaluable opportunity to investigate the interactions that normally exist between those stimuli in an intact system . here , we first review studies on pathological crossmodal extinction , from the original demonstration of its existence , to its role in the exploration of the multisensory neural representation of space and the current theoretical accounts proposed to explain the mechanisms involved in extinction and multisensory competition . then , in the second part of this paper , we report recent findings showing that physiological multisensory competition phenomena resembling clinical crossmodal extinction exist in the healthy brain . we propose that the development of a physiological model of sensory competition is fundamental to deepen our understanding of the cerebral mechanisms of multisensory perception and integration . in addition , a similar approach to develop a model of physiological sensory competition in non - human primates should allow combining functional neuroimaging with more invasive techniques , such as transient focal lesions , in order to bridge the gap between works done in the two species and at different levels of analysis ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: ovarian cancer ranks eighth among all cancers in women in terms of estimated new cases and fifth in estimated deaths . platinum agents , cisplatin or carboplatin , are the most effective first - line treatments ; however , despite initial promising responses , a high percentage of cases develop chemoresistance which significantly hinders successful treatment outcomes . thus , there is a great need to develop agents for treatment of drug resistant ovarian tumors . the epidermal growth factor receptor ( egfr ) family ( erbb family ) of type i receptor tyrosine kinases ( rtks ) has four members : egfr / erbb1 , erbb2 , erbb3 , and erbb4 ( also referred to as her1 , her2 , her3 and her4 ) . all erbb family members share common features including an extracellular ligand - binding domain ( except erbb2 ) , a transmembrane domain , and an intracellular protein tyrosine kinase domain ( except erbb3 ) . the receptors have notable differences in their sequences , which account for differential ligand - binding and diverse affinities for downstream signaling molecules . data suggest that the homo - and heterodimerization between members of the erbb family as well as the ability of their ligands to bind and activate more than one receptor help produce the complex signaling pathways of these membrane - bound proteins . erbb receptors not only play key roles in normal developmental processes but also are implicated in malignant transformation . activated erbb receptors stimulate many intracellular signaling pathways , especially the phosphatidylinositol 3 - kinase ( pi3k ) - akt pathway . akt / protein kinase b is a family of serine - threonine protein kinases that promote cell survival and proliferation . abnormal activation of akt signaling has been reported in several human cancers including approximately 3040 % of ovarian cancers . akt promotes cell survival by mediating inactivating phosphorylation of proapoptotic proteins like bad and caspase - 9 and mediating activating phosphorylation of nf - kappab , which controls expression of prosurvival proteins such as survivin , bcl - 2 , and the caspase - 8 inhibitor flip . additionally , active akt has been shown to confer resistance to chemotherapy in human cancers and is considered a therapeutic target . impairment of apoptotic processes can also be mediated by factors such as flip and survivin . flip and survivin are cytoplasmic proteins that function as inhibitors of caspase - 8 and caspase - 9/3 , respectively , . flip has a similar structure to caspase - 8 without the catalytic domain and thus competitively inhibits caspase - 8 binding to the tumor necrosis factor family of cell surface death receptors thus blocking their apoptotic signaling . survivin is a structurally unique member in the iap ( inhibitor of apoptosis protein ) family and suppresses the processing and catalytic activity of execution caspases , such as casapse - 9 and 3 . our lab has developed a vitamin e analog , 2,5,7,8 - tetramethyl - 2r - ( 4r , 8r , 12 - trimethyl - tridecyl chroman -6-yloxy ) acetic acid , referred to as alpha - tocopherol ether acetic acid analog ( - tea ) , which differs in structure and function from natural vitamin e ( rrr -- tocopherol ) . - tea has an acetic acid moiety linked to the phenolic oxygen at carbon 6 of the chroman head of rrr -- tocopherol by an ether linkage yielding a stable , nonhydrolyzable entity . studies have demonstrated that - tea can reduce tumor burden and inhibit lung metastases when delivered by aerosol or in the diet in preclinical syngeneic transplantable mouse mammary cancer studies ; as well as in xenograft models using immune compromised mice transplanted with human ovarian , breast or prostate cancer cells . immunohistochemical analyses of tumor tissue from - tea treated animals indicated that - tea reduction of tumor burden was associated with increased apoptosis and reduced cell proliferation in tumor tissue . cell culture studies have shown that - tea induces human ovarian , prostate and breast cancer cells to undergo dna synthesis arrest and apoptosis , and that - tea - induced apoptosis involves activation of fas / fas ligand and c - jun nh2 - terminal kinase ( jnk ) proapoptotic pathways ; as well as , suppression of akt , flip , and survivin antiapoptotic / prosurvival factors . in this study , we investigated the effect of - tea on the expression of egfr family proteins and studied the roles of erbb2 and erbb3 in - tea - induced apoptosis and suppression of akt , flip and survivin antiapoptotic / prosurvival factors . ly294002 , a specific inhibitor of the p110 catalytic subunit of pi3k , and wortmannin , a cell - permeable , irreversible inhibitor of pi3k , were purchased from calbiochem ( san diego , ca ) . the human ovarian a2780 cisplatin - sensitive parental cancer cell line ( designated a2780s ) , provided by dr . j. rebecca liu ( university of michigan medical school , ann arbor , mi ) , was originally established from an untreated ovarian cancer patient . the cisplatin - resistant a2780 / cp70 variant ( designated a2780 / cp70r ) , provided by dr . michael j. birrer ( department of cell and cancer biology , national cancer institute , rockville , md ) , was created through intermittent exposure of a2780 cells to increasing concentrations of cisplatin ( up to 70 m ) in vitro . a2780s anda2780 / cp70r cells were grown as monolayers on plastic ( corning plastic ware , corning , ny ) and maintained at 37c in rpmi 1640 ( invitrogen - life technologies , inc . , carlsbad , ca ) , supplemented with 10 % fetal bovine serum ( fbs , gemini bio - products , woodland , ca ) , 100 iu / ml penicillin , 100 g / ml streptomycin , and 2 mm glutamine ( sigma chemical co. , st . cultures were maintained and routinely examined to verify the absence of mycoplasma contamination as described previously . for experiments , were plated at a density of 310 in t75 flasks ( 10 ml ) for western analyses , or at a density of 1.510 / well in 12 - well plates ( 1 ml ) for apoptosis analyses . treatments were conducted at various concentrations of - tea in a final concentration of 0.10.25 % ethanol . equal volume of ethanol was used as vehicle control . to study the effects of - tea on proliferation , a2780s or a2780 / cp70r cellswere trypsinized , and seeded in triplicate into 96 - well plates at a density of 5000 cells / well which yields a 2030 % cell density . - tea at 1.25 , 2.5 or 5 m , or 2.5 , 5 , or 10 m were then added to a2780s or a2780 / cp70r , respectively , and cells were grown in media containing 2 % fbs for 1 to 3 days . viable cell numbers were determined using promega 's celltiter 96 aqueous one solution cell proliferation mts assay ( promega , madison , wi ) according to the manufacturer 's instructions . assessment of apoptosis was performed based on nuclear morphology of dapi - stained cells as described previously . cells in which the nucleus contained clearly condensed chromatin or cells exhibiting fragmented nuclei were scored as apoptotic . apoptotic data are reported as percentage of apoptotic cells in a given cell population sample . for each sample , a minimum of 3 counts involving a minimum of 100200 cells / count were scored . antibodies used to detect pro- and cleaved caspase 3 ( sc - 7148 ) , pro- and cleaved caspase 9 ( sc - 8355 ) , ha - probe ( sc - 805 ) , survivin ( sc - 17799 ) , erbb - 2 ( sc - 284 ) , erbb - 3 ( sc - 285 ) , erbb - 4 ( sc - 283 ) , and parp ( poly ( adp - ribose ) polymerase ) ( sc - 7150 ) , were purchased from santa cruz biotechnology , ( santa cruz , ca ) . antibodies used to detect pro- and cleaved caspase 8 ( # 9746 ) , phospho - akt ( ser 473 ) ( # 9271 ) , akt ( # 9272 ) , phospho - gsk - 3 / ( ser 21/9 ) ( # 9331 ) , gsk - 3 ( # 9332 ) , and erbb1 ( # 2232 ) were purchased from cell signaling technology ( beverly , ma ) . monoclonal antibody to human flip was purchased from alexis biochemical ( alx - 804 - 428 - c050 ) ; and gapdh was made in - house . proteins were separated by using 1015 % sds - page under reducing conditions and were electroblotted onto a nitrocellulose membrane . immunoblotting was performed using primary rabbit or mouse antibodies and peroxidase - conjugated goat antirabbit or antimouse , respectively , as the secondary antibodies ( jackson immunoresearch laboratory , west grove , pa ) at a 1 : 2000 dilution , followed by detection with ecl ( pierce , rockford , il ) . quantification of band intensity was performed using scion image software ( scion corporation , frederick , md ) . erbb2 and erbb3 sirna duplexes were synthesized by qiagen ( valencia , ca , usa ) . the targeted sequences ( sense strand were as follows : erbb3 : aagagcgactagacatcaagc ; nonsilencing control sirna ( sc - 37007 ) was from santa cruz biotechnology , ( santa cruz , ca ) : cells were permitted to attach overnight and then were transiently transfected with erbb2 , erbb3 or non - silencing control sirnas at a final concentration of 30 nm in lipofectamine 2000 reagent from invitrogen corporation ( carlsbad , ca ) following manufacturer 's instructions . after one day transfection , the cells were recultured in 100 mm dish at 210 cells / dish for western blot and 1.510 / 12 well plate for apoptosis . the hemagglutinin epitope - tagged constitutively active ( myr ) - akt2 construct , ha - myr - akt2 , and wildtype survivin expression plasmids were kindly provided by dr . jin q. cheng ( department of pathology , molecular oncology , and drug discovery programs , university of south florida college of medicine , h. lee moffitt cancer center and research institute , tampa , fl ) . the constitutively active akt is tagged at the carboxy - terminus with a hemagglutinin epitope tag and is modified at its aminoterminus with the c - src - derived myristylation signal ( mgsskskpk ) . the wildtype survivin expression plasmid was created by subcloning a pcr product of survivin into myc - tagged pcdna3 .1 and confirmed by dna sequencing analysis . the wildtype his - tagged flip expression construct , pcdna3.1 - his - cflip - l , was kindly provided by dr . the pegfp - c1 vector ( clontech , mountain view , ca ) was used to express enhanced green fluorescent protein ( egfp ) in cells as a measure of transfection efficiency . the pcdna3 .1 expressionxiaofeng li ( md anderson cancer center ) , and the expression construct of erbb2 was kindly provided by dr . atanasio pandiella ( instituto de microbiologia bioquimica and centro de investigacion del cancer , csic , universidad de salamanca , salamanca , spain ) . a2780s and a2780 / cp70r cells were plated at 1.510 cells / 100 mm cell culture dishes for western immunoblot analyses and at 1.510 cells / well in 12 - well plates for apoptosis analyses . cells were permitted to attach overnight and then were transiently transfected with mammalian expression vectors or appropriate vector control . briefly , cells were washed two times with serum - free media ( rpmi ) and were incubated with 0.5 ml of serum - free media ( opti - mem i , gibco , grand island , ny ) containing 100 l of dna / lipofectamine / plus ( invitrogen , carlsbad , ca ) complex for apoptosis studies , and 4 ml of serum free medium ( mem - option ) containing 800 l of dna / lipofectamine / plus complex for western immunoblot studies . dna / lipofectamine / plus reagent complex was made by first mixing 0.7 g of dna / 50 l of serum - free medium with 5 l of plus reagent followed by 15 - minute incubation , and then mixing the dna / plus reagent with 2 l of lipofectamine reagent / 50 l of serum - free media followed by 14 - minute incubation . after overnight transfection , cells were treated with - tea for 2 days before analyses for apoptosis or for 12 hours before western immunoblot analyses . all experiments were performed two or more times and experimental results were analyzed for statistical significance using 2 - tail t test . the significance level was set at p .05 . cells in monolayer cultures were treated with - tea ( 0 , 1.25 , 2.5 , or 5 m for a2780s or 0 , 2.5 , 5 , or 10 m for a2780 / cp70r cells ) for 1 , 2 , or 3 days , and viable cell numbers were determined by mts assay . as illustrated in figure 1 ( a ) , - tea decreased viable a2780s and a2780 / cp70r cell numbers in a dose - and time - dependent manner . to confirm that the reduction in cell viability following - tea treatment was due to the induction of apoptosis , cells were treated with different levels of - tea for 1 , 2 , and 3 days , and apoptosis was measured by morphological analyses of cells stained with the dna dye dapi ( figure 1 ( b ) ) . a2780s cells treated with 2.5 , 5 , 10 , or 20 m - tea for two days exhibited dose dependent apoptosis of 16 , 34 , 72 , and 98 % apoptotic cells ; whereas , a2780 / cp70r cells treated with two - fold higher levels of - tea ( namely , 5 , 10 , 20 , or 40 m ) for two days exhibited dose dependent apoptosis of 5 , 34 , 75 , and 97 % apoptotic cells ( figure 1 ( b ) ) . ec50 values for 2 - day - tea treatments of a2780s and a2780 / cp70r cells were 5.6 and 13 m , respectively . vehicle control treated cells of either type exhibited a low background level of apoptosis of approximately 4 % . since treatment of a2780 and a2780 / cp70r with 20 and 40 m - tea , respectively , induced optimal amounts of apoptosis , these two different concentrations were used for all the following mechanistic studies . treatment of both cell lines with - tea decreased protein levels of flip - l , flip - s and survivin in a time - dependent manner ( figure 2 ( a ) ) . to assess the importance of flip and survivin to - tea - induced apoptosis , cells were transiently transfected with wild - type , his - tagged flip - l , myc - tagged survivin or empty vector ( pcdna3 ) , and treated with either vehicle control or - tea for 24 hours . percentage of apoptotic cells were determined ( figure 2 ( b ) ) and level of ectopically expressed proteins were measured ( figure 2 ( c ) ) . overexpression of either wild - type flip - l or wild - type survivin in both cell lines significantly suppressed - tea - induced apoptosis , compared to empty vector control ( p .001 ; figure 2 ( b ) ) , demonstrating that ectopic expression of flip - l or survivin rescues cells from - tea - induced apoptosis . western blot analyses confirmed that transfections yielded high levels of the ectopically expressed proteins ( figure 2 ( c ) ) . please note , the western blot depicted in figure 2 ( c ) is from a short exposure time that is inadequate for visualizing endogenous wildtype survivin expression . these results demonstrate that - tea downregulation of flip - l and survivin is required , at least in part , for maximum induction of apoptosis . - tea decreased the levels of phospho - akt ( ser 473 ) while having no major effect on levels of total akt protein expression in both ovarian cancer cell types in a time - dependent manner ( figure 3 ( a ) ) . to verify that the decrease in phosphorylation status of akt is correlated with decreased kinase activity , the phosphorylation status of gsk3 , a substrate of akt , was assessed following - tea treatments . reduced phosphorylation status of pgsk3 ( ser 9 ) was detected with little to no corresponding decreases in protein levels , indicating that - tea treatments inhibited akt activity ( figure 3 ( a ) ) . studies were conducted to determine if - tea downregulation of flip and survivin is mediated by akt . a constitutively active form of akt2 ( ha - myr - akt2 ) was overexpressed in both cell types . data show that cells transfected with the constitutively active form of akt exhibited inhibition of - tea 's ability to reduce flip and survivin expression ( figure 3 ( b ) ) . these data suggest that akt is an upstream mediator for both flip and survivin and - tea downregulation of flip and survivin is mediated via suppression of akt . to further investigate the function of active akt in the regulation of flip and survivin , we used pi3k inhibitors ly294002 and wortmannin to determine whether reduced akt activity effects - tea - induced apoptosis and flip and survivin protein expression . data show that both ly294002 and wortmannin effectively inhibited the levels of phosphorylated akt and gsk3 in both cell lines without markedly changing total protein levels ( figure 3 ( c ) , first to fourth panels ) . likewise , flip and survivin expression levels were decreased by treatment with either pi3k inhibitor or - tea singly , and further decreased by co - treatments ( figure 3 ( c ) , fifth and sixth panels ) . cleavage of caspases - 8 , -9 , and -3 were enhanced by combination treatments . likewise , parp proteolytic cleavage as a measure of apoptosis showed that ly294002 and wortmannin augmented the apoptotic response induced by - tea ( figure 3 ( c ) , last 4 panels ) . erbb family members play important roles in regulating epithelial cell proliferation and survival via their downstream mediators , including pi3k / akt . therefore , we investigated whether - tea suppresses akt / flip and survivin pathways via targeting erbb family members in a2780s and a2780 / cp70r cells . western immunoblot data ( figure 4 ) show that a2780s cells expressed undetectable erbb1 and lower levels of erbb2 and erbb3 in comparison with a2780 / cp70r cells . - tea at 20 or 40 m for 3 , 6 , 9 , or 12 hours in a2780s and a2780 / cp70r , respectively , decreased erbb1 ( a2780 / cp70r ) , and erbb2 and erbb3 in both cell lines ( figure 4 ) . gapdh levels were used to normalize densitometric values for any variation in lane loads . in this study , we tested if - tea down regulation of erbb2 or erbb3 contributes to - tea - induced suppression of pakt and - tea - mediated apoptosis . first , we examined the effects of functional knockdown of erbb2 or erbb3 using sirna . data show that erbb2 and erbb3 targeted sirnas produced reductions in levels of pakt in comparison to nonsilencing sirna treated controls ( figure 5 ( a ) ) . as predicted , knockdown of erbb2 and erbb3 enhanced - tea suppression of pakt and increased - tea - mediated apoptosis as measured by parp - cleavage ( figure 5 ( a ) ) . as shown in figure 5 ( b ) , erbb2 and erbb3 were successfully over expressed and - tea 's ability to reduce pakt levels and induce apoptosis were diminished but not totally eliminated , suggesting that - tea might still be an effective anticancer agent even in cases of highly elevated erbb mediated survival . collectively , these results show that erbb2 and erbb3 control basal , constitutively active levels of pakt and down regulation of erbb2 and erbb3 contributes to - tea - induced suppression of pakt and induction of apoptosis in both a2780s and a2780 / cp70r human ovarian cancer cells . conversely , ectopic over expression of erbb2 or erbb3 limited - tea 's ability to induce apoptosis . data in this paper showed the following : ( i ) - tea is an effective stand alone anticancer agent for human ovarian cancer cell lines in that it inhibits both cisplatin - sensitive and - resistant ovarian cancer cells growth in culture by both decreasing cell proliferation and inducing apoptosis . ( ii ) the downregulation of erbb2 and erbb3 / akt / flip and survivin signaling events is necessary for - tea - induced apoptosis , and ( iii ) erbb1 is highly expressed in the a2780 / cp70r cells and below levels of detection in the a2780s cells , suggesting that erbb1 may play a role in cisplatin resistance . taken together with previous data that showed that - tea induces apoptosis via fas fas ( cd95 ) / fasl mitochondrial dependent signaling events , we have summarized our current understanding of - tea induced apoptosis in human ovarian cancer cells in figure 6 . - tea is an effective anticancer agent not only because it triggers apoptosis via activation of membrane death receptor fas ( cd95 ) - mediated proapoptotic signaling but also because it downregulates erbb family members and their downstream antiapoptotic effectors . previously , we reported that - tea in combination with cisplatin significantly reduced a2780 / cp70r ovarian cancer tumor burden and lung metastasis in comparison to single treatments , and that the apoptotic properties of - tea in human ovarian cancer cells was mediated , at least in part , via fas ( cd95 ) mitochondrial - dependent apoptotic signaling pathway . studies by shanker et al . showed that the succinate analog of rrr -- tocopherol , vitamin e succinate , in cell culture inhibited the growth of mdah2774 human ovarian tumor cells via extrinsic and intrinsic apoptotic pathways . in a study that compared the efficacy of - tea versus vitamin e succinate , we showed - tea was a more effective anticancer agent because esterase activity in ovarian cancer cells clipped off the succinic moiety of vitamin e succinate , yielding rrr -- tocopherol which does induce apoptosis . the ability of - tea to induce apoptosis in human ovarian cancer cell lines is not restricted to a2780 and a2780 / cp70r cells but has been shown in a number of human ovarian cancer cell lines including 2008 , 2008 - c13 , hey , ovca - 429 , ovca - 433 , ovca - 432 and sk - ov - 3 . the ability of - tea to induce apoptosis in both a2780s and a2780 / cp70 ovarian cancer cells requires both downregulation of erbb - mediated prosurvival factors ( erbb / akt / flip and survivin ) and activation of fas - mediated mitochondrial dependent apoptosis , two complementary and necessary events . the membrane associated epidermal growth factor receptor family ( erbb ) members possess protein tyrosine kinase activity , are involved in cell survival and proliferation and are amplified in many cancers . amplification of erbb2 protein is found in approximately one third of ovarian cancers and is an indicator of poor prognosis in advanced disease . erbb2 initiates several signaling networks involved in a variety of cellular processes , including pi3k / akt . akt is constitutively active in ovarian cancers , and contributes to tumor cell survival by promoting the expression of survivin . although direct measurements of akt activity were not performed , decreased phosphorylation status of a downstream target of akt , namely gsk3 was observed following - tea treatment , indicating that - tea - is downregulating akt activity . akt was shown to play a role in - tea induced apoptosis since expression of constitutively active akt2 partially prevented - tea - induced apoptosis , and chemical inhibition of the pi3k / akt pathway augmented - tea - induced apoptosis as measured by caspase - 8 and casapse - 9 activation , as well as parp cleavage . furthermore , the ability of - tea , via downregulation of akt , to reduce flip and survivin provide further evidence that erbb / akt / flip / survivin signaling events help maintain ovarian cancers . based on studies reported here that suppression of akt , flip or survivin in the absence of - tea did not induce apoptosis , suggests that these ovarian cancer cells are not addicted to pi3k / akt / cflip / survivin for survival . rather data show that suppression of erbb / akt / flip / survivin antiapoptotic pathway cooperates with - tea - induced death receptor - mediated mitochondrial - dependent apoptotic cascade to sensitize the cells to cell death signals . as depicted in figure 6 , inhibition of flip and survivinare predicted to impact the death signaling pathway at both initiation ( caspase 8 ) and execution ( caspases 9 and 3 ) phases . both flip and survivin have been implicated in contributing to cisplatin resistance in ovarian cancer . therefore , downregulation of erbb / akt / flip and survivin prosurvival pathway by - tea not only enhances - tea - induced apoptosis but may also sensitize ovarian cancer cells to other proapoptotic agents . aberrant activation of erbb receptors and downstream pi3k / akt signaling contributes to the development of many cancers , including ovarian cancer . this report demonstrates that - tea is a potent inducer of apoptosis in both cisplatin - sensitive and - resistant human ovarian cancer cell lines in culture . - tea 's ability to initiate apoptosis is enhanced by its ability to downregulate erbbs and subsequent downstream prosurvival mediators , akt , and akt mediated flip and survivin , yielding a dual - acting agent . a more complete understanding of - tea 's multiple actions , not only adds to our basic understanding of dysregulated signaling in cancer pathophysiology but hopefully will aid in selecting the proper application of - tea in the clinic .\noutput:\n" }, { "from": "agent", "value": "rrr -- tocopherol derivative - tea ( rrr -- tocopherol ether - linked acetic acid analog ) has been shown to be a potent antitumor agent both in vivo and in vitro . in this study , we investigated the effects of - tea on the expression of epidermal growth factor receptor ( egfr ) family members , erbb1 , 2 and 3 , and the role of erbb 2 and 3 in - tea - induced apoptosis and suppression of akt , flip and survivin in the cisplatin - sensitive ( a2780s ) and - resistant ( a2780 / cp70r ) human ovarian cancer cell lines . data show that - tea 's ability to induced apoptosis was associated with reduced expression of erbb1 ( cisplatin - resistant cells ) , 2 and 3 ( both cell types ) and reduced levels of the phosphorylated ( active ) form of akt ; as well as , reduced levels of flip and survivin proteins in both cell types . ectopic overexpression and sirna knockdown studies showed that erbb2 , erbb3 , akt , flip and survivin are involved in - tea - induce apoptosis and that - tea downregulates flip and survivin via suppression of pakt , which is mediated by erbb2 and erb3 . thus , - tea is a potent pro - apoptotic agent for both cisplatin - sensitive and - resistant ovarian cancer cell lines in cell culture and it produces cell death , at least in part , by downregulation of members of the egfr family ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the natural ends of chromosomes must be distinguished from intrachromosomal dna double - strand breaks ( dsbs ) , which activate a dna damage response ( ddr ) including checkpoint - mediated cell cycle arrest and dna repair / recombination pathways . protection of chromosome ends , referred to as capping , is achieved by packaging into protective structures called telomeres . a number of proteins bind the telomeric dna and protect it from fusion , degradation , and recognition as a dsb that would otherwise lead to chromosome instability and cell death . in most eukaryotes , telomeric dna is highly repetitive and consists of short tg - rich nucleotide repeats in the strand running 5 to 3 toward the chromosome end . in addition to double - stranded telomeric dna , the 3 end ( g - strand ) extends beyond its complementary strand ( c - strand ) to form a single - stranded overhang called the g - tail . most telomeric dna is replicated by standard semiconservative dna replication . as dna polymerases replicate dna only in the 5 to 3 direction and need a primer to initiate dna synthesis , removal of the terminal rna primer at the 5 ends of newly replicated strandsleaves a gap that can not be filled in by the canonical dna replication machinery . as a result , telomeric dna sequences become shorter with each round of dna replication . in most eukaryotes , this loss of telomeric dna is counteracted by a ribonucleoprotein enzyme called telomerase , which uses its rna component as a template to add telomere repeats at the telomeric 3 overhang in a reverse transcriptase reaction . in mammalian cells , the minimal catalytic core of telomerase consists of the telomerase reverse transcriptase ( tert ) and the telomerase rna ( terc ) . in saccharomycescerevisiae , the telomerase consists of the reverse transcriptase est2 , the template rna tlc1 , and two accessory proteins est1 and est3 . telomeres can function both as tumor suppressors by limiting the number of cell divisions and as tumor promoters by inducing genome instability . although telomerase is continuously expressed in unicellular eukaryotes , its expression is downregulated in most human somatic tissues . the inability of the replication machinery to fully replicate dna ends , coupled with low / absent telomerase activity , results in progressive telomere shortening that causes cells to stop dividing in a process called replicative senescence . this phenomenon was first described by hayflick and moorhead , who reported that cultured human fibroblasts undergo only a limited number of cell divisions and then stop dividing . similarly , elimination of telomerase in s. cerevisiae leads to progressive telomere shortening and loss of viability within approximately 6080 population doublings , indicating that replicative senescence also occurs in this unicellular eukaryote . in both organisms , loss of telomeric dna repeats results in telomere uncapping that activates a dna damage checkpoint response , which in turn leads to cell cycle arrest and senescence . in the absence of other genetic changes , these cells can remain in a quiescent state that essentially functions as an anticancer mechanism for long - lived species like humans . however , genetic alterations that cause a failure to activate the checkpoint response may allow additional cell divisions , during which the dysfunctional telomeres continue to erode until they eventually become too short to protect the chromosome termini from unscheduled dna repair events . the cells then enter a period called crisis , during which the chromosomes ends undergo end - to - end fusion events and enter a breakage - bridge fusion cycle that leads to genomic instability . although cells entering this state can be eliminated by apoptosis , most cancer cells exhibit upregulation of telomerase activity , indicating that rare surviving cells can avert senescence and crisis by restabilizing telomeres . in this review , we discuss the mechanisms by which telomeres are capped in s. cerevisiae and mammals and the consequences of telomere uncapping for genome stability and carcinogenesis . the presence of telomeres distinguishes natural chromosome ends from internal chromosome breaks , which are potent stimulators of the ddr . the ddr comprises pathways that repair dna lesions and surveillance mechanisms called dna damage checkpoints that inhibit cell cycle progression until dsbs are repaired . repair of dna dsbs can occur by either non - homologous end joining ( nhej ) , which results in ligation of the broken ends , or homologous recombination ( hr ) , which uses a homologous dna sequence to restore the genetic information lost at the break site . the choice of pathway for dsb repair is regulated during the cell cycle , with hr occurring preferentially during s / g2 . this cell cycle specificity is mediated by cyclin - dependent kinases ( cdks ) , which promote the nucleolytic degradation ( resection ) of the 5 dsb ends to yield 3 - ended single - stranded dna ( ssdna ) tails that initiate hr and concomitantly inhibit nhej . when a dsb occurs , the mrx / mrn complex ( mre11 - rad50 - xrs2 in yeast ; mre11 - rad50 - nbs1 in mammals ) and the ku70 / ku80 heterodimer ( hereafter referred to as ku ) are recruited to the break site . ku allows nhej by promoting the binding of nhej factors and by protecting the dsb ends from degradation during the g1 phase of the cell cycle . the mrx / mrn complex , in combination with the sae2 / ctip protein , is important for initiating resection of the dsb ends to generate 3 - ended ssdna overhangs that direct repair toward hr . subsequent extensive nucleolytic degradation of the dsb ends is performed by two pathways , one of which is dependent on the 5 - 3 exonuclease exo1 , while the other depends on the nuclease / helicase dna2 acting in conjunction with the recq helicase sgs1 / blm . dsbs also elicit a checkpoint response ; key players in this response include the protein kinases mec1 and tel1 in s. cerevisiae , or the respective mammalian orthologs atr and atm . tel1 or atm is recruited to unprocessed or minimally processed dsbs via the mrx / mrn complex . upon generation of ssdna , mec1 / atr kinase activity is additionally boosted by the heterotrimeric 9 - 1 - 1 complex ( rad17 , mec3 , and ddc1 in s. cerevisiae ) , which is loaded onto rpa - coated ssdna by the rad24 - rfc complex . once tel1 / atm and / or mec1 / atr are activated by damaged dna , their checkpoint signals are propagated through the protein kinases rad53 and chk1 ( chk2 and chk1 in mammals , respectively ) , whose activation requires conserved mediator proteins , including the brct domain containing protein rad9 and its metazoan ortholog 53bp1 . in turn , both s. cerevisiae rad9 and human 53bp1 limit the generation of ssdna at the dsb ends by acting as barriers toward end - processing enzymes . once recruited to dsbs , tel1 / atm facilitates the activation of mec1 / atr , possibly by facilitating generation of the ssdna that transforms the dsb ends from tel1 / atm substrates to mec1 / atr substrates . in turn , s. cerevisiae mec1 / atr inhibits the generation of ssdna at dsbs , thus preventing excessive nucleolytic degradation of the dsb ends . as the single - stranded 3 overhangs increase in length , mec1 / atr activation is coupled with ssdna - dependent loss of tel1 / atm activation , and this resection - mediated switch from tel1 - to mec1 - dependent signaling activity ensures proper termination of the checkpoint response . the ends of eukaryotic chromosomes are not subjected to dna repair events and do not activate the ddr , despite being physical dna ends . several studies on s. cerevisiae and mammals have revealed that protein complexes with specificity for double - stranded and single - stranded telomeric dna prevent the natural chromosome ends from being recognized as intrachromosomal dsbs ( fig . 1 ) . in s. cerevisiae , the telomeric ssdna is bound by cdc13 , which can be found with stn1 and ten1 in a heterotrimeric complex called cst . cst protects telomeric dna from degradation ; exposure of cells harboring cdc13 , stn1 , or ten1 conditional alleles to restrictive conditions causes telomere degradation by progressive resection of the 5 - ended strand and a checkpoint - dependent cell cycle arrest . the 5 - 3 exonuclease exo1 appears to be the major nuclease that degrades telomeres in cdc13 mutants . as cdc13 binding to the single - stranded telomeric dnareduces the association of mec1 with these dna ends and the cst complex bears a structural resemblance to the rpa complex , cst binding to the telomere has been proposed to prevent rpa recruitment and subsequent mec1 activation . a cst - like complex ( ctc1 - stn1 - ten1 ) has recently been identified in s. pombe , plants , and humans and shown to perform a similar function in telomere capping and telomerase regulation . cerevisiae , rap1 and rif2 inhibit 5 - 3 resection of the telomeric dna ends and also repress the nhej repair pathway . rif1 supports the function of the cst complex in preventing excessive resection at telomeric ends and mec1 - dependent checkpoint activation . in humans , trf2 represses atm signaling and the nhej pathway , whereas pot1 prevents atr activation by inhibiting the binding of the ssdna - binding protein rpa . atm , ataxia telangiectasia mutated ; atr , ataxia telangiectasia and rad3 - related protein ; cst , cdc13 , stn1 , and ten1 ; hr , homologous recombination ; nhej , non - homologous end joining ; rpa , replication protein a. double - stranded telomeric dna in s. cerevisiae is bound by the rap1 - rif1 - rif2 complex . loss of function of this complex has less catastrophic consequences than cst inactivation ; dysfunction of rap1 or rif2 leads to increased amounts of telomeric ssdna and nhej - mediated fusion events . generation of telomeric ssdna in cells defective for rif2 or rap1 requires the mrx complex , suggesting that rap1 and rif2 prevent resection at telomeric ends by interfering with the association between mrx and telomeres . on the other hand , inactivation of rap1 or rif2does not leads to checkpoint activation , suggesting that the exposed telomeric ssdna is still covered by cdc13 , which limits association of mec1 with telomeres . unlike rif2 and rap1 , rif1 is not involved in the prevention of telomeric fusions by nhej and plays a very minor role in protecting telomeres from degradation . instead , rif1 prevents short telomeric ends from activating checkpoint - mediated cell cycle arrest by inhibiting the recruitment of checkpoint proteins to these ends . furthermore , it plays a unique role in supporting cell viability and prevents nucleolytic degradation in mutants defective in the cst complex . interestingly , both cst and rif1 physically and genetically interact with components of the pol - primase complex , raising the possibility that rif1 might promote the ability of cst to fill in the exposed telomeric ssdna through activation / recruitment of the lagging - strand dna replication machinery . degradation of telomeric dna is also counteracted by the ku complex , which acts in a different pathway from rif2 . in fact , while mrx is primarily responsible for nucleolytic degradation of telomeres in rif2 cells , exo1 is the nuclease that degrades telomeric dna in yku70 g1 cells . interestingly , ku protects telomeres in the g1 phase of the cell cycle , when the protective function of cst is dispensable . in vertebrates , telomeres are protected from eliciting the ddr and undergoing degradation or fusion events by a specialized group of proteins collectively called shelterin , which includes trf1 , trf2 , rap1 , tin2 , tpp1 , and pot1 ( fig . 1 ) . although the shelterin complex represents a functional unit , the individual components have specific protective functions . inactivation of trf2 in mouse embryo fibroblasts by either gene deletion or overexpression of a dominant - negative variant causes activation of atm , as well as accumulation of telomere - induced foci formed by ddr factors such as 53bp1 , mrn , atm , and the histone variant h2ax . moreover , trf2 also protects telomeres from nhej - mediated fusion events . in mammals , the telomeric single - stranded overhang can fold back on the double - stranded part of the telomere to form a lariat structure , called a t - loop , which is predicted to prevent the binding of dna repair / checkpoint proteins to the telomeric dna . as trf2 is required for the formation and / or maintenance of t - loops , trf2 - dependent remodeling of telomeres into t - loop structures might explain how trf2 represses nhej and atm signaling at telomeres . based on the finding that pot1 specifically recognizes the telomeric ssdna overhangs , it has been proposed that pot1 and pot1a block atr activation by preventing rpa binding to the telomeric ssdna . this switch from rpa to pot1 on telomeric ssdna is promoted by the heterogeneous nuclear ribonucleoprotein a1 ( hnrnpa1 ) protein through a mechanism that is regulated by telomeric repeat containing rna ( terra ) , a non - coding rna that is transcribed from the telomeric c - rich strand . inhibition of rpa binding by pot1 may also play an important role in preventing hr , which is repressed at telomeres in a redundant manner by pot1 and rap1 . even when mouse telomeres are stripped of shelterin and ku , complete loss of telomeric dna does not occur unless the dna damage response protein 53bp1 is also depleted , suggesting that multiple pathways act in a highly redundant manner to block telomere degradation . a major focus in telomere biology is to understand the structural changes occurring in the switch from a protected to a deprotected state . telomere deprotection can occur by either altering the activities of proteins with capping functions or by erosion of the telomeric dna that occurs spontaneously in human cells with each cell division . furthermore , both elicit a dna damage checkpoint response that leads to cell cycle arrest ( fig . 2 ) . however , although depletion of shelterin leads to acute deprotection that results in telomere fusions and rampant genome instability , the checkpoint elicited by critically short telomeres in aged human cells initiates replicative senescence , during which telomeres accumulate h2a and 53bp1 but do not undergo fusion events . to explain this difference , , the closed state corresponds to a shelterin - and length - dependent structure that protects chromosome ends from eliciting the ddr . telomere shortening disrupts this structure leading to an intermediate state , in which telomeres are recognized as dna damage and induce the ddr , but retain sufficient shelterin proteins to prevent nhej - mediated fusions . further shortening results in an uncappedstate , in which the amount of shelterin is not sufficient to prevent chromosome end - to - end fusions . in agreement with the existence of an intermediate state , telomeres from senescent cells retain sufficient telomeric dna to bind trf2 and confer protection from nhej . in addition , telomere fusions only occur in cells that have bypassed senescence as a result of checkpoint deactivation . interestingly , it has recently been shown that two distinct regions within trf2 are required to inhibit atm signaling and nhej , respectively . while atm is inhibited by the trfh dimerization domain , nhej repression depends on the c - terminal region of the hinge domain , which acts by inhibiting the ubiquitin ligase rnf168 that is necessary for the recruitment of 53bp1 . although intrachromomal double - strand breaks ( dsbs ) elicit a checkpoint response and can be repaired , the natural chromosome ends are protected from fusion and degradation and do not activate the checkpoint . this protective function , referred to as capping , is due to proteins that bind the telomeric dna . loss of capping due to either deficiences in capping proteins or loss of telomeric dna induces a dna damage checkpoint response that leads to cell cycle arrest and senescence , thus providing a potent anticancer mechanism . however , rare failure to activate the checkpoint may allow cells to undergo cell divisions during which uncapped telomeres can be subjected to unscheduled dna repair events . the resulting genomic instability , coupled with activation of telomere restabilizing mechanisms , can drive the oncogenic process . the signal ( s ) that trigger the checkpoint response in senescent cells are far from being fully understood . in mammals , senescence is not determined by the average telomere length , but by the presence of telomeres that are short enough to trigger the ddr . analysis of dysfunctional telomeres with increased population doubling in a variety of human primary cells has shown that the threshold of dna damage signaling corresponds to an average of five dysfunctional telomeres . critically short telomeres are also the major determinant of senescence onset in s. cerevisiae , in which the artificial shortening of a single telomere is sufficient to accelerate the onset of senescence in cells lacking telomerase activity . analysis of telomeres of different lengths in s. cerevisiae cells deprived of telomerase activity has shown that 5 - 3 resection is stimulated at the shortest telomeres , suggesting that an excessive amount of ssdna at telomeres could be the signal triggering checkpoint activation and senescence initiation . consistent with this hypothesis , replicative senescence is regulated by proteins that modulate generation of ssdna at the dsb ends . in fact , the onset of senescence is delayed when the mrx complex , which is known to transiently increase the generation of ssdna at telomeres , is defective . in contrast , senescence is accelerated in the absence of rif2 , which is known to inhibit mrx - mediated resection at telomeres by competing with tel1 for binding to xrs2 . finally , this severe senescence phenotype is reversed by the loss of mrx or tel1 . together , these data suggest that short telomeres become more accessible to the action of nucleases and thus accumulate ssdna that activates the checkpoint . moreover , telomeres might have a role in senescence establishment independent from their shortening / uncapping functions . telomeric dna has been shown to resist dna damage repair and trigger persistent ddr , possibly through the inability to repair dna lesions . these data raise the possibility that telomeres might act as sinks of dna damage that are capable of triggering senescence in nonproliferating tissues . the occurrence of telomere erosion in cancer is evidenced by typically short telomeres in most human cancers relative to normal tissues . although telomerase is constitutively expressed in unicellular eukaryotes , its expression is downregulated in most somatic human tissues , resulting in progressive reduction of telomere repeats at each dna replication cycle . when telomeres become critically short , cells can undergo one of two opposing fates ( fig . 2 ) . dysfunctional telomeres can activate a dna damage checkpoint response that causes cell cycle arrest and entry into senescence , thus preventing cell proliferation . this limit to the number of cell divisions represents an important barrier against cancer because it reduces the risk of accumulating mutations that could lead to malignant transformation . on the other hand , rare cells that have inactivated the checkpoint responseovercome the senescence barrier and continue to divide , resulting in total loss of telomere function . continued telomere erosion could result in high genomic instability that generally results in cell death and therefore constrains full malignant progression . however , the very few cells capable of surviving this period can display a procarcinogenic mutator phenotype . thus , although telomere shortening and repression of telomerase can represent protective mechanisms against cancer development , the associated genome instability has a cancer promoting activity and the stepwise removal of telomere protection provides a mechanism to block cell division before excessive telomere shortening endangers genome stability . indeed , experiments to measure genome stability during telomere shortening demonstrate that s. cerevisiae cells lacking telomerase exhibit increased chromosome rearrangements compared with telomerase - positive cells , with sequence losses being more frequent at the ends of the chromosomes than at internal sites . furthermore , telomere dysfunction in aging telomerase - deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion - bridge breakage . finally , high - resolution analysis of telomere length at different stages of the hematologic malignancy chronic lymphocytic leukemia have shown that telomere erosion and fusion events can be detected in the early stages of the disease and strongly correlate with disease progression . although tumors may arise from cells with eroded telomeres , indicating that telomere dysfunction can drive early stages of cancer development , almost all human cancer cells acquire mechanisms to elongate their telomeres and overcome senescence , suggesting that subsequent restoration of telomere function is critical for malignant progression . most human cancers maintain their telomeres through reactivation of telomerase but on rare occasions telomeres can be elongated through a homologous recombination - mediated process called alternative lengthening of telomeres ( alt ) . the existence of a telomerase - independent telomere maintenance mechanism was first demonstrated in telomerase - negative s. cerevisiae cells . this mechanism was found to be dependent on hr , although other mechanisms have been identified . supporting the view that telomerase serves as an active driver of cancer progression in cells displaying telomere - based genome instability , expression of an engineered inducible version of telomerase in mouse models of prostate cancer and t - cell lymphoma leads to aggressive cancers with rearranged genomes and new tumor biologic capabilities ( i.e. , bone metastases ) . upon subsequent telomerase extinction tumor growth eventually slows , suggesting that tumor progression is constrained by the lack of telomerase . however , growth can subsequently resume as tumors activate alt and other adaptive responses , suggesting that therapies targeting telomere maintenance in cancer should encompass inhibitors of telomerase and inhibitors of alt . uncapping of telomeres as a result of repressed telomerase activity in humans represents a protection mechanism against cancer because it activates the ddr that arrests the cell cycle and initiates senescence . however , proliferation beyond this limit may drive genomic instability that , coupled with the activation of telomere maintenance mechanisms , can lead to malignant transformation . an outstanding gap in our knowledge is the role of telomerase activation in the suppression of genome instability . if telomerase activation provides stability to the genome of a cancer cell , telomerase - based therapies might be effective strategies to limit tumor progression specifically in cancer cells . however , as tumor cells lacking telomerase might activate alternative pathways to maintain their telomeres and gain immortal growth capacity , development of successful therapeutic strategies targeting telomere maintenance in cancers requires a deep understanding of how these mechanisms are activated . we thank giovanna lucchini for critical reading of the manuscript . work in the laboratory of m.p.l . is supported by grants from associazione italiana per la ricerca sulcancro ( airc ) ( grant ig11407 ) and cofinanziamento 20102011 miur / universit di milano - bicocca . c.t . was supported by a fellowship from fondazione italiana ricerca sul cancro ( firc ) . we apologize to all authors whose publications have not been cited because of length limitations .\noutput:\n" }, { "from": "agent", "value": "telomeres are nucleoprotein complexes that protect the natural ends of chromosomes from fusion and degradation and prevent them eliciting a checkpoint response . this protective function , which is called telomere capping , is largely mediated by telomere - binding proteins that suppress checkpoint activation and dna repair activities . telomere dysfunction through progressive shortening or removal of capping proteins leads to a checkpoint - mediated block of cell proliferation , which acts as a cancer - suppressor mechanism . however , genetic alterations that inactivate the checkpoint can lead to further telomere erosion and increased genomic instability that , coupled with the activation of mechanisms to restabilize telomeres , can drive the oncogenic process ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: this girl was born at 39 weeks of gestation to a gravida i para i , 25 - year - old healthy mother and 28 - year - old healthy father , with no history of consanguinity and no remarkable family history . the mother was followed regularly during her pregnancy and had prenatal diagnosis of fetal hydrocephalus at 30 weeks of gestation . the female baby was delivered by cesarean delivery due to fetal distress and was born with apgar scores 8 and 9 at 1 and 5 minutes , respectively . at birth , the baby was noticed to have skin lesion and so she was transferred , at day 1 of life , to the pediatric department at makassed general hospital for further management . upon presentation , the baby had a weight of 3690 g , length of 49 cm , and macrocephaly with head circumference of 37.5 cm ( above the 95th percentile for her age ) . she had flat areas of alopecia on the scalp and multiple small elevated nodules on the right side of the face . nodular lesion at the outer canthus of right eye suggestive of dermoid and reddish lesion on the bulbar conjunctiva suggestive of epibulbar dermoid and aniridia of the right eye were also noted ( figure 1a - c ) . she also had low - set ears with multiple soft subcutaneous masses over the back ( figure 1d ) . there was full passive and active range of motion of the extremities on nervous system examination . a head computed tomography ( ct ) scan was performed , which demonstrated homogeneous low - density lesions in the cistern magna and right cerebellopontine angle indenting smoothly the brachium pontis . the patient underwent magnetic resonance imaging ( mri ) of the head , which showed a lipomatus mass , measured at 2512 mm , seen at the right cerebellopontine angle cistern , indenting smoothly the brachium pontis with no alteration of its signal , also with similar lesions noted in the posterior aspect of foramen magnum ; cervical canal with no bleed , intact brain stem , with atrophic right cerebral hemisphere ; and dilated lateral ventricle and prominent overlying subarachnoid spaces ( figure 2a - d ) . the right periauricular cutaneous lesion was submitted to histopathological examination and showed that the dermis has rudimentary hair follicles surrounded by fibrous connective tissue interpreted by mature fat lobules . the patient was neurologically normal for her age , and no deficiency of the right upper extremity was appreciated during the course of the hospital admission . it was decided to follow the infant closely to observe for increase in her hydrocephalus and for development of any neurological deficit . a and c , clinical photograph showing flat areas of alopecia on the scalp and multiple small elevated nodules on the right side of the face and low - set ears . b , nodular lesion at the outer canthus of right eye suggestive of dermoid and reddish lesion on the bulbar conjunctiva suggestive of epibulbar dermoid and aniridia of the right eye . axial t1 - weighted magnetic resonance imaging of the brain with intravenous contrast showing ( a and b ) the lateral ventricle is dilated and the right cerebral hemisphere is atrophic with prominence of the overlying subarachnoid spaces . imaging studies ( c ) showing a fat containing mass , measured at 2512 mm , is seen at the right cerebellopontine cistern angle , indenting smoothly the brachium pontis with no alteration of its signal , and ( d ) similar lesions are also noted in the posterior aspect of magnum foramen and cervical canal . the patient began to show increase in her head circumference , and neuroimaging showed an increase in the size of her ventricles . at 9 months of age , the patient underwent ventriculoperitoneal shunt and had a significant improvement in motor skills over the following months . the patient could stand independently and was beginning to formulate words at approximately 1 year of age . however , at the age of 1 year 10 months , the patient was admitted with staring , unresponsiveness , and tonic clonic movements associated with weakness in her lower extremities . deep tendon reflexes were hyperactive without clonus ( 3 + ) in both the upper extremities and hyperactive with clonus ( 4 + ) in both the lower extremities , mainly in the left lower limb . electroencephalography ( eeg ) was done , which showed the presence of diffuse slow delta activity related to brain damage ( encephalopathy ) . the patient was started on both phenobarbital and phenytoin , and her seizures were controlled . ultrasound of both kidneys revealed 2 cm cortical cyst in the upper pole of the right kidney . the mri of the spine showed large subpialjuxtamedullary lipoma filling the entire spinal canal , which is widened , and engulfing the spinal cord . the spinal cord is tethered and is remarkably compressed at the thoracic level , displaced to the left and protruding into the left lateral foramina at the level of dorsolumbar junction . the vertebrae are of normal heights and signal , and normally aligned and the discs are unremarkable ( figure 3a and b ) . a , saggital t2 - weighted image showing a large subpial juxtamedullary lipoma filling the entire spinal canal engulfing the spinal cord that is tethered . b , axial t2 - weighted image showing the spinal cord remarkably compressed at the thoracic level displaced to the left and protruding into the left lateral foramina at the level of dorsolumbar junction . this girl was born at 39 weeks of gestation to a gravida i para i , 25 - year - old healthy mother and 28 - year - old healthy father , with no history of consanguinity and no remarkable family history . the mother was followed regularly during her pregnancy and had prenatal diagnosis of fetal hydrocephalus at 30 weeks of gestation . the female baby was delivered by cesarean delivery due to fetal distress and was born with apgar scores 8 and 9 at 1 and 5 minutes , respectively . at birth , the baby was noticed to have skin lesion and so she was transferred , at day 1 of life , to the pediatric department at makassed general hospital for further management . upon presentation , the baby had a weight of 3690 g , length of 49 cm , and macrocephaly with head circumference of 37.5 cm ( above the 95th percentile for her age ) . she had flat areas of alopecia on the scalp and multiple small elevated nodules on the right side of the face . nodular lesion at the outer canthus of right eye suggestive of dermoid and reddish lesion on the bulbar conjunctiva suggestive of epibulbar dermoid and aniridia of the right eye were also noted ( figure 1a - c ) . she also had low - set ears with multiple soft subcutaneous masses over the back ( figure 1d ) . there was full passive and active range of motion of the extremities on nervous system examination . a head computed tomography ( ct ) scan was performed , which demonstrated homogeneous low - density lesions in the cistern magna and right cerebellopontine angle indenting smoothly the brachium pontis . the patient underwent magnetic resonance imaging ( mri ) of the head , which showed a lipomatus mass , measured at 2512 mm , seen at the right cerebellopontine angle cistern , indenting smoothly the brachium pontis with no alteration of its signal , also with similar lesions noted in the posterior aspect of foramen magnum ; cervical canal with no bleed , intact brain stem , with atrophic right cerebral hemisphere ; and dilated lateral ventricle and prominent overlying subarachnoid spaces ( figure 2a - d ) . the right periauricular cutaneous lesion was submitted to histopathological examination and showed that the dermis has rudimentary hair follicles surrounded by fibrous connective tissue interpreted by mature fat lobules . the patient was neurologically normal for her age , and no deficiency of the right upper extremity was appreciated during the course of the hospital admission . it was decided to follow the infant closely to observe for increase in her hydrocephalus and for development of any neurological deficit . a and c , clinical photograph showing flat areas of alopecia on the scalp and multiple small elevated nodules on the right side of the face and low - set ears . b , nodular lesion at the outer canthus of right eye suggestive of dermoid and reddish lesion on the bulbar conjunctiva suggestive of epibulbar dermoid and aniridia of the right eye . axial t1 - weighted magnetic resonance imaging of the brain with intravenous contrast showing ( a and b ) the lateral ventricle is dilated and the right cerebral hemisphere is atrophic with prominence of the overlying subarachnoid spaces . imaging studies ( c ) showing a fat containing mass , measured at 2512 mm , is seen at the right cerebellopontine cistern angle , indenting smoothly the brachium pontis with no alteration of its signal , and ( d ) similar lesions are also noted in the posterior aspect of magnum foramen and cervical canal . the patient began to show increase in her head circumference , and neuroimaging showed an increase in the size of her ventricles . at 9 months of age , the patient underwent ventriculoperitoneal shunt and had a significant improvement in motor skills over the following months . the patient could stand independently and was beginning to formulate words at approximately 1 year of age . however , at the age of 1 year 10 months , the patient was admitted with staring , unresponsiveness , and tonic clonic movements associated with weakness in her lower extremities . deep tendon reflexes were hyperactive without clonus ( 3 + ) in both the upper extremities and hyperactive with clonus ( 4 + ) in both the lower extremities , mainly in the left lower limb . electroencephalography ( eeg ) was done , which showed the presence of diffuse slow delta activity related to brain damage ( encephalopathy ) . the patient was started on both phenobarbital and phenytoin , and her seizures were controlled . ultrasound of both kidneys revealed 2 cm cortical cyst in the upper pole of the right kidney . the mri of the spine showed large subpialjuxtamedullary lipoma filling the entire spinal canal , which is widened , and engulfing the spinal cord . the spinal cord is tethered and is remarkably compressed at the thoracic level , displaced to the left and protruding into the left lateral foramina at the level of dorsolumbar junction . the vertebrae are of normal heights and signal , and normally aligned and the discs are unremarkable ( figure 3a and b ) . a , saggital t2 - weighted image showing a large subpial juxtamedullary lipoma filling the entire spinal canal engulfing the spinal cord that is tethered . b , axial t2 - weighted image showing the spinal cord remarkably compressed at the thoracic level displaced to the left and protruding into the left lateral foramina at the level of dorsolumbar junction . encephalocraniocutaneous lipomatosis is a rare , congenital neurocutaneous syndrome , not inherited in a mendelian fashion . the tissues and organs primarily affected are of ectoderm and mesoderm origin , namely skin , eye , adipose tissue , and brain . encephalocraniocutaneous lipomatosis is limited to one side of the cranium , the face , and brain . the most typical lesions , which occur almost exclusively in this syndrome , are subcutaneous soft tumors , consistent with lipomas , and areas of alopecia ; other common findings are ocular lesions , such as defects of the eyelids and epibulbar dermoids . our patient presented with many of the classic features of encephalocraniocutaneous lipomatosis , such as nevus psiloliparus , ocular lipodermoid , aniridia , bilateral optic disc coloboma , and intracranial and spinal lipomas ( figures 13 ) . these clinical findings are considered major diagnostic criteria by hunter and surpass the requirement of two or more major criteria to make a definitive diagnosis of encephalocraniocutaneous lipomatosis . histopathological examinations of the skin colored papules / nodular tags represent lipomas , fibromas , fibrolipomas , and connective tissue nevi or hamartomatous tissue consisting of cartilage , fat , and connective tissue . the alopecic area of the scalp usually shows focal dermal fibrosis associated with increased amounts of subcutaneous fat extending into the reticular dermis . the first neurological problem that our patient presented with was hydrocephalus , which could be seen on her earliest brain imaging studies ( figure 2 ) . however , the patient had no symptoms of hydrocephalus at initial presentation and was therefore treated with observation . symptoms did not manifest until several months later , and the patient successfully underwent ventriculoperitoneal shunt insertion . hydrocephalus is not an uncommon problem in encephalocraniocutaneous lipomatosis , and several patients with this syndrome have undergone successful placement of ventriculoperitoneal shunts . ventriculomegaly , porencephalic cysts , and macrocephaly are common findings in patients with encephalocraniocutaneous lipomatosis , but not all patients with these findings develop hydrocephalus . hydrocephalus was diagnosed in approximately one - third of patients with encephalocraniocutaneous lipomatosis and ventriculomegaly , making longitudinal observation of these patients necessary to determine who will need shunt placement . our patient had a lipomatus mass at the right cerebellopontine angle with similar lesions noted in the posterior aspect of the forum magnum and cervical canal as shown by her mri of the brain . lipomas were the most prominent feature and were found on neuroimaging in 33 of the 54 patients . intracranial lipomas ( 31 of 54 ) were often located in the cerebellopontine angle ( 19 of 31 ) , which is exceptional because , in general , lipomas are more often found between the hemispheres . at the age of 1 year 10 months , when our patient presented with weakness of her lower extremities , she also had multiple subcutaneous nodules over her back , which were present since birth . the mri of the spine showed large subpialjuxtamedullary lipoma filling the entire spinal canal with tethered spinal cord . spinal lipomas were found in most of the patients when looked for ( 12 of 14 ) , which can extend over the whole length of the spinal cord . both intra - and extramedullary lipomas have been described , most of which are asymptomatic . it is therefore recommended that a spinal mri is performed when encephalocraniocutaneous lipomatosis is suspected . subcutaneous fatty masses can overly be the spinal lipomas or are found next to the spinal cord . surprisingly , tethered cord has not been previously described in encephalocraniocutaneous lipomatosis except in a 3 - month - old boy described by ayer et al , who was diagnosed with encephalocraniocutaneous lipomatosis having intraspinal lipoma associated with tethered spinal cord . he presented at the 19 months of age with progressive lower limb weakness and severe scoliosis . he underwent posterior fossa craniectomy , c1 - c6 laminectomies , and debulking of the cervicomedullary junction lipoma , and he was treated for his scoliosis with a brace . this indicates a rare association between encephalocraniocutaneous lipomatosis and tethered spinal cord syndrome , making our case the second one with this rare association to be described in the literature . our patient developed seizures at the age of 1 year 10 months , which was controlled by antiepileptic medications . upon reviewing the literature , it was found that 27 patients with encephalocraniocutaneous lipomatosis had a history of epileptic seizures and 3 did not ; in 24 patients , no information was given on whether or not seizures occurred . in 9 of the 27 patients with seizures , seizure onset was during the first month of life , in 7 it was during the first year , in 6 after the age of 1 year , and no documentation was given for 5 patients . of the 27 patients , 8 had refractory epilepsy , and , in a further 6 , the seizures were at least difficult to treat . in 13 patients , seizures responded well to antiepileptic treatment . developmental data were available for 45 patients with encephalocraniocutaneous lipomatosis . of these , 13 developed normally up to a reported age ranging from 3 months to 24 years ( mean 7 years ) , 16 cases showed mild retardation , and 16 moderate to severe or unspecified retardation . although serial mri studies of the brain obtained with and without contrast demonstrated no vascular abnormalities , progressive aneurysmal dilation of cerebral vessels has been described in this syndrome , with 1 patient developing subarachnoid hemorrhage . cerebrovascular dysplasia and leptomeningeal angiomas have been described in 9 patients with encephalocraniocutaneous lipomatosis , and vascular anomalies are believed to be responsible for the development of cerebral atrophy , thin white matter , porencephaly , and calcifications that are often seen in the syndrome . our patient has not demonstrated any of these characteristics , but the prevalence of developing these abnormalities over the life span of a patient with encephalocraniocutaneous lipomatosis is unknown . it is something that has to be considered , should there be any changes in neurological status , and may warrant performance of routine surveillance imaging . this case report and review of relevant literature is to describe the first pediatric case from lebanon , presenting with encephalocraniocutaneous lipomatosis . based on the review of the literature , this is the second case with encephalocraniocutaneous lipomatosis associated with tethered spinal cord syndrome . although the incidence of tethered cord syndrome in patients with encephalocraniocutaneous lipomatosis is unknown , it is probably significant . besides , serial observation of patients with ventricular abnormalities is recommended , given that approximately one - third of these patients can develop hydrocephalus . additionally , baseline neuroimaging is part of the initial assessment , but routine serial imaging of lipomas is probably not warranted , given the benign nature of the masses and their documented lack of growth . the monitoring of these patients for signs of myelopathy is probably required for those with imaging findings that are a cause for concern . patients should be monitored for the development of these conditions , and their families should be educated on the signs and symptoms of their development . however , the limited information provided by the literature does not supply enough evidence to support any specific recommendations .\noutput:\n" }, { "from": "agent", "value": "encephalocraniocutaneous lipomatosis or haberland syndrome is a rare , congenital neurocutaneous syndrome . it is characterized by unilateral lipomatous hamartomata of the scalp , eyelid , and outer globe of the eye and ipsilateral neurologic malformations . we describe the first case from lebanon , an infant with classical encephalocraniocutaneous lipomatosis characterized by nevus psiloliparus , unilateral right facial and frontal temporal subcutaneous lipomas , alopecia , ocular coloboma , aniridia and eyelid nodular tags , ventriculomegaly with intracranial and intraspinal lipomas , and tethered spinal cord . we report this case of rare association between encephalocraniocutaneous lipomatosis and tethered spinal cord syndrome and stress on the importance of spinal cord evaluation in encephalocraniocutaneous lipomatosis ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in spite of great advances in the management of heart failure ( hf ) , the prognosis of hf patients remains poor . the reasons for poor prognosis are not clear , but most hf patients have 1 or more disorders in addition to hf , such as chronic kidney disease , hypertension , chronic lung disease , and anemia , which possibly makes hf refractory to treatment . a large proportion of patients with acute decompensated hf ( adhf ) have various degrees of heart and renal dysfunction concomitantly . earlier crosssectional studies have demonstrated that baseline renal function , as reflected by the estimated glomerular filtration rate ( egfr ) , is a strong prognostic predictor in hf . however , during the management of adhf , renal function often deteriorates . reduced renal perfusion due to low cardiac output often leads to prerenal failure and the use of angiotensinconverting enzyme inhibitors or angiotensin receptor blockers that can worsen renal function ; also , hypovolemia secondary to loop diuretics usually elevate serum creatinine ( scr ) level . therefore , in addition to baseline renal function , worsening of renal function ( wrf ) has gained attention in recent years . some previous studies have reported that wrf during the first hospitalization for adhf is a strong and independent predictor of adverse outcomes . therefore , how wrf during longterm followup influences the prognosis of patients with adhf remains unclear . in this context , the aim of the present study is to determine the clinical impact of wrf during the year after discharge ( 1ywrf ) on prognosis in adhf patients in the nara registry and analyses for heart failure 2 ( the narahf study 2 ) cohort study . the narahf study 2 recruited 611 consecutive patients emergently admitted to our department or the coronary care unit at our hospital with documented adhf ( either acute newonset or acuteonchronic hf ) between january 2007 and december 2012 . patients with both reduced and preserved left ventricular ejection fraction ( lvef ) were included , but patients with acute myocardial infarction , acute myocarditis , and acute hf with acute pulmonary embolism were excluded . the study protocol was approved by the ethics committee in nara medical university , and written informed consent was obtained from all patients according to the declaration of helsinki ethical principles for medical research involving human subjects . of the 611 patients ,378 patients were excluded because 116 patients died within 1 year after discharge , 56 patients were treated with dialysis , 4 patients were prescribed vasopressin type 2 receptor antagonists , 186 patients did not have available scr values at 1 year after discharge , and 16 patients were lost to followup . consequently , we included 233 patients in whom scr levels were measured 3 times : on admission , at discharge , and at 1 year after discharge . for each patient , baseline data included age , sex , body mass index , hf etiology , medical history , vital signs , laboratory and echocardiographic data , and medications on admission and at discharge . for loop diuretics other than furosemide , we converted the dose to furosemide equivalent doses : 4 mg of torasemide and 30 mg of azosemide were considered equivalent to 20 mg of furosemide , respectively . we measured scr on admission , at discharge , and at 1 year after discharge . wrf was defined , according to previously published studies , as an absolute increase in scr 0.3 mg / dl ( 26.5 mol / l ) in combination with a 25 % increase in scr . we evaluated the occurrence of 1ywrf at the time point from discharge to 1 year of followup . patients were divided into the 1ywrf group ( n = 48 ) and the nonwrf group ( n = 185 ) according to the presence or absence of 1ywrf . cardiovascular death was defined as death due to hf , acute myocardial infarction , sudden death , stroke , or vascular diseases such as aortic dissection . when this information was unavailable , we telephoned patients or their families . information regarding cardiovascular events such as nonfatal acute myocardial infarction , nonfatal stroke , and unexpected rehospitalization due to recurrence of adhf was also obtained . continuous variables were expressed as means sd , and betweengroup differences were compared using student t test . multivariable cox proportional hazards models performed using forced inclusion models incorporated the 8 prognostic factors that were identified during past studies in hf patients : age , sex , body mass index , hemoglobin , egfr , btype natriuretic peptide ( bnp ) , lvef , and systolic blood pressure . we constructed 6 models adjusting for covariates : model 1 , unadjusted ; model 2 , adjusted for age , sex , and body mass index ; model 3 , adjusted for all factors in model 2 , plus hemoglobin , egfr , and bnp ; model 4 , adjusted for all factors in model 3 , plus lvef and systolic blood pressure ; model 5 , adjusted for the same factors as model 4 except replacing egfr at 1 year after discharge from egfr at discharge ; model 6 , adjusted for the same factors as model 4 except replacing egfr between hospital discharge and 1 year after discharge from egfr at discharge . egfr was calculated using the japanese equations that take into account age , sex , and scr . results were reported as hazard ratio ( hr ) , 95 % confidence interval ( ci ) , and p values . hr for outcomes in the wrf group were compared with those in the nonwrf group . a p value 0.05 was used as the criterion for variables to stay in the model . jmp version 10 for windows ( sas institute inc , cary , nc ) was used for all statistical analyses . the narahf study 2 recruited 611 consecutive patients emergently admitted to our department or the coronary care unit at our hospital with documented adhf ( either acute newonset or acuteonchronic hf ) between january 2007 and december 2012 . patients with both reduced and preserved left ventricular ejection fraction ( lvef ) were included , but patients with acute myocardial infarction , acute myocarditis , and acute hf with acute pulmonary embolism were excluded . the study protocol was approved by the ethics committee in nara medical university , and written informed consent was obtained from all patients according to the declaration of helsinki ethical principles for medical research involving human subjects . of the 611 patients ,378 patients were excluded because 116 patients died within 1 year after discharge , 56 patients were treated with dialysis , 4 patients were prescribed vasopressin type 2 receptor antagonists , 186 patients did not have available scr values at 1 year after discharge , and 16 patients were lost to followup . consequently , we included 233 patients in whom scr levels were measured 3 times : on admission , at discharge , and at 1 year after discharge . for each patient , baseline data included age , sex , body mass index , hf etiology , medical history , vital signs , laboratory and echocardiographic data , and medications on admission and at discharge . for loop diuretics other than furosemide , we converted the dose to furosemide equivalent doses : 4 mg of torasemide and 30 mg of azosemide were considered equivalent to 20 mg of furosemide , respectively . we measured scr on admission , at discharge , and at 1 year after discharge . wrf was defined , according to previously published studies , as an absolute increase in scr 0.3 mg / dl ( 26.5 mol / l ) in combination with a 25 % increase in scr . we evaluated the occurrence of 1ywrf at the time point from discharge to 1 year of followup . patients were divided into the 1ywrf group ( n = 48 ) and the nonwrf group ( n = 185 ) according to the presence or absence of 1ywrf . cardiovascular death was defined as death due to hf , acute myocardial infarction , sudden death , stroke , or vascular diseases such as aortic dissection . when this information was unavailable , we telephoned patients or their families . information regarding cardiovascular events such as nonfatal acute myocardial infarction , nonfatal stroke , and unexpected rehospitalization due to recurrence of adhf was also obtained . continuous variables were expressed as means sd , and betweengroup differences were compared using student t test . multivariable cox proportional hazards models performed using forced inclusion models incorporated the 8 prognostic factors that were identified during past studies in hf patients : age , sex , body mass index , hemoglobin , egfr , btype natriuretic peptide ( bnp ) , lvef , and systolic blood pressure . we constructed 6 models adjusting for covariates : model 1 , unadjusted ; model 2 , adjusted for age , sex , and body mass index ; model 3 , adjusted for all factors in model 2 , plus hemoglobin , egfr , and bnp ; model 4 , adjusted for all factors in model 3 , plus lvef and systolic blood pressure ; model 5 , adjusted for the same factors as model 4 except replacing egfr at 1 year after discharge from egfr at discharge ; model 6 , adjusted for the same factors as model 4 except replacing egfr between hospital discharge and 1 year after discharge from egfr at discharge . egfr was calculated using the japanese equations that take into account age , sex , and scr . results were reported as hazard ratio ( hr ) , 95 % confidence interval ( ci ) , and p values . hr for outcomes in the wrf group were compared with those in the nonwrf group . a p value 0.05 was used as the criterion for variables to stay in the model . jmp version 10 for windows ( sas institute inc , cary , nc ) was used for all statistical analyses . as shown in table 1 , the mean age was 72.211.6 ( meansd ) years , and 43.3 % of the patients were women . based on the aforementioned definition , 1ywrf occurred in 48 patients ( 20.6 % ) . to investigate the impact of 1ywrf on adhf prognosis , we divided patients into 2 groups according to the presence or absence of 1ywrf . age , body mass index , and the sex distribution were similar in both groups . there were no significant differences in the etiology of hf or the proportion of comorbidities between the 2 groups . moreover , new york heart association functional class , vital signs on admission , lvef , and left ventricular enddiastolic diameter were also similar . scr on admission was equal between the 1ywrf group and the nonwrf group ( 1.27 and 1.13 mg / dl , respectively , p = 0.1163 ) . however , at discharge , the 1ywrf group had significantly lower hemoglobin and higher bnp compared to the nonwrf group . baseline characteristics of hf patients with and without 1ywrf data are shown as percentages , meanssd . bmi indicates body mass index ; bnp , btype natriuretic peptide ; cabg , coronary artery bypass grafting ; ckd , chronic kidney disease ; crt , cardiac resynchronization therapy ; ef , ejection fraction ; egfr , estimated glomerular filtration rate ; hf , heart failure ; icd , implantable cardioverter defibrillator ; lvedd , left ventricular enddiastolic diameter ; lvef , left ventricular ejection fraction ; nyha , new york heart association ; pci , percutaneous coronary intervention ; 1ywrf , worsening of renal function during the year after discharge . table 2 compares the medications on admission and at discharge of the patients in the 2 groups . the proportion of patients treated with angiotensinconverting enzyme inhibitors or angiotensin receptor blockers , blockers , loop diuretics , mineralocorticoid receptor blockers , and calcium channel blockers were similar in the 2 groups , both on admission and at discharge . there were no significant differences in the furosemide equivalent dose at all time points ( on admission , at discharge , and at 1 year after discharge ) between the 1ywrf and nonwrf groups . however , dose increases for loop diuretics between hospital discharge and 1 year afterwards were significantly larger in the 1ywrf group than in the nonwrf group . medications on admission and at discharge , and loop diuretic dose dose increased refers to an increase between discharge and 1 y afterwards . ace indicates angiotensinconverting enzyme ; arb , angiotensin receptor blocker ; ca , calcium ; mr , mineralocorticoid receptor ; 1ywrf , worsening of renal function during the year after discharge . during the mean followup period of 35.4 months , 66 ( 28.3 % ) meier survival curves , the 1ywrf group had a much higher rate of allcause death ( logrank p 0.0001 ) and cardiovascular death ( logrank p 0.0001 ) ( figure 1 ) . table 3 shows the unadjusted and adjusted hrs for outcomes in the 2 groups : 1ywrf predicted allcause and cardiovascular mortality ( hr , 3.136 ; 95 % ci , 1.8935.127 ; p 0.0001 and hr , 4.571 ; 95 % ci , 2.3888.783 ; p 0.0001 , respectively ) . even after adjusting for age , sex , and cardiovascular risk factors such as plasma bnp levels , lvef , etc . , associations between 1ywrf and allcause and cardiovascular mortality remained significant ( table 3 ) . moreover , in the models including the absolute value of egfr at 1 year after discharge ( table 3 , model 5 ) and the egfr between hospital discharge and 1 year after discharge ( table 3 , model 6 ) , 1ywrf remained a strong independent predictor of allcause and cardiovascular mortality . hr and 95 % ci for allcause and cardiovascular death according to 1ywrf status hemoglobin , plasma bnp and sbp values were at the time of discharge . egfr values are at the time of discharge in models 3 and 4 and at 1 year after discharge in model 5 . egfr is the change in egfr between hospital discharge and 1 year after discharge in model 6 . bnp indicates btype natriuretic peptide ; egfr , estimated glomerular filtration rate ; hr , hazard ratio ; lvef , left ventricular ejection fraction ; sbp , systolic blood pressure ; 1ywrf , worsening of renal function during the year after discharge . meier eventfree survival curves for ( a ) allcause death and ( b ) cardiovascular death in patients with nonwrf ( dotted line ; n = 185 ) compared with patients with 1ywrf ( solid line ; n = 48 ) . hemoglobin and bnp at discharge , as well as lvef 50 % , were independent risk factors for 1ywrf , but not age and egfr at discharge . predictors of 1ywrf in the multivariate analysis hemoglobin , plasma bnp , and egfr values are at the time of discharge . increase in loop diuretic dose refers to the increase in dose from the time of discharge to 1 year after discharge . bnp indicates btype natriuretic peptide ; egfr , estimated glomerular filtration rate ; lvef , left ventricular ejection fraction ; 1ywrf , worsening of renal function during the year after discharge . as shown in table 1 , the mean age was 72.211.6 ( meansd ) years , and 43.3 % of the patients were women . based on the aforementioned definition , 1ywrf occurred in 48 patients ( 20.6 % ) . to investigate the impact of 1ywrf on adhf prognosis , we divided patients into 2 groups according to the presence or absence of 1ywrf . age , body mass index , and the sex distribution were similar in both groups . there were no significant differences in the etiology of hf or the proportion of comorbidities between the 2 groups . moreover , new york heart association functional class , vital signs on admission , lvef , and left ventricular enddiastolic diameter were also similar . scr on admission was equal between the 1ywrf group and the nonwrf group ( 1.27 and 1.13 mg / dl , respectively , p = 0.1163 ) . however , at discharge , the 1ywrf group had significantly lower hemoglobin and higher bnp compared to the nonwrf group . baseline characteristics of hf patients with and without 1ywrf data are shown as percentages , meanssd . bmi indicates body mass index ; bnp , btype natriuretic peptide ; cabg , coronary artery bypass grafting ; ckd , chronic kidney disease ; crt , cardiac resynchronization therapy ; ef , ejection fraction ; egfr , estimated glomerular filtration rate ; hf , heart failure ; icd , implantable cardioverter defibrillator ; lvedd , left ventricular enddiastolic diameter ; lvef , left ventricular ejection fraction ; nyha , new york heart association ; pci , percutaneous coronary intervention ; 1ywrf , worsening of renal function during the year after discharge . table 2 compares the medications on admission and at discharge of the patients in the 2 groups . the proportion of patients treated with angiotensinconverting enzyme inhibitors or angiotensin receptor blockers , blockers , loop diuretics , mineralocorticoid receptor blockers , and calcium channel blockers were similar in the 2 groups , both on admission and at discharge . there were no significant differences in the furosemide equivalent dose at all time points ( on admission , at discharge , and at 1 year after discharge ) between the 1ywrf and nonwrf groups . however , dose increases for loop diuretics between hospital discharge and 1 year afterwards were significantly larger in the 1ywrf group than in the nonwrf group . medications on admission and at discharge , and loop diuretic dose dose increased refers to an increase between discharge and 1 y afterwards . ace indicates angiotensinconverting enzyme ; arb , angiotensin receptor blocker ; ca , calcium ; mr , mineralocorticoid receptor ; 1ywrf , worsening of renal function during the year after discharge . during the mean followup period of 35.4 months , 66 ( 28.3 % ) patients died ; 38 ( 16.3 % ) were from cardiovascular causes . meier survival curves , the 1ywrf group had a much higher rate of allcause death ( logrank p 0.0001 ) and cardiovascular death ( logrank p 0.0001 ) ( figure 1 ) . table 3 shows the unadjusted and adjusted hrs for outcomes in the 2 groups : 1ywrf predicted allcause and cardiovascular mortality ( hr , 3.136 ; 95 % ci , 1.8935.127 ; p 0.0001 and hr , 4.571 ; 95 % ci , 2.3888.783 ; p 0.0001 , respectively ) . even after adjusting for age , sex , and cardiovascular risk factors such as plasma bnp levels , lvef , etc . , associations between 1ywrf and allcause and cardiovascular mortality remained significant ( table 3 ) . moreover , in the models including the absolute value of egfr at 1 year after discharge ( table 3 , model 5 ) and the egfr between hospital discharge and 1 year after discharge ( table 3 , model 6 ) , 1ywrf remained a strong independent predictor of allcause and cardiovascular mortality . hr and 95 % ci for allcause and cardiovascular death according to 1ywrf status hemoglobin , plasma bnp and sbp values were at the time of discharge . egfr values are at the time of discharge in models 3 and 4 and at 1 year after discharge in model 5 . egfr is the change in egfr between hospital discharge and 1 year after discharge in model 6 . bnp indicates btype natriuretic peptide ; egfr , estimated glomerular filtration rate ; hr , hazard ratio ; lvef , left ventricular ejection fraction ; sbp , systolic blood pressure ; 1ywrf , worsening of renal function during the year after discharge . meier eventfree survival curves for ( a ) allcause death and ( b ) cardiovascular death in patients with nonwrf ( dotted line ; n = 185 ) compared with patients with 1ywrf ( solid line ; n = 48 ) . hemoglobin and bnp at discharge , as well as lvef 50 % , were independent risk factors for 1ywrf , but not age and egfr at discharge . predictors of 1ywrf in the multivariate analysis hemoglobin , plasma bnp , and egfr values are at the time of discharge . increase in loop diuretic dose refers to the increase in dose from the time of discharge to 1 year after discharge . bnp indicates btype natriuretic peptide ; egfr , estimated glomerular filtration rate ; lvef , left ventricular ejection fraction ; 1ywrf , worsening of renal function during the year after discharge . the present study demonstrates that 1ywrf is a strong and independent risk factor for allcause mortality and cardiovascular events in patients with adhf . during the past decade , many studies reported a significant association between renal impairment and prognosis in hf . many of these studies defined renal impairment as baseline scr or wrf during hospitalization . in the present study , we evaluated longitudinal changes in renal function over the year after hospital discharge as a prognostic factor in adhf . a large proportion of patients with adhf have chronic kidney disease , which can exacerbate adhf , and vice versa . more than half of the patients with adhf in our study had egfr 60 ml / min per 1.73 m at admission , and 20 % of the patients who were alive for 1 year after discharge had wrf , defined as an absolute increase in scr 0.3 mg / dl ( 26.5 mol / l ) in combination with a 25 % increase in scr at 1 year after discharge . these figures are comparable to or slightly higher than those in previous studies , which were conducted in europe and recruited patients with systolic heart failure . many crosssectional studies have demonstrated that impaired renal function is an independent risk factor for poor outcomes in hf . in our study , however , the close association between 1ywrf and allcause mortality or cardiovascular events remained after adjustment for several factors including the absolute value of egfr at 1 year after discharge . these observations provide clinically relevant information to physicians , namely , the importance of maintaining renal function when treating patients with hf . this concept is currently accepted as the cardiorenal connection , the mechanism of which may involve a complex interplay between hf and renal dysfunction through hemodynamic , pathological , and humoral dysregulation . although inhospital wrf was observed in 20 % of the study patients , it was not significantly associated with allcause mortality or cardiovascular events ( logrank p = 0.7636 and logrank p = 0.5908 , respectively ) ( figure 2 ) . in prior studies , inhospital wrf . however , some recent reports showed it was not , which is consistent with our results . in our study , only 2 patients had both inhospital and 1ywrf ; in other words , most of patients with inhospital wrf had preserved renal function at 1 year after discharge . meier eventfree survival curves for ( a ) allcause death and ( b ) cardiovascular death in patients with nonwrf ( dotted line ; the mechanisms for 1ywrf and inhospital wrf may differ , but this was not discernable from a clinical cohort study . the proportion of patients with hypertension and diabetes mellitus , as well as previous myocardial infarction , which are risk factors for wrf in outpatients , was similar in the 1ywrf and nonwrf groups . however , the plasma bnp level was significantly higher in the 1ywrf group than in the nonwrf group , and multiple logistic regression showed that plasma bnp level , lvef 50 % , and anemia were significant risk factors for 1ywrf ( tables 1 , 2 , and 4 ) . thus , it is plausible that more advanced hf is more likely to be accompanied by wrf . alternatively , the high levels of plasma bnp in the wrf group might be associated with continuing high venous pressure and negative effects on the kidney due to congestion . in our study , the furosemide equivalent dose of loop diuretics at discharge was similar in the 1ywrf and nonwrf groups , but at 1 year , the 1ywrf group had a nonsignificantly higher dose compared to the nonwrf group . as earlier reports reported that wrf has been attributed to hypoperfusion of the kidney due to intravascular volume depletion secondary to overdose of diuretics , patients with hf should be treated with the lowest effective dose of loop diuretics , to avoid wrf . in our institution , physicians would take bnp levels into account to prevent overuse of loop diuretics . since the definition of wrf is not uniform , there are many ways to assess changes in wrf . we chose a strict definition , an absolute scr increase 0.3 mg / dl ( 26.5 mol / l ) in combination with a 25 % increase in scr , which has been used by previous studies . some investigators have used an absolute scr increase 0.3 mg / dl from baseline . therefore , we examined other definitions of 1ywrf , such as an absolute scr increase 0.3 mg / dl between discharge and followup at 1 year ( 53 patients with 1ywrf ) . using this definition , the kaplanmeier survival analysis showed that the 1ywrf group had a much higher rate of allcause death ( logrank p 0.0001 ) and cardiovascular death ( logrank p 0.0001 ) ( data not shown ) . the major limitation is that the sample size was moderate , the study was retrospective in nature , and that it was based at a single center . we did not collect data on variables that can potentially influence adhf prognosis such as respiratory function and qrs complex widening on admission . we could not compare the influence of thiazides between the 2 groups because there are no official doseconversion formulas for converting between loop diuretics and thiazides . the major limitation is that the sample size was moderate , the study was retrospective in nature , and that it was based at a single center . we did not collect data on variables that can potentially influence adhf prognosis such as respiratory function and qrs complex widening on admission . we could not compare the influence of thiazides between the 2 groups because there are no official doseconversion formulas for converting between loop diuretics and thiazides . wrf at 1 year after hospital discharge for adhf is a strong predictor of allcause and cardiovascular death .\noutput:\n" }, { "from": "agent", "value": "backgroundrenal impairment is a common comorbidity and the strongest risk factor for poor prognosis in acute decompensated heart failure ( adhf ) . in clinical practice , renal function is labile during episodes of adhf , and often worsens after discharge . the significance of worsening of renal function ( wrf ) after discharge has not been investigated as extensively as baseline renal function at admission or wrf during hospitalization.methods and resultsamong 611 consecutive patients with adhf emergently admitted to our hospital , 233 patients with 3 measurements of serum creatinine ( scr ) level measurements ( on admission , at discharge , and 1 year after discharge ) were included in the present study . patients were divided into 2 groups according to the presence or absence of wrf at 1 year after discharge ( 1ywrf ) , defined as an absolute increase in scr > 0.3 mg / dl ( > 26.5 mol / l ) plus a 25 % increase in scr at 1 year after discharge compared to the scr value at discharge . allcause and cardiovascular mortality were assessed as adverse outcomes . during a mean followup of 35.4 months , 1ywrf occurred in 48 of 233 patients . there were 66 deaths from all causes . allcause and cardiovascular mortality were significantly higher in patients with 1ywrf ( logrank p < 0.0001 and p < 0.0001 , respectively ) according to kaplan meier analysis . in a multivariate cox proportional hazards model , 1ywrf was a strong and independent predictor of allcause and cardiovascular mortality . hemoglobin and btype natriuretic peptide at discharge , as well as left ventricular ejection fraction < 50 % , were independent predictors of 1ywrf . conclusionsin patients with adhf , 1ywrf is a strong predictor of allcause and cardiovascular mortality ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: retrocalcaneal bursitis ( rcb ) is a disabling condition characterized by pain that is anterior to the achilles tendon , and just superior to its insertion in the os calcis .1 the retrocalcaneal bursa lies between the anterior aspect of the tendon and the posterosuperior aspect of the calcaneum . patrick haglund ( 1928 ) was credited for the first description of enlargement of the posterosuperior portion of the calcaneus ; 2 the syndrome bearing his name has come to represent a painful condition of the heel caused by mechanically induced inflammation of the retrocalcaneal and / or supracalcaneal bursae , which become inflamed , hypertrophied , and adherent to the underlying tendon .3 examination reveals painful dorsiflexion of the ankle and tenderness on either side or anterior aspect of the achilles tendon . the lateral view radiograph of the ankle joint shows posterosuperior bony prominence and intratendinous calcification that confirms the diagnosis . the tendon degenerative changes can also be demonstrated by using an ultrasound scan .4 various modalities of conservative treatment have been recommended , including change of footwear , use of heel pads , moist heat , stretching exercises , local steroid injections , and extracorporeal shock wave therapy .57 in cases where conservative treatment fails , surgery may be indicated . several methods of surgical treatment have been described previously including excision of the retrocalcaneal bursa , calcaneal osteotomy , and endoscopic decompression of the retrocalcaneal space .810 minimally invasive surgeries allow early postoperative recovery , minimal pain , and better cosmetic appearance , but the results are inconsistent .11 we report the outcome of the endoscopic decompression of retrocalacaneal bursa and posterosuperior bony spur and compared the results in patients with retrocalcaneal bursitis alone , with those having additional limited intratendinous calcifications ( x - ray finding ) , and noninsertional tendinosis ( ultrasound finding ) . this prospective study was conducted from may 2008 to august 2011 and included 25 heels of 23 patients ( two patients with both heels ) in 9 men and 14 women attending the outpatient department at our hospital , with posterior heel pain , who did not respond to conservative treatment and had symptomatic haglunds spur and / or noninsertional achilles tendinosis . the mean age was 51.447.92 years ( range 3866 years ) . the average duration of the nonoperative treatment before the surgery was 13.406.67 months ( range 630 months ) . failed conservative treatment included modified footwear , nonsteroidal anti inflammatory agents ( nsaid ) , physical therapy , and steroid injections ( in other institutions ) . patients were evaluated with preoperative clinical examination , routine blood investigations , x - rays , and ultrasound scan , to rule out insertional tendinitis and degenerative changes . patients with severe calcific deposits and insertional tendinitis were excluded from the study .12 functional outcome was evaluated aofas . a standing , lateral view of plain x - ray was taken preoperatively , to assess the posterosuperior bony spur ,13 ( which was present in all patients ) and to calculate the extent of bony resection required . out of 23 patients , the parallel pitch lines ( ppls ) determine the prominence of the bony projection on preoperative x - ray [ figure 1a ] . the lower ppl ( a ) is the baseline , drawn from the anterior tubercle to the medial posterior tubercle . the upper ppl ( b ) is drawn parallel to the baseline at a distance d , starting from the talar articular surface anteriorly to the posterior tuberosity . a bony projection touching or below line b is normal and not prominent ( ppl - negative ) and a bony projection above b is considered prominent ( ppl - positive ) , which needs surgical excision . both preoperative and postoperative x - rays were compared , to determine the extent of resection . preoperative x - ray ankle joint lateral view showing ( a ) the parallel pitch lines ( ppls ) determine the prominence of the bony projection . ( b ) ultrasound ankle showing achilles tendon , retrocalcaneal bursa and calcaneum achilles tendon and the surrounding tissues were examined with the patient in a prone position by the same radiologist using high - frequency ( 13 mhz ) linear transducer ( siemens medical systems ) [ figure 1b ] . based on the hypoechoic areas in the tendon substance , grading was done using the ordinal scale ,12 whereby , 0 represented normal echogenicity , 1 represented mild hypoechogenicity , 2 represented moderate hypoechoic regions , and 3 represented marked hypoechogenicity . the presence or absence of intratendinous calcification was documented by identifying the linear areas of hyperechogenicity within the tendon proper .12 patients with grade 3 tendinosis ( degeneration ) and severe calcification were excluded from the study . the aofas ankle - hindfoot scale was used to evaluate patients preoperatively and postoperatively at three weeks , six weeks , six months , and twelve months respectively . the aofas score evaluates pain ( 40 points ) , function ( 50 points ) , and alignment ( 10 points ) .14 the maryland 100 point foot score was used only postoperatively at the six and 12 - month followups . for validation of the subjective satisfaction of the patients for better patient understanding10both preoperative and postoperative evaluations were performed by a single investigator , to avoid interobserver errors . the data was analyzed using the statistical package for social sciences ( spss ) version 11.0 . frequencies and proportions were calculated and the mean ( standard deviation ) values were calculated for continuous variables , such as , age , duration of conservative treatment before surgery , preoperative and postoperative scores , duration of surgery , and followup . spearman correlation was performed to evaluate the relationship between preoperative ultrasound findings and postoperative maryland scores . the endoscopic procedure was performed with the patient in a prone or semi - prone position , with the foot hanging down the table , under spinal anesthesia and tourniquet control [ figure 2 ] . a medial portal ( working portal ) was made and an arthroscopic shaver ( 4.0 mm stryker ) was introduced for removing the fat and retrocalcaneal bursa , and the lateral portal was used for visualization , ( stryker endoscopy video system and 30 scope ) . osseous resection was done with a burr under endoscopic guidance , to avoid injury to the achilles tendon . the tendon was then visualized with an endoscope and if necessary , the diseased achilles tissue was debrided with the shaver . up to 50 % of the achilles tendoncould be released safely for complete removal of the spur .15 wound closure was done with 2 - o nylon in a single layer and tight compressive dressing was applied till a middle third of the leg . subsequently , the patients were allowed to walk with modified footwear for three months , followed by normal footwear . peroperative clinical photograph showing medial and lateral portals with patient 's foot hanging free in a prone positionthis prospective study was conducted from may 2008 to august 2011 and included 25 heels of 23 patients ( two patients with both heels ) in 9 men and 14 women attending the outpatient department at our hospital , with posterior heel pain , who did not respond to conservative treatment and had symptomatic haglunds spur and / or noninsertional achilles tendinosis . the mean age was 51.447.92 years ( range 3866 years ) . the average duration of the nonoperative treatment before the surgery was 13.406.67 months ( range 630 months ) . failed conservative treatment included modified footwear , nonsteroidal anti inflammatory agents ( nsaid ) , physical therapy , and steroid injections ( in other institutions ) . patients were evaluated with preoperative clinical examination , routine blood investigations , x - rays , and ultrasound scan , to rule out insertional tendinitis and degenerative changes . patients with severe calcific deposits and insertional tendinitis were excluded from the study .12 functional outcome was evaluated aofas . a standing , lateral view of plain x - ray was taken preoperatively , to assess the posterosuperior bony spur ,13 ( which was present in all patients ) and to calculate the extent of bony resection required . out of 23 patients , the parallel pitch lines ( ppls ) determine the prominence of the bony projection on preoperative x - ray [ figure 1a ] . the lower ppl ( a ) is the baseline , drawn from the anterior tubercle to the medial posterior tubercle . the upper ppl ( b ) is drawn parallel to the baseline at a distance d , starting from the talar articular surface anteriorly to the posterior tuberosity . a bony projection touching or below line b is normal and not prominent ( ppl - negative ) and a bony projection above b is considered prominent ( ppl - positive ) , which needs surgical excision . both preoperative and postoperative x - rays were compared , to determine the extent of resection . preoperative x - ray ankle joint lateral view showing ( a ) the parallel pitch lines ( ppls ) determine the prominence of the bony projection . achilles tendon and the surrounding tissues were examined with the patient in a prone position by the same radiologist using high - frequency ( 13 mhz ) linear transducer ( siemens medical systems ) [ figure 1b ] . based on the hypoechoic areas in the tendon substance , grading was done using the ordinal scale ,12 whereby , 0 represented normal echogenicity , 1 represented mild hypoechogenicity , 2 represented moderate hypoechoic regions , and 3 represented marked hypoechogenicity . the presence or absence of intratendinous calcification was documented by identifying the linear areas of hyperechogenicity within the tendon proper .12 patients with grade 3 tendinosis ( degeneration ) and severe calcification were excluded from the study . the aofas ankle - hindfoot scale was used to evaluate patients preoperatively and postoperatively at three weeks , six weeks , six months , and twelve months respectively . the aofas score evaluates pain ( 40 points ) , function ( 50 points ) , and alignment ( 10 points ) .14 the maryland 100 point foot score was used only postoperatively at the six and 12 - month followups . for validation of the subjective satisfaction of the patients for better patient understanding10both preoperative and postoperative evaluations were performed by a single investigator , to avoid interobserver errors . the data was analyzed using the statistical package for social sciences ( spss ) version 11.0 . frequencies and proportions were calculated and the mean ( standard deviation ) values were calculated for continuous variables , such as , age , duration of conservative treatment before surgery , preoperative and postoperative scores , duration of surgery , and followup . spearman correlation was performed to evaluate the relationship between preoperative ultrasound findings and postoperative maryland scores . the endoscopic procedure was performed with the patient in a prone or semi - prone position , with the foot hanging down the table , under spinal anesthesia and tourniquet control [ figure 2 ] . a medial portal ( working portal ) was made and an arthroscopic shaver ( 4.0 mm stryker ) was introduced for removing the fat and retrocalcaneal bursa , and the lateral portal was used for visualization , ( stryker endoscopy video system and 30 scope ) . osseous resection was done with a burr under endoscopic guidance , to avoid injury to the achilles tendon . the tendon was then visualized with an endoscope and if necessary , the diseased achilles tissue was debrided with the shaver . up to 50 % of the achilles tendoncould be released safely for complete removal of the spur .15 wound closure was done with 2 - o nylon in a single layer and tight compressive dressing was applied till a middle third of the leg . subsequently , the patients were allowed to walk with modified footwear for three months , followed by normal footwear . peroperative clinical photograph showing medial and lateral portals with patient 's foot hanging free in a prone positionthe post operative x - rays in all patients showed adequate resection of the bony spur . the resection angle was not measured on postoperative x - rays [ figure 3a ] . minimal bony debris , which was not removed during surgery , was visible in a few postoperative radiographs and there was no evidence of heterotrophic calcification at one year followup . ( b and c ) clinical photograph showing postoperative scar at the one - year followup the mean followup was 16.4 months ( range 12 - 30 months ) . the average preoperative aofas score of 57.926.224 points and postoperative score of 89.085.267 points , indicating a significant increase in the scores after the operation ( p 0.01 ) . the university of maryland scores were categorized into nonparametric categories , with 100 to 90 points indicating an excellent score ; 89 to 80 points good ; 79 to 70 pointspoor .10 it was observed that 16 patients had an excellent outcome , six good , three fair , and there were no poor results . in our study , there were 12 heels having noninsertional tendinosis on ultrasound and they had low aofas scores compared to 13 heels having retrocalcaneal bursitis alone . the six patients who demonstrated calcification on radiographs , in addition to ultrasound changes , had less pain relief at the one year followup , compared to those with ultrasound changes alone . at the one year followup , correlation for preoperative usg assessment of tendoachilles degeneration versus a postoperative maryland score ( spearman correlation ) has shown a strong negative correlation . as the usg grade of degeneration ( grade 2 ) increased , the postoperative score decreased and the association was significant ( p 0.01 ) . one patient had postoperative wound infection , which healed with secondary intention , two had sural neuropathy probably due to improper lateral port placement and one had dvt that resolved in two weeks , after a medical line of management [ figure 3b ] . the post operative x - rays in all patients showed adequate resection of the bony spur . the resection angle was not measured on postoperative x - rays [ figure 3a ] . minimal bony debris , which was not removed during surgery , was visible in a few postoperative radiographs and there was no evidence of heterotrophic calcification at one year followup . ( b and c ) clinical photograph showing postoperative scar at the one - year followupthe average preoperative aofas score of 57.926.224 points and postoperative score of 89.085.267 points , indicating a significant increase in the scores after the operation ( p 0.01 ) . the university of maryland scores were categorized into nonparametric categories , with 100 to 90 points indicating an excellent score ; 89 to 80 points good ; 79 to 70 pointspoor .10 it was observed that 16 patients had an excellent outcome , six good , three fair , and there were no poor results . in our study , there were 12 heels having noninsertional tendinosis on ultrasound and they had low aofas scores compared to 13 heels having retrocalcaneal bursitis alone . the six patients who demonstrated calcification on radiographs , in addition to ultrasound changes , had less pain relief at the one year followup , compared to those with ultrasound changes alone . at the one year followup , correlation for preoperative usg assessment of tendoachilles degeneration versus a postoperative maryland score ( spearman correlation ) has shown a strong negative correlation . as the usg grade of degeneration ( grade 2 ) increased , the postoperative score decreased and the association was significant ( p 0.01 ) . one patient had postoperative wound infection , which healed with secondary intention , two had sural neuropathy probably due to improper lateral port placement and one had dvt that resolved in two weeks , after a medical line of management [ figure 3b ] . posterior heel pain is multifactorial and the causes include , retrocalcaneal bursitis , insertional tendinosis , noninsertional tendinosis , superficial retroachilles bursitis , and gastrocnemius contracture . achilles tendinopathy is a degenerative process within the tendon substance causing microtears and reactive fibrotic scar formation that causes mechanical irritation of the surrounding tissues , followed by inflammatory reaction and attenuated repair .16 the tendon disease can be more proximal ( noninsertional ) or at the level of insertion , adjacent to the prominent bone . after the initial inflammatory stage , the tendinopathy progresses to a tendonosis ( intrasubstance tendon fiber degeneration ) , where conservative measures are less likely to have a significant effect .17 histopathologically , noninsertional achilles tendinitis is classified into three subgroups : paratendinitis , paratendinitis with tendinosis , and tendinosis by puddu et al. 18 it is clinically difficult to differentiate the contribution of insertional achilles tendinitis , noninsertional tendinosis ( tendon substance degeneration ) , and retrocalcaneal bursitis to cause pain in most patients , as they often co - exist . treatment of achilles tendinosis can be planned depending on the stage of degeneration , eccentric calf strengthening for mild and moderate tendinosis and debridement of tendon with reconstruction for severe tendinosis . radiographs can give an idea about the bony morphology ( posterosuperior spur ) and tendon calcification , but not the tendon substance details . ultrasound is used commonly to examine achilles tendon disorders ,1921 and it is a better option when compared to magnetic resonance imaging ( mri ) , as it allows dynamic assessment and reveals the details of the tendon and inflamed bursae more accurately .22 it also picks degeneration ( calcification ) of the tendon before the changes appear on the radiographs . in our series , radiographs of noninsertional tendinosis of 12 heels demonstrated six normal , five mild , and one moderate calcification , while the ultrasound demonstrated moderate degeneration in six and mild in the rest , proving that the ultrasound can help in diagnosing noninsertional tendinosis before the changes appear on the radiographs . the group with ultrasound changes alone had a better functional outcome than the group with calcification on radiographs , in addition to ultrasound changes . hence , we strongly believe that ultrasound examination preoperatively is helpful in getting the finer details of the achilles tendon , than those that appear on radiographs and it helps in choosing the ideal patient for endoscopic decompression . leitz et al. 10 performed a prospective study comparing open resection in 17 patients with the endoscopic technique in 33 patients . they found that in the endoscopic group , the aofas scores averaged 61.8 points preoperatively and 87.5 points postoperatively , and the results were similar to ours . ortmann et al. 16 reported on 30 patients ( 32 heels ) , who were managed with endoscopic osseous and soft tissue decompression for the treatment of retrocalcaneal bursitis . our study showed similar results , in terms of patient satisfaction with the use of the maryland score at the one year followup . a limitation of this study was that the sample size was very small and the average followup was only - 16.4 months . in conclusion , endoscopic calcaneal resection is highly effective in patients with no degeneration than the patients with degenerative changes . it yields cosmetically better results with fewer complications as the procedures allow better visualization of the bony spur and resect adequately . preoperative ultrasound is very helpful in identifying the ideal patient for endoscopic procedure and helps to predict the prognostic outcome following endoscopic decompression to a certain extent .\noutput:\n" }, { "from": "agent", "value": "background : posterior heel pain due to retrocalcaneal bursitis , is a disabling condition that responds well to the conventional methods of treatment . patients who do not respond to conservative treatment may require surgical intervention . this study evaluates the outcome of endoscopic decompression of retrocalcaneal bursitis , with resection of posterosuperior eminence of the calcaneum.materials and methods : this present study included 25 heels from 23 consecutive patients with posterior heel pain , who did not respond to conservative treatment and underwent endoscopic decompression of the retrocalcaneal bursae and excision of bony spurs . the functional outcome was evaluated by comparing the pre and postoperative american orthopedic foot and ankle society ( aofas ) scores . the maryland ankle and foot score was used postoperatively to assess the patient 's satisfaction at the one - year followup.results : the university of maryland scores of 25 heels were categorized as the nonparametric categories , and it was observed that 16 patients had an excellent outcome , six good , three fair and there were no poor results . the aofas scores averaged 57.92 6.224 points preoperatively and 89.08 5.267 points postoperatively ( p < 0.001 ) , at an average followup of 16.4 months . the 12 heels having noninsertional tendinosis on ultrasound had low aofas scores compared to 13 heels having retrocalcaneal bursitis alone . at one year followup , correlation for preoperative ultrasound assessment of tendoachilles degeneration versus postoperative maryland score ( spearman correlation ) had shown a strong negative correlation.conclusion : endoscopic calcaneal resection is highly effective in patients with mild or no degeneration and yields cosmetically better results with fewer complications . patients with degenerative changes in achilles tendon had poorer outcomes in terms of subjective satisfaction ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: regional differences and inequalities in diseases are much more clear in cancer cases which can be seen as reflections of worldwide socioeconomic , politic , and environmental inequalities . according to globocan 2012 data , 8.2 million people die from cancer worldwide and more than half of them ( 64.9 % ) are in less developed countries .70 % of deaths from gastric and esophageal cancers , which rank 3rd and 6th in the cancer deaths worldwide , respectively , are seen in developing countries including our country . according to 2011 data from the ministry of health , esophageal cancer is not one of the 10 most common cancers in turkey , whereas the incidence of gastric cancer is 8.6 in females and 21.6 in males per 100.000 per year . in the eastern region of turkey , especially in van lake region , yet there are no serious epidemiological studies ; most recently in 2006 , in a study conducted in 1584 cancer patients , alc et al . reported that gastric cancer ( 26.5 % ) and esophageal cancer ( 15.8 % ) rank first and second most common cancers , respectively . regional differences in gastric and esophageal cancers both in the same country and around the world often have been linked to eating and lifestyle habits and frequency of hp infection . studies made in geographies , known as the esophageal cancer belt or line ( which if somewhat extended , eastern anatolian region can be included ) that connect the high - risk zones for esophageal cancer ( china 's central northern region , central asian republics , iran 's northern parts ) , have put emphasis on , in particular , eating and drinking very hot foods and drinks , consumption of smoked and brined products , lack of fresh fruit and vegetable consumption , and smoking and those studies reported significant risks . lifestyles and eating habits of the people in van lake region , one of the endemic areas for gastric and esophageal cancers , are peculiar to this geography ; besides they are similar in risky regions mentioned before . in this studywe aimed to evaluate the relationship between esophageal and gastric cancers and hp infection , herby cheese consumption , drinking hot tea , cooking bread on tandoor , and smoking which were seen as potential risks and recommended to be investigated in etiopathogenesis in the previous studies conducted in here , van lake region . van regional training and research hospital ( vtrh ) and yznc yl university faculty of medicine hospital ( yyu - fmh ) are the most important medical centers serving van and all the provinces of van lake region . after getting vtrh ethics board approval , the study was planned as a case - control study and it includes the pathologic reports of the patients who underwent surgery in vtrh and yyu - fmh for two years between january 1 , 2012 , and december 31 , 2013 . the control group comprised randomly selected individuals , who were admitted to hospital for reasons other than cancer , with socioeconomic profile , age , and sex similar to those of the patient group . therefore when setting the control group , we have made a selection from the nearest population of patients in the study group . our inclusion criteria for control group were being in a similar socioeconomic status with study group , being in a same age group , and living in close proximity to the patient group . our exclusion criteria for control group were having any health problems , particularly cancer or other chronic diseases , those who do not wish to participate in the study , and living in a different city from the patient group . after obtaining informed consent , the same questionnaire was administered face to face or over the phone to both patient and control groups . in the questionnaire , individuals were asked primarily for demographic information such as age and sex , then smoking habits ( pack / year was asked and grouped as nonsmoker , smokers with a history of 05 packs / year , 510 packs / year , 1020 packs / year , and over 20 packs / year ) , and tea consumption ( daily amount of consumption is asked based on the number of cups and one cup was quantified as 80 cc ) . traditionally , people start to consume herby cheese from childhood until death . some of the inhabitants of this region consume herby cheese in three meals a day while some others consume it only in breakfast . andalso some people eat only one or two bites at every meal ; some of them can eat about 200 to 300 grams . so , to assess the consumption of cheese patients were asked how many meals in which they consumed herby cheese before symptoms have started . and we also asked the control group how many meals they generally consume herby cheese . to assess the amount of cheese consumed in grams , we wanted both groups to think of a matchbox or we showed them a matchbox . finally , we calculated the quantity of herby cheese consumed per day by collecting total amount of cheese consumed per meal . a tandoor is a cylindrical clay oven used for cooking and baking in many countries like pakistan , india , turkey , iran , afghanistan , burma , and bangladesh . in the east part of turkeytandoor exposure was asked based on year ( grouped as no exposure , 010 years , 1020 years , over 20 years exposure ) and recorded . pathologic evaluation of the patient group 's resection materials was performed after classifying the tumors as esophagus , gastric cardia , corpus , and antrum ( esophagus was coded as 0 , cardia 1 , corpus 2 , and antrum 3 ) according to localization . esophageal tumors were divided into two ( well differentiated and moderately differentiated squamous cell carcinoma ) and gastric tumors into three ( well differentiated , moderately differentiated , and poorly differentiated ) groups histopathologically . additionally gastrointestinal stromal tumors and other rarely seen tumors were separately grouped and coded as gist and other , respectively . when we retrospectively reviewed patients ' files , we found that in some cases hp status of patients had noted in their endoscopy report and also in their endoscopic biopsy report which had performed before surgery . so , we categorized hp status as negative ( in those hp was studied and was negative ) , positive ( in those hp was studied and was positive ) , and unknown ( whose hp status was not studied or not reported ) . hp diagnosis of all patients , whose hp status studied , was made by histological examination after being stained with giemsa . the data was divided into three groups as unknown , positive , and negative ones . for normally distributed data , one - way anova and , for nonnormal distributed data , nonparametric tests mann - whitney u and kruskall - wallis were used for the comparisons between groups . for correlation analysis , spearman method , forrate comparisons and determining relative risk estimate , chi - square test , and , for calculating cut - off point , logistic regression analysis methods were used . in all analyses , p value less than 0.05 patient group comprised a total of 113 esophageal or gastric cancer patients and the control group included 100 subjects . both groups were similar in terms of sex , number of people , and age ( table 1 ) . herby cheese ( total daily amount in grams ) and tea consumptions of the patient and control group were found as indicated in table 2 . although there was no significant difference between the groups , hot tea ( 84c = temperature in a tea cup ) consumption before cooling down , which is one of the habits peculiar to eastern anatolia , was found to be too much in both groups ( p = 0.055 ) . herby cheese consumption , in both meals and daily total amount in grams , was found to be significantly higher in the patient group ( p 0.001 ) . significant differences were found between the groups in terms of smoking , tandoor exposure , and herby cheese consumption in meals ( figure 1 ) . when we looked at smoking based on pack - year , it was found that nonsmokers were the majority in control group whereas smokers over 5 packs / year were 65.5 % of the patient group . tandoor exposure was found to be a condition only seen in women in both control and patient groups . traditionally , cooking bread on tandoor is only made by women . a significant difference was found between female patients and female controls in terms of tandoor exposure ( p = 0.0013 ) . nonexposure to tandoor was 7.1 % in female patients whereas it was 36.0 % in control group . in addition , 48.2 % of the women who were exposed to tandoor had more than 20 years of exposure . when we considered herby cheese consumption in terms of meals , interestingly we found that individuals in both patient and control groups , who eat herby cheese at breakfast and lunch , always have it for dinner .77.0 % of the patient group consumes herby cheese at 3 meals whereas this rate was 17 % in control group . as a result of the analysis of daily herby cheese consumption ( amount in grams ) of the groups with logistic regression ( nagelkerke 's r of 0,519 ) and roc ( figure 2 ) , it was found that for every 1 gram over 150 gr consumption the risk increases 1.7 % ( odds ratio : 1.017 ; 95 % cl : 1.0121.022 ) . when we looked at the tumor characteristics and eating and lifestyle habits of a total of 113 cancer patients , 37 of the tumors ( 32.74 % ) were found to be located in esophagus , 43 ( 38.05 % ) in cardia , 12 ( 10.62 % ) in corpus , and 21 ( 18.8 % ) in antrum . when we looked at the gender distribution according to tumor localization ( figure 3 ) , in 44.64 % of the female patients tumors were located in esophagus , 26.79 % in cardia , 10.71 % in corpus , and 17.86 % in antrum whereas these rates were found to be 21.05 % , 49.12 % , 10.53 % , and 19.30 % , respectively , in male patients ( p = 0.0336 ) . esophageal cancers were in the majority of female patients whereas in male patients it was found that almost half of the tumors were located in cardia . there was no significant relation between gender and histologic type and stage of the tumor ( p = 0.86 and p = 0.092 , resp . ) . when we compared the tumor localization and stage according to gender differences ( table 3 ) , the distal tumors were found to be diagnosed at a later stage than the proximal tumors . when we looked at the relationship between daily amount of tea and herby cheese consumption and tumor localization ( figure 4 ) , it was found that the amount of consumption was considerably higher in patients with esophagus and cardia tumors than in patients with corpus and antrum tumors ( p 0.001 ) . moderate correlation was detected between the amount of herby cheese and tea consumption and tumor localization ( for herby cheese spearmen rho : 0.50 , for tea spearmen rho : 0.543 , p 0.001 ) . it was found that the more distally located tumor the less amount of herby cheese and tea consumption . when we evaluated the tumor localization with the amount of cigarettes smoked , the exposure time to tandoor , and the amount of herby cheese consumption per meal ( figure 5 ) , it was found that all the patients with 1020 packs / year and more than 20 packs / year history of smoking had esophageal or gastric cardia tumors . similarly , the vast majority of the female patients with esophageal or gastric cardia tumors ( 92 % and 93.4 % , resp . ) were exposed to tandoor for 1020 years or more than 20 years . all the patients with esophageal tumors were found to consume herby cheese in 3 meals , whereas 93 % of the patients with gastric cardia tumors consume it in 3 meals per day . there was a high correlation between herby cheese consumption per meal and tumor localization ( spearman rho : 0.615 , p 0.001 ) . significant relationship was detected between hp positivity and histologic type and localization of tumor ( p = 0.004 and p = 0.01 , resp . ) . the hp positivity ratio was 63.3 % in poorly differentiated adenocarcinoma cases and 68.4 % in moderately differentiated adenocarcinoma cases whereas it was found to be 15.4 % in moderately differentiated squamous cell carcinomas ( figure 6 ) . according to the world health organization ( who ) at least one - third of all cancer cases are preventable and also about 40 % of them can be treated with early diagnosis . in some high - risk areas of the world ( e.g. , linxina region of china , golestan province of iran ) the incidence and mortality of esophageal and gastric cancers are about 10 times more common when compared to other low - risk areas . esophageal and gastric cancers , which rank first among preventable cancers in van lake region of eastern turkey , are still serious public problems just like in those regions mentioned above . in particular common features of some of the eating and lifestyle habits are being emphasized in areas where esophageal and gastric cancers are common . some of these common risks such as low socioeconomic status , heavy cigarette smoking , consuming very hot drinks , high frequency of hp , and too salty foods are also common in the eastern anatolia whereas indoor cooking bread on tandoor is much more unique for van lake region . these risks should be discussed for also van lake region to reduce the cancer incidence . in this sense , when we investigated the characteristics of eating and lifestyle habits of van lake region , tea consumption at high temperature ( drinking very hot tea before cooling down with a lump of sugar in one 's mouth , a drinking style called ktlama ) , heavy cigarette smoking of males from younger ages , consumption of heavily salt - brined herby cheese , and indoor bread cooking on tandoor , a serious source of carcinogens especially for women , are all important issues drawing the attention . in this study we investigated the relationship between esophagus and gastric tumors , which are endemic in van lake region , and those aforementioned eating habits , which have been the subject of many studies ; there were no statistically significant effects of those hot drinks emphasized in the literature . however , it is an undeniable fact that drinking at a temperature of approximately 84c with an amount of up to1 liter of black tea per day can cause thermal injury to the esophagus . islami et al . reported in their systemic study that there is little evidence showing the relationship between the amount of tea and coffee consumption and esophageal cancer whereas there are strong evidences showing that the temperature of the drinks increases the cancer risk . we considered that the habit of drinking very hot tea right after pouring the cup , with a lump of sugar in one 's mouth , so - called ktlama type drinking in the region , exposes the esophagus to high temperatures . it is widely accepted in both western and eastern studies that smoking increases the risk of esophageal and gastric cancer . we believed that heavy cigarette smoking is much more common among men whereas , for women , dense smoke , released from dung cake ( called tezek in the region ) burning when used for tandoor fuel , is a considerable risk . squamous cell carcinoma is 2 - 3 times more common in males than females in low - risk areas of the world whereas these ratios become equal in some of the regions of china and iran , known as high - risk areas . however , interestingly , in our study , esophageal tumors were found to be 2 times more common in females than males in contrast to the literature . in this case , we thought that tandoor exposure , which is seen only in females , might have role . furthermore , in our study , it was reported that approximately 66 % of the female patients with esophageal cancer were exposed to tandoor for more than 20 years . traditionally , herby cheese is heavily salt - brined and it is consumed after waiting for 3 - 4 months in the region . high amounts of salt , nitrate and nitrite , which are found in brined foods and also in herby cheese , are known to be possible risks for esophageal and gastric cancers . the detected amount of nitrate and nitrite was found to be significantly higher in herby cheese in comparison with normal white cheese . in our studywe reported that more than 150 gr herby cheese consumption per day increases the cancer risk ( p 0.001 ) and majority of the patient group ( 70 % ) consumes it 3 meals per day . these findings , when considered together with the exposure to high levels of nitrous components , might be important in cancer etiopathogenesis . since the hp was accepted as a biological carcinogen by who , it has been reported in many studies in the literature that hp positivity increases the risk of gastric ( especially the distal tumors ) cancer . when socioeconomic status of the van lake region and unawareness and poor hygiene status of the inhabitants are taken into consideration together with the fact that very low levels of hp eradication are applied in the region , in particular in cardia located cancers positivity rates were too high far beyond the literature . although there are studies indicating that hp positivity decreases the risk of esophageal cancer , debates in this issue still continues . in parallel with this information , also in our study , we found that hp positivity was significantly lower compared to other localizations ( p = 0.004 ) . as with all retrospective case - control studies , the most important limitations of our study were the subjects ' mistakes in remembrance of the data and prejudices of the data collectors . nevertheless , we believe that noticing the negative relationship between lifestyle and eating habits and esophageal and gastric cancers in van lake region and taking community - based measures towards these problems can decrease the incidence and mortality rates of these tumors although not reaching the rates of who .\noutput:\n" }, { "from": "agent", "value": "purpose . to examine the relationship between esophageal and gastric cancers commonly seen in van lake region and the traditional eating habits of the geography . materials and methods . esophageal and gastric cancer cases , who underwent surgery between january 1 , 2012 , and december 31 , 2013 , were examined . pathology reports of the patients and presence of helicobacter pylori ( hp ) were recorded . surveys were filled by face to face meeting or telephone call . control group was created with randomly selected individuals without any cancer diagnosis having age , gender , and socioeconomic characteristics similar to patient group . all data were analyzed using sas .9.3 statistical programme . results . compared with the control group , herby cheese consumption ( a component of eating habits ) and smoking were significantly higher in the patient group ( p < 0.001 ) . tandoor exposure is compared in terms of female gender , and significant difference was found between the groups ( p = 0.0013 ) . as a result of the analysis with logistic regression more than 150 gr of herby cheese consumption per day was found to increase the cancer risk ( odds ratio 1.017 ; 95 % ci : 1.0121.022 ) . conclusion . a high consumption of herby cheese , cooking bread on tandoor , and heavy smoking were seen to be important risk factors for esophageal and gastric cancers ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: uterine leiomyoma is a benign subclinical gynecological tumor occurring frequently in women of childbearing age . the symptoms include menorrhagia , abnormal vaginal bleeding , dysmenorrhea , dyspareunia , pelvic pain , and urination frequency . the infrequent acute complications include thromboembolism , acute torsion , renal failure , acute pain due to secondary degeneration , mesenteric vein thrombosis , and intestinal gangrene .1 they are very rare complications that their exact incidence is not known . this paper reports the case in which the uterus was normal , but the subserosal leiomyoma was twisted to cause acute abdominal pain . due to the rarity and difficulty of preoperative diagnosis by ultrasonography ( us ) , computed tomography ( ct ) scan and magnetic resonance imaging ( mri ) , furthermore , if the diagnosis is not made promptly , ischemic gangrene and peritonitis can occur .2,3 thus , the torsion of subserosal leiomyoma should be diagnosed and treated by a surgical approach immediately upon suspicion . with a review of related literature , we discuss a case of torsion of subserosal leiomyoma , where the patient was misdiagnosed as secondary degeneration of uterine leiomyoma at our hospital prior to the operation . a 26 - year - old woman visited our emergency department with acute lower abdominal pain and diarrhea on 2 october 2012 . the abdominal pain developed 2 weeks ago and increased in intensity over the past few hours . she had three episodes of watery diarrhea per day . prior to presenting to our emergency departmenteven though she was taking probiotics and analgesics , the symptoms did not improve , resulting in her referral to our emergency department . on physical examination , the temperature was 37.5 , and there was direct and rebound tenderness in the lower abdomen . the white blood cell count was 9,430 / l ( normal value 4,000 - 10,000 / l ) with 78.1 % segment neutrophils ( normal value 40.0 - 74.0 % ) , and c - reactive protein was elevated to 2.1 mg / dl ( normal value 0.5 mg / dl ) . a transvaginal us showed a deviated uterus with a heterogeneous echoic globular mass , measuring 476 cm ( fig .1 ) . pelvic mri revealed a pelvic mass connected to the posterior aspect of the uterine corpus with a distinct border , measuring 48.45.5 cm , in conjunction with a small amount of ascites . we presumed that it could be torsion or red degeneration of a pedunculated subserosal uterine leiomyoma . the patient underwent an emergency diagnostic laparoscopy under general anesthesia on the day of admission . at the time of laparoscopy , a dark blue subserosal leiomyoma , approximately 8 cm in size , was identified on a twisted pedicle to the posterior surface of the uterus ( fig . the bilateral ovaries and fallopian tubes were grossly normal and there was approximately 15 ml of ascites . on pathologic report , leiomyomatous tissue with multifocal hemorrhage and congestion was noted with dilatated vessels . postoperative course was uneventful , and she was discharged from the hospital three days after the operation . the etiology of uterine leiomyoma is not yet defined , but since leiomyomas arise after menarche and decrease in size after menopause , serum estrogen concentration is expected to have influence on the physiological changes of leiomyoma .4 recently , there has been a new approach to cause analysis , prevention and management of leiomyoma with the study of polymorphisms of estrogen receptor .5 in general , when a patient with a leiomyoma experiences acute abdominal pain , the cause may be due to other organs rather than uterine leiomyoma ; therefore , it is necessary to exclude the possibilities of appendicitis , gastroenteritis , pelvic inflammatory disease , and torsion of ovarian cyst . even when the acute complication is due to uterine leiomyoma , the pain is mostly caused by secondary degeneration . although cases on torsion of subserosal leiomyoma are mostly subclinical , the presenting symptoms are non specific . in addition , due to its rarity , the diagnosis can not be confirmed preoperatively . there have been several cases reported on torsion of uterine leiomyoma .6,7 however , there are only a handful of case reports on torsion of subserosal leiomyoma . in fact , the diagnosis is usually difficult preoperatively , partly because there are no known specific findings associated with this condition . us can identify a subserosal leiomyoma , but not its torsion . the torsion of subserosal leiomyoma may be suspected when color doppler demonstrates twisted pedicle or when the distance between the leiomyoma and the uterus is observed . us may not be an effective method especially when twisted pedicle is thin .8 non - necrotic or non - degenerated uterine leiomyomas on mri show hypo - intense homogeneous t2 signal and iso - intense t1 signals . however , gangrenous uterine leiomyomas show heterogeneous hyper - intense t2 signals and hyper or iso - intense t1 signals .3 regardless of utilization of many imaging modalities , torsion of subserosal leiomyoma is a rare condition and is seldom diagnosed preoperatively , partly because twisted pedicle is often invisibly thin and the absence of contrast enhancement is not specific . there are nonsurgical management methods such as radiofrequency ( rf ) or uterine artery embolization ( uae ) , but may lead to complications such as pyometra .9 for our case , the patient had suffered from abdominal pain for 2 weeks before the operation . because her condition had not improved , she was led to admission at our hospital . although ultrasound and clinical findings suggested subserosal leiomyoma at our hospital , the possibility of torsion was not considered just from the us findings . we judged that the abdominal pain was caused by secondary degeneration of uterine leiomyoma , and further confirmed by laparoscopic surgery that the torsion occurred . in addition to the difficult preoperative diagnosis , a delayed diagnosis may result in ischemic necrosis and continuous abdominal pain , which in turn could lead to peritonitis .10 as discussed above , even with all the imaging modalities , it is very difficult to make an accurate preoperative diagnosis of torsion of a leiomyoma . actually , based on our case and previous case reports , thus , for a patient with lower abdominal pain and tenderness around the leiomyoma , after excluding other possible causes of abdominal pain , we may consider the secondary degeneration of a uterine leiomyoma . this also applies for pregnant women , and it is a necessary step for treatment of infertility .11,12 as this case shows , for patients with persistent pain and subseroal myoma , we should consider the possibility of torsion . furthermore , our experience suggests that laparoscopic surgery should be preferred for more accurate diagnosis and treatment . in conclusion , with a review of related literature , we report the case of a patient with torsion of a subserosal leiomyoma .\noutput:\n" }, { "from": "agent", "value": "uterine leiomyoma is one of the most common gynecological tumor , whereas acute torsion of the uterine leiomyoma is very rare . we report a case of subserosal leiomyoma that was first detected by ultrasonography , and further confirmed as torsion of subserosal leiomyoma by laparoscopic surgery ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: patients with chronic kidney disease ( ckd ) show a very high cardiovascular morbidity and mortality . oxidative stress and rapid progression of atherosclerosis play an especially important role in increased risk of cardiovascular complications in ckd patients . the mechanisms responsible for enhanced oxidative stress in ckd patients include increased production of reactive oxygen species ( ros ) and dysfunction of the antioxidant defense system . increased serum concentration of the main lipid peroxidation product , malondialdehyde ( mda ) , in plasma and erythrocytes indicates overproduction of ros in ckd patients . data in the literature confirm dysfunction of the antioxidant defense system decreases activity of superoxide dismutase ( sod ) , glutathione peroxidase ( gsh - px ) , and catalase ( cat ) in ckd patients . glomerular filtration rate ( gfr ) has been reported to be inversely associated with mda concentration and positively correlated with sod activity . many published studies show that renal anemia plays a very important role in pathogenesis of increased oxidative stress in ckd patients ; higher degree of renal anemia is associated with stronger oxidative stress . erythropoiesis - stimulating agents ( esas ) , which are widely used in anemia treatment in ckd patients , seem to have renoprotective effects and slow progression of ckd , in addition to improving patient outcomes and quality of life . most publications on these renoprotective effects concern short half - life esas with possible renoprotective mechanisms as antiapoptotic , anti - inflammatory , and antioxidant effects . some evidence indicates that esa treatment caused increased activity of erythrocyte antioxidative enzymes and decrease of plasma and erythrocyte mda concentrations . long half - life esas such as darbepoetin - and especially methoxy polyethylene glycol - epoetin beta seem to be the best choice to achieve this long and slow renoprotective effect in predialysis patients with ckd . there is scant data about the influence of anemia treatment with darbepoetin - on oxidative stress in ckd patients . the lack of data in the literature concerning the influence of methoxy polyethylene glycol - epoetin beta on oxidative stress in predialysis ckd patients was the reason for conducting this study . thirty predialysis patients ( 20 men and 10 women ) with anemia and ckd in stage iv and v treated with methoxy polyethylene glycol - epoetin beta ( mircera , roche , basel , switzerland ) were enrolled in the study . causes of ckd were : hypertonic nephropathy ( 40 % ) , chronic tubule - interstitial nephritis ( 23 % ) , chronic glomerulonephritis ( 20 % ) , and polycystic kidney disease ( 17 % ) . the control group included 15 volunteers ( 10 men and 5 women ) without ckd ( egfr 60 ml / min , normal hemoglobin level , normal urine analysis , and kidney ultrasound ) . ckd patients with hemoglobin ( hb ) level 10 g / dl and egfr 30 ml / min , after excluding bleeding , iron deficiency , hemolysis , infection , and severe secondary hyperparathyroidism , received a subcutaneous injection of mircera in doses of 0.6 g / kg once monthly . treatment was continued until reaching the target hb level of 1112 g / dl , achieved by 28 patients who were enrolled in the second part of the study . the average mircera dose was 50 g / monthly ( from 30 to 75 g ) . we excluded patients with diabetes , blood transfusion in the past 3 months , acute infection , chronic infection ( hepatitis b and c ) , immunological disease , immunosuppressive therapy or history of malignancy . more data from patients who achieved target hb and the control group are presented in table 1 . the study was approved by the research ethics committee of the medical university of lodzerythrocytes play a key role in maintenance of the systemic and local antioxidant defense system ; therefore , evaluation of sod , gsh - px , and cat in erythrocytes is a reliable method for use in studying this system . similarly , increased mda concentration in plasma and erythrocytes is well known as a marker of ros overproduction and increased lipid peroxidation , and is strongly connected with oxidative stress . therefore , in our study , we assessed activity of sod , gsh - px , and cat in erythrocytes and mda concentration in plasma and erythrocytes as markers of oxidative stress . peripheral blood was drawn from ckd patients 2 times : before treatment with mircera and after achieving target hbvenous blood was collected into heparinized tubes and centrifuged for 15 min at 1500 g. plasma was separated and the erythrocytic mass was washed 3 times with a double volume of physiological saline solution and then hemolyzed . in the hemolysate , sod activity was determined by the adrenaline method according to misra and fridovich ; gsh - px activity was determined by the method with ellman s reagent of sedlak and lindsay , as modified by little and obrien with the use of cumene hydroperoxide as a substrate ; and cat activity was determined by the spectrophotometric method for measuring the breakdown of hydrogen peroxide of beers and sizer . the activities of these enzymes were expressed in units per gram of hemoglobin ( u / ghb ) . the degree of lipid peroxidation in erythrocytes and plasma was expressed as the concentration of thiobarbituric acid reactive substances ( tbars ) , mainly malondialdehyde ( mda ) , according to placer et al . . mda concentration in erythrocytes ( mda rbc ) is expressed in mol / ghb , and in plasma ( mda plasma ) in mol / ml plasma . evaluation of statistical significance was performed by t - test for paired and unpaired data . correlation between hb concentration and investigated markers of oxidative stress was evaluated by calculation of pearson r correlation coefficient . thirty predialysis patients ( 20 men and 10 women ) with anemia and ckd in stage iv and v treated with methoxy polyethylene glycol - epoetin beta ( mircera , roche , basel , switzerland ) were enrolled in the study . causes of ckd were : hypertonic nephropathy ( 40 % ) , chronic tubule - interstitial nephritis ( 23 % ) , chronic glomerulonephritis ( 20 % ) , and polycystic kidney disease ( 17 % ) . the control group included 15 volunteers ( 10 men and 5 women ) without ckd ( egfr 60 ml / min , normal hemoglobin level , normal urine analysis , and kidney ultrasound ) . ckd patients with hemoglobin ( hb ) level 10 g / dl and egfr 30 ml / min , after excluding bleeding , iron deficiency , hemolysis , infection , and severe secondary hyperparathyroidism , received a subcutaneous injection of mircera in doses of 0.6 g / kg once monthly . treatment was continued until reaching the target hb level of 1112 g / dl , achieved by 28 patients who were enrolled in the second part of the study . the average mircera dose was 50 g / monthly ( from 30 to 75 g ) . we excluded patients with diabetes , blood transfusion in the past 3 months , acute infection , chronic infection ( hepatitis b and c ) , immunological disease , immunosuppressive therapy or history of malignancy . more data from patients who achieved target hb and the control group are presented in table 1 . the study was approved by the research ethics committee of the medical university of lodzerythrocytes play a key role in maintenance of the systemic and local antioxidant defense system ; therefore , evaluation of sod , gsh - px , and cat in erythrocytes is a reliable method for use in studying this system . similarly , increased mda concentration in plasma and erythrocytes is well known as a marker of ros overproduction and increased lipid peroxidation , and is strongly connected with oxidative stress . therefore , in our study , we assessed activity of sod , gsh - px , and cat in erythrocytes and mda concentration in plasma and erythrocytes as markers of oxidative stress . peripheral blood was drawn from ckd patients 2 times : before treatment with mircera and after achieving target hbvenous blood was collected into heparinized tubes and centrifuged for 15 min at 1500 g. plasma was separated and the erythrocytic mass was washed 3 times with a double volume of physiological saline solution and then hemolyzed . in the hemolysate , sod activity was determined by the adrenaline method according to misra and fridovich ; gsh - px activity was determined by the method with ellman s reagent of sedlak and lindsay , as modified by little and obrien with the use of cumene hydroperoxide as a substrate ; and cat activity was determined by the spectrophotometric method for measuring the breakdown of hydrogen peroxide of beers and sizer . the activities of these enzymes were expressed in units per gram of hemoglobin ( u / ghb ) . the degree of lipid peroxidation in erythrocytes and plasma was expressed as the concentration of thiobarbituric acid reactive substances ( tbars ) , mainly malondialdehyde ( mda ) , according to placer et al . . mda concentration in erythrocytes ( mda rbc ) is expressed in mol / ghb , and in plasma ( mda plasma ) in mol / ml plasma . evaluation of statistical significance was performed by t - test for paired and unpaired data . correlation between hb concentration and investigated markers of oxidative stress was evaluated by calculation of pearson r correlation coefficient . the results concerning patients with ckd before esa treatment and the control group are shown in table 2 . sod , cat , and gsh - px activity were similar between ckd patients before esa treatment and the control group . mda concentrations in erythrocytes and in plasma were significantly higher in patients with ckd before esa treatment in comparison to the control group . the results concerning patients with ckd after esa treatment and the control group are shown in table 3 . there were no differences in activity of sod , cat , and gsh - px in ckd patients after esa treatment and the control group . mda concentrations in erythrocytes and in plasma were similar in ckd patients after esa treatment in comparison to the control group . the results concerning patients with ckd before and after esa treatment are shown in table 4 . hb concentration after esa treatment was significantly higher but creatinine concentration and egfr were comparable to those before esa treatment . activity of sod , cat , and gsh - px was significantly higher after esa treatment , but mda concentrations in erythrocytes and in plasma were significantly lower after esa treatment in comparison with those before treatment . the correlation between hb concentration and markers of oxidative stress is shown in table 5 . we did not find a significant correlation between hb concentration and activity of sod , cat , gsh - px , and mda concentration in erythrocytes and in plasma in ckd patients . analysis of all investigated groups showed a significant negative correlation between hb concentration and plasma mda concentration . our study shows that sod , cat , and gsh - px activity was similar in ckd patients before methoxy polyethylene glycol - epoetin beta treatment to that of the control group . in addition we observed that mda concentrations in erythrocytes and in plasma were significantly higher in patients with ckd before treatment in comparison to the control group . our findings , similar to those reported in the literature , but concerning short half - life esas , indicate that ckd is connected with increased oxidative stress . the literature regarding ckd patients indicates decreased sod , cat , and gsh - px activity and increased mda concentrations in plasma and erythrocytes as a result of increased ros production . increased ros production and a reduced antioxidant defense system , caused by oxidative stress , play an important role in pathogenesis of accelerated atherosclerosis , hypertension , and cardiovascular disease , which are the major cause of death in patients with ckd . the pathogenesis of oxidative stress in ckd pre - dialysis patients includes uremic toxins , malnutrition , and intravenous iron supplementation . inflammation , immunological cell activation , and release of cytokines are connected with ros overproduction and could be triggers of oxidative stress in ckd . recent data indicate a relationship between the progression of ckd and the activities of gsh - px , sod , cat genotypes , and oxidative stress . some data in the literature indicate a link between oxidative stress and anemia , which is very common in ckd patients . hypoxia due to anemia can cause overproduction of mitochondrial ros and enhance oxidative stress . in the management of renal anemia , short half - life epoetin alfa or beta and long half - life darbepoetin - or methoxy polyethylene glycol - epoetin beta have been successfully used , both in patients treated with dialysis and in predialysis . erythropoietin ( epo ) , through its main action ( stimulation of red blood cell precursor with subsequent correction of anemia , improvement of blood flow and tissue oxygenation ) , may inhibit oxidative stress , apoptosis , and tissue fibrosis , which in turn may slow down the progression of ckd and decrease cardiovascular morbidity and mortality . there is some evidence that anemia treatment with epo is associated with improvement of oxidative stress by reducing ros production and by improving the antioxidant defense system . in the available literature , we found no data regarding the effect of methoxy polyethylene glycol - epoetin beta on oxidative stress in ckd patients . the results of our study indicate that ckd patients treated with methoxy polyethylene glycol - epoetin beta , after reaching the target hemoglobin level , showed a significantly higher activity of sod , cat , and gsh - px and significant reduction in plasma and erythrocyte mda concentrations in comparison to ckd patients before esa treatment . we did not observe a significant correlation between hb concentrations in all investigated groups and activities of sod , cat , and gsh - px , and with erythrocyte mda concentrations . analysis of all investigated groups showed a significant negative correlation between hb concentration and plasma mda concentration only . our findings indicate that anemia treatment with methoxy polyethylene glycol - epoetin beta may reduce ros overproduction and lipid peroxidation and enhance the antioxidant defense system in predialysis ckd patients . there are no data on the possible mechanisms of inhibition of oxidative stress by methoxy polyethylene glycol - epoetin beta in the literature . most likely , these mechanisms are similar to those described in the case of short half - life esas . proposed mechanisms of antioxidative effects of epo include : increasing heme oxygenase - 1 expression , induction of antioxidative enzymes , reduction of ros production , depleting body iron , and increasing the number of circulating young red blood cells with increased levels of erythrocyte antioxidative enzymes . it is worth noting that in our study there was no deterioration of renal excretory function during or after reaching the target level of hb compared to the value before esa treatment . perhaps this was because the average duration of treatment required to achieve the target hg level was relatively long and the applied doses of esas were small . a search of the literature shows that the most favorable renoprotection is achievable using the slow correction of anemia with a lower dose of preferably long half - life esas . the results of our study suggest that treatment of anemia with methoxy polyethylene glycol - epoetin beta may inhibit oxidative stress in ckd pre - dialysis patients due to enhancing the antioxidant defense system and reducing ros production . the treatment of anemia with methoxy polyethylene glycol - epoetin beta in predialysis ckd patients could be associated with the nephroprotective action arising from the compensation of anemia , improvement of blood circulation and oxygenation of tissues and organs , as well as from the inhibition of oxidative stress . further intensive research on large groups of patients is needed to confirm the nephroprotective properties of methoxy polyethylene glycol - epoetin beta and to establish the mechanisms of this nephroprotection .\noutput:\n" }, { "from": "agent", "value": "backgroundthere is data in the literature indicating increased oxidative stress in chronic kidney disease ( ckd ) . erythropoiesis - stimulating agents ( esas ) , which are commonly used to treat anemia in patients with ckd , seem to have an antioxidant action , which could be a part of nephroprotection . the aim of the current study was to investigate the effect of a long half - life esa , methoxy polyethylene glycol - epoetin beta ( mircera ) , on some markers of oxidative stress in predialysis patients with ckd.material / methodsperipheral blood was collected from 28 predialysis ckd patients 2 times , before mircera treatment and after achieving target hemoglobin ( hb ) , and 15 healthy subjects ( control group ) . superoxide dismutase ( sod ) , glutathione peroxidase ( gsh - px ) , and catalase ( cat ) activity in erythrocytes were measured according to commonly used methods as a function of the antioxidant defense system . to assess reactive oxygen species ( ros ) production , malondialdehyde ( mda ) concentration in erythrocytes and in plasma was measured according to a commonly used method.resultssod , gsh - px , and cat activity were similar , but plasma and erythrocyte mda concentrations were significantly higher in ckd patients before esa treatment in comparison to the control group . sod , gsh - px , and cat activity was significantly higher , but plasma and erythrocyte mda concentrations were significantly lower , in ckd patients after esa treatment in comparison to these patients before treatment . we did not find a significant correlation between hb concentration and sod , gsh - px , and cat activity and plasma , as well as erythrocyte mda concentrations . analysis of all investigated groups showed a significant negative correlation between hb concentration and plasma mda concentration.conclusionsour results suggest that treatment of anemia with methoxy polyethylene glycol - epoetin beta may inhibit oxidative stress in predialysis patients with ckd by enhancing the antioxidant defense system and reducing ros production ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: progressive dysfunction of the right ventricle ( rv ) are the most important threatening factors in the long - term prognosis of these patients . correlation between fatal arrhythmias and increased qrs duration 180 ms has been reviewed . magnetic resonance imaging ( mri ) is considered the best method of investigating pr severity and rv dysfunction in corrected tof patients . however , studies showed correlation with echocardiographic findings which is cheaper and more available . in this study we assessed the correlation between qrs duration on electrocardiogram ( ecg ) , pr and rv performance index ( rvmpi ) to examine whether severe pr and rv dysfunction can be detected by surface ecg . children with corrected tof who visited our outpatient clinic from march 2008 to august 2010 were enrolled in this study . patients with more than mild tricuspid valve insufficiency , residual ventricular septal defect ( vsd ) with a size 4 mm , residual pulmonary stenosis ( ps ) with a gradient 35 mmhg , left ventricle ejection fraction ( lvef ) 50 % , and other types of tof including pulmonary atresia / vsd and double outlet right ventricle / vsd / ps were excluded from the study . on ecg , qrs complex duration in lead ii was measured from the start of q wave to end of s wave . pr was evaluated by continuous doppler echocardiography at parasternal short axis view : pr duration and total time of diastole were measured and their ratio ( pr index , pri ) was calculated . we measured the time of blood ejection from the pulmonary artery using continuous doppler at parasternal short axis view ( a ) and tricuspid valve opening to closure time using tricuspid valve continuous doppler ( b ) and calculated rv mpi by the formula \" ( a - b ) / b \" . a bivariate correlation was performed using pearson correlation coefficient between qrs duration and both pri and rvmpi . fifty seven patients were enrolled in the study ( 30 males and 27 females ) with the mean age 7.15.3 years at the time of study and the mean interval after surgery 2.32.1 years . pearson analysis showed a strong inverse correlation between qrs complex duration and pri ( r = - .536 , p 0.001 ) ( fig . correlation between qrsd , qrs duration ; prix , pri ( r = - .536 , p 0.001 ) . there was no statistically significant correlation between qrs complex duration and rvmpi ( r = 0.242 , p = 0.084 ) . one of the 3 was a 7 year - old boy who had a corrective surgery at the age of 1.5 years . his qrs complex duration and rvmpi were 180 ms and 0.6 , respectively . because of progressive rv dysfunction , cardiomegaly and hepatomegaly , the other 2 patients with severe pr ( pri 0.5 ) were 7 and 9 year - old boys with corrective surgery at the ages of 1 and 4 years , respectively . there were 7 other patients in the cohort with qrs duration 160 ms but pri 0.5 . therefore , a qrs duration 160 ms can predict severe pr with 100 % sensitivity and 87 % specificity . tof is the most common cyanotic heart disease ( 3.5 - 9 % of congenital heart diseases ) . several studies showed that pulmonary valve replacement improves ventricular function and functional class , stabilizes qrs duration , and decreases the rate of ventricular and atrial arrhythmias while its mortality is about 2 % with few complications . murphy et al reported that among patients with surgically repaired tof ( rtof ) , the overall 32 - year actuarial survival rate was 86 percent ; however , it remains lower than that in the general population . the risk of late sudden death is low . the presence and degree of pr influence exercise tolerance , the incidence of atrial and ventricular arrhythmias , and the risk of sudden cardiac death ( scd ) . incidence may be as high as 6 % , and until the past decade there were no consistent identifiable risk factors for distinguishing patients at risk . gatzoulis et al provided the first clues to potential causes for ventricular arrhythmias in rtof . they reviewed the clinical data of 178 adult survivors with rtof after a mean follow - up of 21.4 years . nine patients were found to have sustained ventricular arrhythmias , and four patients had postoperative scd . they found that qrs duration 180 ms predicted sustained ventricular arrhythmias and scd with 100 % sensitivity , and that qrs duration correlated with rv size . over the next few years , data supported the idea that the scd risk in rtof is a time - related risk factor that accelerates 20 to 25 years after surgical repair . according to li et al , the ratio of pr time to total diastolic time is correlated with pr fraction in mri : a value 50 % indicates severe pr . long qrs duration is a result of rv dilation , which itself can be a result of severe pr . we used rvmpi as a factor to assess rv systolic and diastolic functions ( normal range 0.3 ) . this may be due to small number of patients for detecting a weak correlation , late occurrence of rv dysfunction in the presence of severe pr and long qrs duration , and imperfectness of pulsed - doppler rvmpi to precisely reflect rv function . yasuoka et al showed that tissue doppler rvmpi measurement is superior to pulse doppler method used in our study , to detect rv dysfunction in rtof patient with pr .\noutput:\n" }, { "from": "agent", "value": "objectivedespite progresses in surgical correction of tetralogy of fallot , pulmonary insufficiency and progressive dysfunction of the right ventricle impress its long - term prognosis . in this study we examined the correlations between qrs duration , pulmonary insufficiency and right ventricular performance index.methodswe enrolled 57 repaired tetralogy of fallot patients . qrs duration on electrocardiogram , pulmonary regurgitation index ( regurgitation time to diastolic time ratio ) , and right ventricular myocardial performance index were measured.findingsthere was a strong inverse correlation between qrs duration and pulmonary regurgitation index . however , significant correlation did not exist between qrs duration and right ventricular myocardial performance index . qrs duration 160 ms predicted severe pulmonary regurgitation with 100 % sensitivity and 87 % specificity.conclusionincreased qrs duration can predict severity of pulmonary regurgitation ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: h and c - nmr spectra : varian unity - 400 spectrophotometers , at 400 ( h ) and 100 ( c ) mhz , with me4si as internal standard ; in ppm , j in hz . the meoh extract was applied to a si gel column and eluted with chcl3 to yield justicidin e ( 5 mg ) . elution with n - hexane - etoac ( 8:1 ) yielded diphyllin ( 13 mg ) and 11 ( 11 mg ) . elution with n - hexane - etoac ( 4:1 ) yielded justicidin a ( 105 mg ) , 10 ( 15 mg ) , 14 ( 35 mg ) , 12 ( 10 mg ) . elution with n - hexane - etoac ( 3:1 ) yielded 9 ( 12 mg ) . elution with n - hexane - etoac ( 2:1 ) yielded 16 ( 15 mg ) . the isolated compounds were identified by spectroscopic methods and comparison with the spectroscopic data reported in literature . platelet aggregation in human prp assays were performed by the method described previously . the reaction mixture ( 0.1 m tris - hcl , ph 8.0 , 5 mm tryptophan , 8 mm hematin , test drugs , and 10 g / ml of ram seminal vesicles cox was incubated for 3 min at 30 c . the velocity of oxygen consumption in the reaction mixture was monitored continuously with a clark - type oxygen electrode using a ysi biological oxygen monitor ( model 5300 ) . the coordinates for the x - ray crystal structure of the enzyme cox - 1 was obtained from the rcsb protein data bank and hydrogens were added . the docking experiment on cox - 1 was carried out by superimposing the energy - minimized ligand on flp in the pdb file 1cqe after which flp was detected . the chemistry at harvard molecular mechanics force field ( charmm ) was employed for all docking purposes . the optical binding orientation of the ligand - enzyme site obtained after docking was further minimized for 1000 iterations using the conjugate gradient method until a convergence of 0.001 kcal / mol - . s. e. m. one - way analysis was used for multiple comparison , and if there are significant variation between the treatment groups and the inhibitor - treated groups , they were then compared with control group by student s t - test . h and c - nmr spectra : varian unity - 400 spectrophotometers , at 400 ( h ) and 100 ( c ) mhz , with me4si as internal standard ; in ppm , j in hz . the meoh extract was applied to a si gel column and eluted with chcl3 to yield justicidin e ( 5 mg ) . elution with n - hexane - etoac ( 8:1 ) yielded diphyllin ( 13 mg ) and 11 ( 11 mg ) . elution with n - hexane - etoac ( 4:1 ) yielded justicidin a ( 105 mg ) , 10 ( 15 mg ) , 14 ( 35 mg ) , 12 ( 10 mg ) . elution with n - hexane - etoac ( 3:1 ) yielded 9 ( 12 mg ) . elution with n - hexane - etoac ( 2:1 ) yielded 16 ( 15 mg ) . the isolated compounds were identified by spectroscopic methods and comparison with the spectroscopic data reported in literature . the reaction mixture ( 0.1 m tris - hcl , ph 8.0 , 5 mm tryptophan , 8 mm hematin , test drugs , and 10 g / ml of ram seminal vesicles cox was incubated for 3 min at 30 c . the reaction was initiated by adding 100 m aa . the velocity of oxygen consumption in the reaction mixture was monitored continuously with a clark - type oxygen electrode using a ysi biological oxygen monitor ( model 5300 ) . docking experiments were performed using ds modeling 1.2 ( accelrys inc . ) . the coordinates for the x - ray crystal structure of the enzyme cox - 1 was obtained from the rcsb protein data bank and hydrogens were added . the ligand molecules were constructed using ds modeling 1.1 and energy - minimized . the docking experiment on cox - 1was carried out by superimposing the energy - minimized ligand on flp in the pdb file 1cqe after which flp was detected . the chemistry at harvard molecular mechanics force field ( charmm ) was employed for all docking purposes . the optical binding orientation of the ligand - enzyme site obtained after docking was further minimized for 1000 iterations using the conjugate gradient method until a convergence of 0.001 kcal / mol - . s. e. m. one - way analysis was used for multiple comparison , and if there are significant variation between the treatment groups and the inhibitor - treated groups , they were then compared with control group by student s t - test .\noutput:\n" }, { "from": "agent", "value": "the known flavonoids ginkgetin ( 1 ) , taiwanhomoflavone a ( 2 ) , taiwanhomoflavone b ( 3 ) , and taiwanhomoflavone c ( 4 ) and eight known lignans : justicidin b ( 9 ) , justicidin c ( 10 ) , justicidin d ( 11 ) , chinensinaphthol methyl ether ( 12 ) , procumphthalide a ( 13 ) , procumbenoside a ( 15 ) , and ciliatosides a ( 16 ) and b ( 17 ) were isolated from cephalotaxus wilsoniana and justicia species , respectively . the antiplatelet effects of the above constituents on human platelet - rich plasma ( prp ) were evaluated . of the compounds tested on human prp , compounds 1 , 4 , 9 , and 11 showed inhibition of secondary aggregation induced by adrenaline . compound 1 had an inhibitory effect on cyclooxygenase - 1 ( cox - 1 ) . molecular docking studies revealed that 1 and the related compounds apigenin ( 5 ) , cycloheterophyllin ( 6 ) , broussoflavone f ( 7 ) , and quercetin ( 8 ) were docked near the gate of active site of cox - 1 . it indicated that the antiplatelet effect of 1 , 4 , 9 , and 11 is partially owed to suppression of cox - 1 activity and reduced thromboxane formation . flavonoids , 1 , 5 , 6 , 7 , and 8 may block the gate of the active site of cox - 1 and interfere the conversion of arachidonic acid to prostaglandin ( pg ) h2 in the cox - 1 active site ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: controlled - release multiunit dosage forms ( e.g. , pellets , granules , or microparticles ) are becoming more and more important on the pharmaceutical market , as they provide several advantages compared to single - unit dosage forms ( e.g. , tablets or capsules ) . with regard to the final dosage form , the multiunits can be filled into hard gelatin capsules or be compressed into disintegrating tablets . the advantages of tableting multiunits include less difficulty in oesophageal transport , and thus a better patient compliance . tablets can be prepared at a lower cost because of the higher production rate of tabletting process . the expensive control of capsules integrity after filling is also eliminated . in addition , tablets containing multiunits could be scored without losing the controlled release properties , which allows a more flexible dosing regimen . one challenge in the production of such systems is maintaining the desired drug release after compaction as the application of compaction pressure can lead to structural changes in the film coating and consequently altered drug release . the compression - induced changes in the structure of a film coating may depend on formulation factors such as mechanical properties of the film and incorporated excipients of pellets . another important parameter that should be considered is choosing of proper cushioning agent to prevent of undesirable fusion of coated pellets by the compression . in this study , a colon delivery formulation of budesonide was designed based on ph and time - dependent approach where film - coated pellets were compressed into multiparticulate tablets . budesonide , a potent glucocorticoid , is a standard drug for the localized treatment of inflammatory bowel diseases . current available oral formulations of budesonide have low efficacy against ulcerative colitis ( uc ) because of the premature drug release in the upper part of the gastrointestinal tract ( git ) . in this study , the pellets were prepared by extrusion / spheronization method and further coated sequentially with various polymers . then they were compressed into tablets using cellactose 80 or pearlitol 200 granules as tabletting excipient . the expected in vitro release pattern selected for the colon targeting was no drug release in simulated gastric fluid and not more than 10 % of drug release up to the end of small intestine ( 4 hrs ) and more than 80 % of drug release up to 24 hrs in the simulated colon . eudragit fs 30 d , eudragit ne30d , and eudragit l30d55 were donated by evonik degussa corporation ( germany ) . fmc ( ireland ) provided the microcrystalline cellulose as avicel ph 101 and avicel rc581 . talc and triethyl citrate ( tec ) were obtained from kirsh pharma ( germany ) ; lactose monohydrate 200 and cellactose 80 ( coprocessed lactose - cellulose - compound ) were obtained from meggle ( germany ) . all other materials used were of analytical reagent grade and purchased from merck co. ( darmstadt , germany ) . core pellets containing budesonide ( 1.5 % w / w ) , avicel ph 101 ( 6 % w / w ) , avicel rc581 ( 24 % w / w ) and lactose ( 68.5 % w / w ) were prepared by extrusion - spheronization using model 20 extruder and model 250 spheronizer ( caleva , uk ) . they were dried at room temperature for 24 h. pellets with the size range of 8401000 m were used for subsequent coating . budesonide containing pellet cores were coated with various polymers ( figure 1 ) using a top spray fluidized bed coater ( vector corporation , marion , iowa ) at coating conditions as shown in table 1 . a dispersion containing 0.25 % w / v of xanthan gum prepared by dispersing gum in 70 : 30 ethanol : water mixture containing plastisizer , triethyl citrate ( tec ) ( 5 % w / v , based on amount of solvent ) . before addition of plasticizer , gum mucilage was stirred gently for a period of 10 min with magnetic stirrer and the dispersion was allowed to equilibrate for a period of 3 h. the solution was allowed to stand at room temperature for 24 h. eudragit ne30d and eudragit l30d55 : the mixture of these two polymers ( 9 : 1 , 8 : 2 , and 7 : 3 ratio ( w / w ) ) was added to a beaker , placed on a magnetic stir plate and mixed with a slow agitation for a period of 1 h. talc , equal to 50 % ( w / w ) of the total dry polymer weight and tec equal to 20 % ( w / w ) of eudragit l30d55 dry polymer weight were added in a separate volume of water and dispersed via high shear mixing . the resulting dispersion had a total solid content of 15 % and was allowed to mix for a further 10 min prior to application to the budesonide pellets . talc ( 50 % on dry polymer weight ) and tec ( 10 % on dry polymer weight ) were added as glidant and plasticizer , respectively . after each coating run , pellets were fluidized for a further 15 min before checking the weight gain and then subsequently cured . a series of coated products were produced with different film thicknesses and quantified by the total weight gain ( % twg ) . the compositions of various pellet formulations are shown in table 2 . to produce multiple unit tablets , the optimized batch of coated pellets in size range of 11901410 m were mixed with different ratios and different proportion of the inert tabletting granules . distilled water ( the granulating liquid ) was added to cellactose or pearlitol and mixed for 10 min to produce a wet mass of suitable consistency , which was passed through 1 mm diameter sieve and were dried in an oven at 50c . the coated budesonide pellets and inert granules were compressed into tablets using a single punch - tabletting machine fitted with round flat faced 11.6 - mm - diameter punches and dies at 70 n compressions to get sufficient strength . the dissolution performance of the coated pellets and prepared tablets was tested using usp method 2 ( rotating paddle at 50 rpm , 370.5 c , n = 6 ) . for the first two hours of the test , 0.1 n hcl ( ph 1.2 ) ( 250 ml ) was used as the test medium . after two hours , the test medium was changed to phosphate buffer solution ( pbs ) ph 7.4 ( 250 ml ) for four hours and finally to pbs ph 6.8 ( 250 ml ) for 18 h. in all drug release studies , 0.5 percent ( w / v ) of sodium lauryl sulphate was used in each dissolution medium to maintain sink conditions . samples were withdrawn from the dissolution vessels at regular intervals and the concentration of budesonide in solution was monitored by hplc method described below . all tests were done on 6 tablets of each formulation and the mean of results was considered in release profiles . the quantitative determination of budesonide in assay and dissolution studies was performed by hplc method equipped with uv detector using dexamethasone as an internal standard . the analysis was carried out by using a shimpack c8 column ( 150 mm 4.6 mm , 5 mm particle size ) at a wavelength of 244 nm . the mobile phase consisted of acetonitrile , monobasic potassium phosphate ( 0.025 m ) ( 55 : 45 , ph of 3.2 ) . the flow rate was 1.0 ml / min and injection volume , 20 l . quantitation was achieved by measurement of the peak area ratios of the drug to the internal standard . optimized formulation was kept in the humidity chamber maintained at 40c and 75 % relative humidity for 3 months . at the end of studythe data of drug release were analyzed using one - way analysis of variance ( anova ) . the release profiles of optimized formulation were compared in stability and reproducibility tests using model - independent approach , with the similarity factor ( f2 ) defined by : ( 1 ) f2 = 50 + log { [ 1 + ( 1n ) t = 1nn ( rttt ) 2 ] 0.5100 } . the two release profiles were considered to be similar if f2 value was more than 50 ( between 50 and 100 ) . during this study , budesonide pellet core formulation was developed using extrusion - spheronization technique . the pellets had a 912.83 % budesonide release after 2 hrs in ph 6.8 , so any later slow release could be attributed to the coating system ( s ) being studied . in designing an ideal colon - targeted drug delivery system , the drug should not be released in the stomach and small intestine , and the release of drug must be completed within the residence time of the dosage form in the colon . in the case of the present study , it was assumed that for colon - targeting purpose , an 18 h extended release formulation with a delay in onset of about 6 h would be suitable . this lag time would ensure the passage of the formulation intact through the stomach and small intestine without noticeable drug loss . the approach of using mixed polymeric coating of eudragit ne 30d and eudragit l30d - 55 blends in time release applications has been reported previously . eudragit ne30d is an acrylic copolymer with neutral groups that enables controlled time release of the active ingredient by ph - independent swelling . as its softening temperature is ca .12 c , it forms very flexible film suitable for compression with an elongation limit up to 300 % due to the lack of strong interchain interaction . eudragit l30d - 55 is an anionic polymer , which contains cooh as a functional group that dissolves at ph 5.5 . l30d - 55 is known to be quite rigid with 20 % elongation using 10 % triethyl citrate as a plasticizer . four representative formulations of coated pellets were prepared by varying the ratio of eudragit l to eudragit ne as shown in table 2 . the results of in vitro drug release studies ( figure 2 ) indicated that increasing the polymer coating level of eudragit ne30d from 15 % to 30 % ( w / w ) caused a significant reduction in the drug release . the pellets coated with eudragit ne30d at a coating level of 30 % ( w / w ) showed negligible release during the 6 h of dissolution test in hcl 0.1 n and pbs ( ph 7.4 ) . nevertheless , at the end of dissolution studies , the mean percent drug released was only 58 % . the effect of coating with eudragit ne30d : eudragit l30d - 55 blend on in vitro drug release for three different batches of weight gains of 30 % ( w / w ) is shown in figure 3 . batches f4 , f5 , and f6 released no drug in acidic medium , 12.8 % , 18.5 % , and 23.3 % , at the end of 6 hrs , while 57.4 % , 70.5 % , and 84.3 % of drug was released at the end of 24 hrs , respectively . in pbs ( ph 7.4 ) , the enteric polymer ( eudragit l30d - 55 ) dissolved or leached out , thus increasing the permeability of the coating , offering less resistance for budesonide diffusion . although drug release of formulation f6 in simulating intestinal fluid was not optimal , the 3 : 7 ratio of eudragit l30d - 55 to eudragit ne30d was selected for further studies in consideration of the near complete release at the end of dissolution run . to achieve a desired release profile , xanthan gum as a release retardant polymer was chosen as the coating polymer for inner coating layer . xanthan gum rapidly forms a gel layer that retards seeping of dissolution fluids into the core pellets and reduces the diffusion of drug from the core to negligible level and decreases the drug release from the formulation . figure 4 shows the release of budesonide from pellets coated with various coating levels of xanthan gum as inner coating . coating with 2.5 % ( w / w ) xanthan gum ( f7 ) was not sufficient , and the drug release was the same as f6 ( p 0.05 ) . however , increasing the xanthan gum coating level to 12 % ( w / w ) resulted in lower release in simulated intestinal fluid significantly ( p 0.05 ) with no effect on the total amount of drug released in 24 hrs . it seems that rapid swelling and rapid erosion properties of xanthan gum played an important role in this regard . by observing the above results , it was found that f9 batch released 12.160.83 % of the drug in the simulated intestinal fluid and released up to 84.540.17 % at the end of the 24 hrs in the simulated colonic medium considered as suitable batch for colon targeting . to further provids mechanical resistance and resistance against the influence of gastric juice , different coating thicknesses of eudragit fs 30deudragit fs 30d is an anionic polymer of methacrylic acid and methacrylates that contains cooh as a functional group and dissolves at ph 7 . at the same time , fs 30d can achieve up to 300 % elongation that enables decreased damage to the pellet coating during tabletting . all eudragit fs 30d coated pellets with 12 % , as well as 20 % ( w / w ) weight gain further suppressed budesonide release in simulated intestinal fluid but had no significant effect on total budesonide released at the end of dissolution run ( figure 5 ) . as a thicker coatingcan prevent damage due to compression compared to the thinner coating and as the ability of pellets to undergo plastic and elastic deformation increases with increasing coating level , formulation f11 was selected to be combined with the inert tabletting granules in the preparation of multiple unit tablets . a major problem in compaction of coated pellets is that the coating can rupture on compaction , resulting in significant differences in dissolution profiles of coated pellets prior to and after compaction . there are two approaches in pellet tabletting : tabletting of pellets without other excipients and tabletting of pellets together with pharmaceutically acceptable excipients . the approach of pellets compacting without other excipients does not have the problem of particle segregation , but formulation of pellet cores and also the coating of produced tablets is very difficult . pellet cores must be deformable enough so that they form coherent tablets , and the coatings of pellets must be able to withstand compacting without damages , which can be ensured by formulating the coating of multiple units in such a way that the coating possesses improved elasticity . the approach of compacting of pellets together with tabletting excipients moderates requirements for the pellet coating elasticity , since plastically deformable tabletting excipients are able to partly absorb compaction forces and protect pellets from mechanical damages . this approach also enables easier obtaining of pellet - based tablets that have appropriate hardness and friability . to develop multiunit tablets of budesonide , coated pellets of f11 batch were mixed with cellactose or pearlitol granules as cushioning agents and compressed . the amount of cushioning agent was modified and studied for their effect on physical parameters of tablets and dissolution . four tablet formulations were studied ( f12 , f13 , f14 and f15 ) ( table 2 ) which were prepared at the same adjustment of press machine . all formulations were highly compressible resulting in tablets of enough crushing strength ( table 3 ) . friability of the tablets was also in the limits below 1 % after 4 min of testing . the results presented in table 3 show that the content uniformity and average weight of f12 and f13 batches significantly changed during the tabletting . in contrast , the use of cellactose produced tablets with improved content uniformity and average weight ( f14 and f15 ) . for these reasons f12 and f13the in vitro drug release patterns of the f14 and f15 batches were compared and also compared to the pellets before compression as shown in figure 5 . in the case of batch f14 ,7.96 % of the drug was released after 2 hrs in gastric ph compared to negligible release from the pellets before compression . then , the release became 14.32 % after 4 hrs in phosphate buffer ( ph 7.4 ) , compared to 8.16 % released from the pellets before compression . on the other hand , there was no difference in budesonide release from f15 and uncompressed pellets and the f2 value was 74.85 . we conclude that the increasing concentration of cellactose to 40 % minimizes contact of multiple units with each other and protects the pellets from deformation under compression pressure . recently a new technique has been introduced as mmx technology for production of colon - targeted tablets . multimatrix ( mmx ) technology is a promising new delivery system that can improve efficacy of current and new drugs , augmenting targeting to the affected tract , thereby increasing response and remission rates for those drugs in patients with ibd . this technology comprises hydrophilic and lipophilic excipients , enclosed within a gastroresistant , ph - dependent coating of acrylic copolymers , which delay the release until the tablet reaches the indicated intestinal location where the programmed dissolution begins . mesalamine mmx induces clinical and endoscopic remission in patients with mild - to - moderate ulcerative colitis ( uc ) compared with placebo . in a pilot study involving ten patients with uc , efficacy of heparin - mmx as an ibd therapypositive results have also been observed with mmx budesonide 9 mg extended - release tablets in phase i studies . budesonide - mmx induced a fast and significant clinical improvement of active left - sided uc without suppression of adrenocortical functions and without important toxicity . in comparison with budesonide - mmx tablets , the designed pellet based tablets of our study contains 3 mg budesonide and is a ph - and time - controlled colon - targeted delivery system . in addition , tablets containing multiunits could be scored without losing the controlled release properties , which allows a more flexible dosing regimen and a more uniform spreading of the pellets through the colon . figure 5 shows the release profiles of optimized formulation ( f15 ) at zero time and during storage period . no significant difference was found between the drug release profiles of the stored samples after three - month storage under accelerated conditions and f2 was 66.4 . the drug content was comparable with that of the control samples and within limits ( 10 % ) . on the basis of these results , it can be concluded that the formulation had enough stability under accelerated stability test conditions for three months . the study discusses the formulation of colon targeted multi unit tablets of budesonide for the treatment of uc . the pellets prepared for colon targeting of drug sufficiently protected drug release in the simulated environment of stomach as well as small intestine , and majority of drug release occurred in the simulated environment of colon . the budesonide - loaded pellets coated with 12 % ( w / w ) xanthan gum , 30 % ( w / w ) mixture of eudragit ne : eudragit l30d - 55 ( 7 : 3 ratio ) and 25 % ( w / w ) eudragit fs 30d exhibited a promising dissolution profile . cellactose granules as tabletting excipient , not only produced tablets with acceptable physical parameters , but also were able to protect the coated pellets from damage during tabletting and prevent premature drug release . the developed formulations were considered stable during 3 months of storage at accelerated stability conditions . although the proposed formulation is moderately complex , its manufacture is simple and reproducible , and could also be easily manufactured on a large - scale in a reasonable processing time using standard pharmaceutical equipments . however , it should not be forgotten that the in vitro studies of the effects of ph and time on the release characteristics are really only a prelude to in vivo studies in human volunteers and then in patients with active ulcerative colitis . it should be considered that colonic ph changes in the presence of active inflammation , that small bowel transit usually slows with severe colitis , and that there is often stasis in the right colon in the presence of active distal disease . thus , in vivo data are needed to really know whether the recommended formulation is going to be relevant .\noutput:\n" }, { "from": "agent", "value": "budesonide , a potent glucocorticoid , is used for the treatment of inflammatory bowel diseases . current available oral formulations of budesonide have low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract . in this paper a ph - and time - controlled colon - targeted pellet - based tablet of budesonide was established . pellet cores were prepared by extrusion - spheronization method and further coated with xanthan gum ( barrier layer ) , eudragit ne30d and l30d55 combination ( inner layer ) , and eudragit fs30 ( as enteric layer ) sequentially to achieve the required release profile . the coated pellets then compressed into tablets using inert tabletting granules of cellactose or pearlitol . release studies , performed in simulated gastric , intestinal , and colon ph were used in sequence to mimic the gastrointestinal transit . the influence of formulation variables like barrier layer thickness , inner layer composition , and enteric coat thickness on drug release were investigated and the coated pellets that contained 12 % weight gain in xanthan gum layer , eudragit l30d55 and eudragit ne30d with a ratio of 3 : 7 in inner layer with 30 % weight gain and 25 % weight gain in eudragit fs layer were found to protect the drug release in stomach and small intestine and 83.35 2.4 of budesonide was released at 24 h. the drug release from the tablets prepared using 40 % cellactose 80 as tableting excipient was found to be closely similar to that of uncompressed pellets ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: adoptive transfer of immune cells into a cancer - bearing host has been shown to be efficacious both in animal models and in human trials . several approaches have been used , such as the use of tumor - infiltrating lymphocytes , dendritic cell vaccines , lymphokine - activated killer cells , vaccine - primed lymph nodes , chimeric antigen receptor - modified t cells , and tumor - draining lymph node ( tdln ) cells . several groups have explored adoptive immunotherapy ( ait ) using tdln , which has shown significant therapeutic activity against a variety of murine tumors . lymph nodes ( ln ) draining progressively growing subcutaneous tumors contain antigen - specific preeffector t cells which have been sensitized to tumor cells but are not fully functional effector t cells . following ex vivo activation with anti - cd3 and culture with interleukin - 2 ( il - 2 ) , these preeffector cells acquire tumor - specific effector function against established tumor in vivo . despite the polyclonal nature of the cell culture with anti - cd3 and il - 2 , the resultant t cells mediate in vivo antitumor effect only against the tumor with which they were stimulated in vivo . though demonstrating in vivo therapeutic effect , these cells do not exhibit cytotoxic activity against tumor targets in vitro in some experimental models while they do in others . activated tdlns secrete interferon - ( ifn - ) in response to exposure to tumor cells in vitro . to optimize therapeutic efficacy , ex vivo expansion with anti - cd3 and il - 2 not only expands the number of cells by several folds but also activates the cells for therapeutic effect . in addition , t cells with low expression of the t cell homing receptor l - selectin ( l - selectin ) represent a group of potent tumor reactive t cells from within the total tdln cell population . transferred l - selectin cells isolated from tdln had a 30-fold greater therapeutic efficacy than unfractionated tdln cells . cytokine secretion is induced by exposure of activated t cells to tumor cells in vitro . transfer of only l - selectin cells had no therapeutic effect . l - selectin cells have been shown to act as suppressor t cells that can prevent l - selectin t cell antitumor activity . after expansion and activation with anti - cd3 and il - 2 , the cell population is enriched with t cells . during in vivotumor growth , sensitization of cd8 t cells in the tdln occurs independently from sensitization of cd4 t cells . during in vitro expansion and activation with anti - cd3 and il - 2 , cd8 cells require the helper function of cd4 cells . in some experimental models , transfer of either cd4 or cd8 cells activated tdln cells induced in vivo tumor regression , while in other models cd4 alone or cd8 alone was therapeutically ineffective . the role of the host immune system in adoptive t cell therapy is not entirely clear . regulatory t cells suppress tumor reactive t cells , and lymphodepletion with chemotherapy has been used as an approach to enhance adoptive t cell therapy . the purpose of this study was to determine the cellular effectors that play a central role in the antitumor efficacy of adoptive immunotherapy using tdln in an animal model . in this report , we demonstrate that treatment with l - selectin t cells from tdln draining 4t1 mammary tumors cause tumor regression . natural killer ( nk ) cells and / or other components of the innate immune system in the tumor - bearing host are necessary for antitumor effect of the transferred tdln cells . the 4t1 is a 6 - thioguanine - resistant cell line that was selected from a tumor cell line derived from a single spontaneously arising mammary tumor in a balb / c3h mouse . eight 12 - week - old female balb / c mice were inoculated subcutaneously with 1104t1 mammary tumor cells in the bilateral flanks . after 9 days of tumor growth , draining inguinal lymph nodes were surgically obtained and single cells were prepared and activated in complete media on 24 - well plates ( costar , cambridge , ma ) with immobilized anti - cd3 monoclonal antibody ( clone 145 - 2c11 ) at a density of 410 cells / 2 ml / well for 48 hours . following activation , cells were harvested and expanded with 25 u / ml il - 2 for 72 hours . activated t cells were resuspended in hank 's balanced salt solution ( hbss ) and adoptively transferred in 1 ml intravenously via the tail vein to mice bearing 3 - day established 4t1 subcutaneous tumors . freshly harvested 4t1 tdlns were subjected to immunodepletion using immunomagnetic beads and columns ( miltenyi biotec ) . cd62l ( l - selectin ) microbeads were used to derive the l - selectin prior to anti - cd3 / il - 2 culture activation . a second round of immunoselection was performed using cd4 and cd8 microbeads in select experiments . activated 4t1 tdlns were adoptively transferred into 3 - day established tumor - bearing recipient balb / c mice . the recipient mice included balb / c wild - type mice , balb / c scid ( lacking t and b lymphocytes as well as nk cells ) , and balb / c rag2 deficient mice ( lacking functional t and b lymphocytes ) . subcutaneous tumors were established in balb / c mice using 4t1 cells as well as the murine renal cancer cell line renca . activated t cells were cocultured with irradiated 4t1 or renca cells from freshly harvested subcutaneous tumors at an effector t cell to tumor target ( e : t ) ratio of 2 : 1 in 24 well plates . supernatants from activated t cell cultures were analyzed for interferon - ( ifn - ) using elisa ( r & d systems ) . it is known that naive t cells express high levels of cd62l ( l - selectin ) . l - selectin expression is lost during the effector phase and activated t cells are l - selectin . in order to characterize the t cell population obtained from tdln , the following experiments were performed . tdlns were harvested from the inguinal region of balb / c mice inoculated with 4t1 mammary cancer cell line . approximately 30 % of the tdln cell population prior to culture activation was l - selectin , suggesting antigen - priming of t cells within tdln in vivo ( table 1 ) . both the l - selectin and the l - selectin populations consisted of a mix of cd4 and cd8 t cells as well as b lymphocytes as indicated by the b220 antigen . after 5 - day culture activation of the l - selectin cell population , the final culture consists predominantly of a mixture of cd4 and cd8 cells at a 3 : 2 ratio . the next experiment sought to measure the secretion of interferon - ( ifn - ) by effector t cells , which is a major contributor to the antigen - specific therapeutic response in ait . secretion of the cytokine ifn - by 4t1 tdln was examined under multiple conditions to assess tumor - specific reactivity in vitro ( figure 2 ) .4 t1 tdlns were fractionated to derive l - selectin effector t cells which were then activated in culture for 5 days with anti - cd3 and il - 2 . the activated t cells were then cultured for 24 hours under 4 different conditions : ( 1 ) tdln alone as a negative control , ( 2 ) tdln with immobilized anti - cd3 as a positive control , ( 3 ) tdln with irradiated 4t1 , and ( 4 ) tdln with the irradiated renal cancer cell line renca , which is mhc - compatible with 4t1 ( mhc haplotype : h - 2k ) .4 t1 tdln exhibited tumor - specific reactivity to 4t1 cells compared to renca cells as measured by secretion of ifn - . these data suggest that the culture - activated t cells obtained from lymph nodes draining 4t1 mammary cancers in this animal model are primed specifically against tumor antigens from the 4t1 cell line . the next series of experiments sought to determine the therapeutic activity of tdln in balb / c mice in vivo . first , we evaluated the transfer of l - selectin cells into immunocompetent wild - type balb / c recipients bearing 3 - day established tumors ( figure 3 ( a ) ) . in contrast , all 5 mice treated with 4t1 tdln demonstrated shrinkage of tumor with ultimate disappearance and cure . this finding shows that ait using 4t1 l - selectin tdln completely treats established 4t1 mammary cancers in this model . in order to determine the contribution of the cd4 + and cd8 + t cell subtypes in the adoptively transferred cells to the overall therapeutic activity , balb / c mice bearing 3 - day established tumors were treated with adoptive transfer of tdln depleted of cd4 + or cd8 + cells ( figure 3 ( b ) ) . mice treated with t cells containing only cd8 + or cd4 + cells demonstrated tumor response and survival to 40 days , suggesting that both t cell subtypes play a role in antitumor activity . the majority of mice treated with only cd4 + t cells demonstrated cure , suggesting that the therapeutic efficacy appears to be primarily related to cd4 + t cells in this model system . finally , the contribution of the tumor bearing host 's immune system on the therapeutic effects of adoptive t cell therapy was determined using recipient mice with specific immune deficiencies .4 t1 tumors were established subcutaneously in scid mice , which lack t cells , b cells , and nk cells . all tumor - bearing scid mice died of metastatic disease regardless of treatment with control injection or tdln which was curative in immunocompetent wild - type balb / c mice ( figure 3 ( c ) ) . this finding suggests that some level of immune competence in the host is necessary for therapeutic efficacy of adoptively transferred tdln .4 t1 tumors were also established subcutaneously in rag2 deficient mice , which lack only t and b cells . tumor - bearing rag2 deficient mice that were administered control treatment died of metastatic disease , whereas those treated with tdln were cured ( figure 3 ( d ) ) . this finding suggests that nk cells or other components of the innate immune system within the tumor - bearing host are necessary for anti - tumor efficacy of transferred tdln in this model . in this study , we demonstrated that ait using culture - activated l - selectin t cells derived from 4t1 tdln cause tumor regression in a syngeneic murine model of mammary cancer . culture - activated 4t1 tdln cells demonstrated tumor - specific t cell reactivity evidenced by secretion ifn - in response to 4t1 , but not renca tumor cells , in vitro . both cd4 and cd8 t cells were necessary for maximal antitumor effect , but cd4 cells demonstrated more therapeutic activity than cd8 cells . using mice deficient in components of the immune system , we found that nk cells and / or other components of the innate immune system in the tumor - bearing host are necessary for antitumor effect of the transferred tdln cells in this model . modulating the immune system in order to treatadoptive immunotherapy with the activation of immune cells ex vivo followed by cell transfer into the tumor - bearing host has been a method used for over 20 years , with moderate clinical success . this includes infusion of tumor - infiltrating lymphocytes ( tils ) , lymphokine - activated killer cells ( laks ) , vaccine - primed lymphocytes , t cells genetically engineered to express tumor - specific antigen receptors , and t cells with chimeric antigen receptors ( cars ) . t cell therapy has been combined with infusion of the t cell growth factor il - 2 , as well as nonmyeloablative leukoreductive therapy using chemotherapy with or without total body radiation . the combined therapy using nonmyeloablative chemotherapy , t cell infusion , and systemic il - 2 has demonstrated 20 % complete response rate and 70 % overall response rate in melanoma patients . isolating t cells from tumor - draining lymph nodes provides another source for cellular immunotherapy . lymph nodes draining a growing tumor contain tumor - sensitized pre - effector t cells . ex vivo activation and expansion with anti - cd3 and il - 2 differentiate these preeffector cells into effector t cells . numerous animal studies have shown the therapeutic efficacy of tdln immunotherapy , and in vitro studies have shown tumors cytotoxicity of human tdln cells to human melanoma cells . down regulation of l - selectin on t cells is an early event in the response of antigenic stimulation . l - selectin t cells comprised 30 % of our tdln population , which is consistent with other reports . adoptive transfer of isolated l - selectin t cells has demonstrated therapeutic antitumor efficacy in a sarcoma animal model , while isolated infusion of l - selectin t cells was ineffective . in addition , interferon - production in response to tumor exposure is significantly higher in l - selectin versus l selectin t cells , suggesting this population contains more tumor reactive t cells . furthermore , infusion of l - selectin cells from tdln have been shown to block effector responses in adoptive immunotherapy protocols using tdln in an animal model . the use of l - selectin t cells is an attractive methodology for immunotherapy protocols as it allows for isolation of a population of highly reactive antitumor effector cells which can then be expanded tremendously . although adoptive immunotherapy using l - selectin cells from tdln in other animal models has used sublethal radiation for conditioning , the therapy described in our experimental model did not use radiation or il - 2 as an adjunct . this has potential relevance for clinical application of this therapy administered in the absence of conditioning with radiation or il - 2 , which both have their toxicities . although both adoptively transferred cd4 and cd8 cells were required for tumor regression , cd4 cells were more effective . cd8 + cytotoxic t cells are exclusively used in many adoptive immunotherapy models as these are known to have effector function after activation . in a sarcoma model using anti - cd3 activated tdln , cd8 cells caused tumor regression while cd4 cells did not result in tumor regression but instead provided a helper function to cd8 cells that could be replaced with exogenous il - 2 . however , in a similar sarcoma model using tdln which were anti - cd3 / anti - cd28 activated , cd4 cells were more potent effector cells than cd8 cells . similarly , another report showed that l - selectin cd4 cells caused tumor regression . it has also been reported that progressive tumor growth in syngeneic mice leads to independent sensitization of both tdln l - selectin cd4 and cd8 cells , with cd4 cells being more effective against 3 - day established intracranial and pulmonary tumors and cd8 cells more effective against 10 - day established tumors . in the current study , cd4 cells demonstrate direct cytotoxicity and likely provide a supportive role by secretion of cytokines to enhance cd8 cells cytotoxicity . though not investigated in the current study , it is possible that adoptively transferred b cells played a role in mediating tumor regression . b cells predominantly perform antigen - presentation and antibody production . although t cells are the predominant effector cells , b cells can also function as effector cells . in a mouse model of pulmonary metastases , cells in adoptive immunotherapy of solid tumors have demonstrated regression of sarcoma , melanoma , and breast cancer . the mechanism for b cell tumor activity is unknown , but the b cells may support the antitumor activity of the activated t cells in culture . in addition , b cells ' role as antigen - presenting cells may enhance the host 's t cell response . the adoptive transfer of activated b cells specific for 4t1 into hosts bearing 4t1 tumors resulted in the induction of systemic t cell immunity to 4t1 . nk cells are effector lymphocytes of the innate immune system which were found to be an integral component within the host for tumor response in the studied model system . nk cells do not require antigen recognition and are able to lyse tumor cells without prior stimulation . mechanisms involved in tumor cytotoxicity include perforin / granzyme mediated cytotoxicity , death receptor mediated apoptosis , and ifn - secretion . nk cells play a role in tumor immunosurveillance as evidenced by the fact that mice deficient in nk cells are more susceptible to methylcholanthrene - induced sarcomas . in addition , nk cells mitigate the growth of lymphomas in mice lacking perforin and 2 microglobulin . furthermore , nk cells prevent pulmonary and peritoneal metastases and peritoneal dissemination in murine models . for example , in a murine model of intraperitoneal tumors of mesenchymal origin , complete tumor rejection was dependent on both t cells and nk cells . similarly , in a murine model of subcutaneous and lung tumors , treatment of subcutaneous tumors using photodynamic therapy led to a cd8 and nk dependent inhibition of growth of untreated lung tumors . in treatment models using dendritic cell - based adoptive immunotherapy , the interaction of nk cells with dendritic cells and t cells has been shown to be important for antitumor responses . in the model used in the current study , there is evidence of cooperation of the innate and adaptive immune systems . alternatively , cytokine release from cd4 and / or cd8 cells may trigger an nk cell response . in conclusion , the present study demonstrated that ( 1 ) adoptive transfer of culture - activated 4t1 tdln cells into immunocompetent syngeneic tumor - bearing hosts results in tumor regression , ( 2 ) culture - activated 4t1 tdln cells secrete interferon - gamma in response to 4t1 but not renca tumor cells in vitro , demonstrating the presence of tumor - specific t cell reactivity , ( 3 ) adoptive transfer of l - selectin subpopulations into immunocompetent tumor - bearing hosts suggests that cd4 cells within the culture - activated tdln mediate a significant proportion of the antitumor effect , and ( 4 ) adoptive transfer of culture - activated 4t1 tdln into scid and rag2 deficient mice suggests that nk cells within the tumor - bearing host are critical to the observed antitumor effect . these results demonstrate the interaction between cellular components of both the adaptive and innate immune systems in this model of ait using tdlns . strategies to enhance the interaction between adoptively transferred t cells and resident nk cells or innate immunity may result in improved antitumor therapeutic efficacy .\noutput:\n" }, { "from": "agent", "value": "background . the purpose of this study was to determine the cellular effectors of both the adoptively transferred cells and the tumor - bearing host that participate in the antitumor response to adoptive immunotherapy using culture - activated tumor - draining lymph nodes ( tdlns ) . methods . tdlns harvested from mice with 4t1 carcinoma cells were fractionated to derive the l - selectinlow subpopulation and activated ex vivo prior to in vitro cytokine release assays and adoptive transfer into balb / c mice bearing 3 - day established subcutaneous tumors . tumor - bearing recipients were scid ( lacking t , b , and nk cells ) , rag2 deficient ( lacking t and b cells ) , and wild - type balb / c mice . results . culture - activated l - selectinlow 4t1 tdln from balb / c mice secreted significant levels of interferon - gamma in response to 4t1 but not control tumor cells in vitro . cd4 cells within the adoptively transferred effector cell population contributed significantly to the antitumor effect in vivo . culture - activated l - selectinlow tdlns from balb / c wild - type mice were able to cure rag2 deficient but not scid mice bearing 4t1 subcutaneous tumors , suggesting a requirement of nk cells within the innate immune system of the tumor - bearing host during the antitumor response . conclusions . these results identify the cellular effectors involved in tumor regression following adoptive transfer and demonstrate the requirement for intact innate immunity within the tumor - bearing host ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: malaria is a disease caused by parasites from the genus plasmodium and is transmitted to a human host when a vector , an infected female anopheles mosquito , bites the host . p. falciparum and p. vivax are responsible for most malaria infections , which has become one of the major public health problems in many regions of africa , asia , and latin america . the world health organization ( who ) estimated 198 million cases of malaria and 584000 deaths occurred globally in 2013 with the most occurrence in africa . resistance to antimalarials has been reported in both p. falciparum and p. vivax , but their resistance pattern differs and requires the development of new candidates of effective antimalarial drugs . younis et al . identified 3,5 - diaryl -2-aminopyridines as potential antimalarial drug candidates based on in vivo efficacy data obtained from a p. berghei infected mouse model . these compounds were identified from an image - based high - throughput screening of a biofocus dpi softfocus kinase library of promising selective in vitro antiplasmodial hits . a number of active compounds with varying aryl groups at positions 3 and 5 of the aminopyridine core were identified and analogues were synthesized in order to explore the structure - activity relationship ( sar ) around aryl substitution . some of these analogues showed good oral bioavailability in a pharmacokinetic study performed in rats , identifying them as potential clinical candidates . this led to the synthesis of new derivatives of 3,5 - diaryl -2-aminopyridines with the aim of overcoming liabilities such as the human ether - - go - go - related gene ( herg ) activity , which was identified in an earlier study as a property that is not ideal for a clinical candidate . compounds 1 and 2 ( figure 1 ) are derivatives of compound 3 , an active 3,5 - diaryl -2-aminopyridine antimalarial ( figure 1 ) . studies conducted by gonzalez cabrera et al . presented data that showed the potential antimalarial activity of these derivatives when tested in vitro against chloroquine - sensitive and chloroquine - resistant p. falciparum strains displayed activity in a p. berghei infected mouse model . these compounds also showed metabolic stability and reduced herg activity compared to the parent , that is , compound 3 . dimethyl sulfoxide ( merck ) , phosphate buffered saline tablets ( sigma ) , and heparin - coated minicollect plasma tubes ( lasec sa ) were obtained . male and female c57bl / 6 mice ( 2030 g ) were obtained from the university of cape town medical school animal unit . the mice were housed in ventilated cages at room temperature ( approximately 22c ) with a constant supply of food and water and were monitored twice daily . the study was authorized by the university of cape town 's faculty of health science animal research ethics committee before its commencement ( reference number 012/020 ) . the compounds ( figure 1 ) were dissolved in dmso and diluted further with phosphate buffered saline ( pbs ) to give a final dmso concentration of 1 % . comprehensive pk studies were performed on groups of five animals to determine the pharmacokinetic properties of the test compounds . this involved the oral dosing ( 200 l ) of 10 - week - old c57bl / 6 male mice at 20 mg / kg and intravenous dosing ( 100 l ) under anesthesia at 4 mg / kg via the dorsal penile vein . for the oral dosagea gavage needle was used for the administration of test compounds directly into the lower esophagus or stomach . blood samples ( approximately 30 l ) were collected serially by needle prick on the tail vein near to the tip of the tail at 0 , 0.17 , 0.5 , 1 , 2 , 3 , 5 , 7 , and 9 hours after dosing . the collected blood samples were placed on ice immediately after sampling and were frozen at 80c until analyzed . the blood samples were brought to room temperature and then mixed by vortexing to ensure homogeneity . twenty microliters of blood was mixed with 50 l milli - q water and 150 l acetonitrile . the sample was vortexed for 15 seconds , sonicated for 10 minutes , and centrifuged at 13000 g for 5 minutes . the supernatant was transferred to a flat - bottom glass insert and placed in a glass vial for analysis . the liquid chromatography ( lc ) system employed was an ultrafast liquid chromatography ( uflc ) system ( shimadzu ) and the separation of the compounds was performed on a phenomenex , luna 5 m pfp ( 2 ) , 100 , and 50 mm 2 mm analytical column . for method development , the compounds were prepared at 1 mg / ml stock in methanol and were further diluted with 50 % acetonitrile : 0.1 % formic acid to make a final concentration of 1 g / ml . analyst software version 1.5.2 ( ab sciex ) was employed for data acquisition , peak - area integration , and quantitation of compounds in blood samples . the mobile phase a consisted of 0.1 % formic acid in water ( v / v ) and mobile phase b consisted of acetonitrile . the flow rate was set at 500 l / min and the temperature of the column was maintained at 40c . for the separation of the compounds the mobile phase was increased from 5 % to 95 % b over 2 minutes and returned to 5 % b within 0.1 minutes and then equilibrated for 3 minutes . calibration curves were derived in each analytical run in duplicate and were employed to extrapolate the concentration of the compounds in the blood samples . the ms system consisted of an ab sciex 3200 q - trap mass spectrometer which was operated at unit resolution in the multiple reaction monitoring ( mrm ) mode . the calibration range for all the compounds was between 7.8 and 1000 ng / ml and the accuracy ( % nom ) for the calibration curves was between 90.31 and 104.0 % . noncompartmental analysis was performed on each individual set of data using pk solutions 2.0 pharmacokinetic analysis software ( summit research services , montrose , usa ) , which uses an automated excel - based program . the following pk parameters were calculated using pk solutions equations listed in program ( http://www.summitpk.com/equations/equations.htm ) : maximum blood concentration ( cmax [ m ] ) and corresponding time ( tmax [ min ] ) , apparent terminal half - life ( t1 / 2 [ min ] ) , total exposure ( auc0 [ mmin ] ) , volume of distribution ( vss [ l / kg ] ) , blood clearance ( cl [ l / min / kg ] ) , and percentage oral bioavailability ( % ba ) . a pharmacokinetic study was performed on two 2 - aminopyridine compounds , namely , compounds 1 and 2 . five mice were used for each route of administration , where each compound was dosed at 20 mg / kg orally and 4 mg / kg intravenously ( iv ) . the mean concentration versus time profiles of compounds 1 and 2 obtained after the mice were dosed is given in figure 2 . the pharmacokinetic parameters for the oral and iv groups are presented in table 2 . after administering 20 mg / kg of compound 1 orally , a maximum concentration of 1.9150.03 mwas reached within 1 hour with a moderate terminal half - life of 2.530.1 hours , which was longer than the iv half - life of 0.870.03 hours . the oral auc0 was 359.397 and the iv auc was 103.411 mmin , respectively . a high volume of distribution of 9.511 l / kg and a high clearance rate of 83.612 ml / min / kg were observed . compound 2 reached a maximum concentration of 3.340.2 m within 30 minutes and had moderate terminal half - life of 2.960.2 hours , which was longer than a half - life of 0.680.6 hours for the intravenous dose . auc0 for the mice dosed orally was 313.630 and 105.123 mmin for mice dosed intravenously . the volume of distribution was very high at 271.3 l / kg with a high clearance rate of 92.619 ml / min / kg . the two compounds evaluated in this study are potent antimalarials derived from 3,5 - diaryl -2-aminopyridine ( compound 3 ) that was identified as a potential clinical trial candidate for antimalarial treatment in a previous study . compounds 1 and 2 were synthesized in order to minimise the liabilities such as herg activity associated with compound 3 . the activity of the derivatives was evaluated in another study and improved ic50 values were observed in the range from 7 to 14 nm for p. falciparum chloroquine - sensitive strains ( d10 and 3d7 ) and chloroquine - resistant strains ( dd2 and k1 ) when comparing to the parent compound 3 with ic50 values in the range from 16 to 194 nm . this study was designed , therefore , to evaluate the pharmacokinetic properties of these two derivatives in a mouse model . both compounds 1 and 2data in table 2 showed a rapid absorption with maximum concentrations reached within 1 hour after drug administration . the high volume of distribution and a high clearance rate may have influenced the short half - life of these compounds , which range between 2.5 and 3 hours for mice dosed orally and between 0.68 and 0.87 hours for mice dosed intravenously . even though the bioavailability of compounds 1 and 2 was high , it is a parameter that determines the amount of compound reaching the systemic circulation , which in turn may affect the pharmacological response . these parameters include an increased clearance rate and a significant reduction in their half - life . a pharmacokinetic study of compound 3 was performed on male sprague dawley rats with a clearance rate of 18.3 ml / min / kg and apparent t1 / 2 values of 6.5 and 8 hours for rats dosed orally and intravenously , respectively . the oral and intravenous auc values of compound 3 were 6880 and 789 mmin , respectively , with an oral bioavailability of 100 % . unfortunately , the pk parameters presented in this study for compounds 1 and 2 could not be compared to those of the parent compound 3 because of the physiological differences between the two species . therefore , the data presented in this study can provide a baseline for further exploration of more derivatives in order to optimize the pharmacokinetic properties while retaining high potency in vitro and metabolic stability .\noutput:\n" }, { "from": "agent", "value": "malaria caused by plasmodium falciparum is responsible for approximately 80 % of the incidence and 90 % of deaths which occur in the world health organization ( who ) african region , with children and pregnant women having the highest incidence . p. falciparum has developed resistance , and therefore new effective candidate antimalarial drugs need to be developed . previous studies identified 3,5 - diaryl -2-aminopyridines as potential antimalarial drug candidates ; therefore , derivatives of these compounds were synthesized in order to improve their desired properties and pharmacokinetic ( pk ) properties of the derivatives were investigated in a mouse model which was dosed orally and intravenously . collected blood samples were analyzed using liquid chromatography coupled to mass spectrometer ( lc - ms / ms ) . the mean peak plasma level of 1.9 m was obtained at 1 hour for compound 1 and 3.3 m at 0.5 hours for compound 2 . a decline in concentration was observed with a half - life of 2.53 and 0.87 hours for compound 1 in mice dosed orally and intravenously , respectively . for compound 2 a half - life of 2.96 and 0.68 hours was recorded . the bioavailability was 69 % and 59.7 % for compound 1 and compound 2 , respectively ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: obesity has become a worldwide epidemic in the twenty - first century due to its increasing prevalence in recent decades , as well as its impacts on morbidity , mortality and quality of life , and its economic burden . morbid obesity [ body mass index ( bmi ) 40 kg / m ] is a type of obesity that does not respond to medical treatment ; it requires a surgical approach and its prevalence has continued to rise at an alarming rate . the distribution of obesity ( bmi 30 kg / m ) is not consistent across geographic regions , and its prevalence in europe ranges from 4 to 28 % in men and from 6.2 to 36.5 % in women . the obesity epidemic , which is the result of combined effects of genetic predisposition , increased accessibility to high - calorie foods and decreased physical activity , has led to an increase in the risk of developing cardiovascular disease , diabetes , dyslipidaemia , hypertension and / or renal disease . consequently , in obese patients , overall cardiovascular morbidity and mortality are increased . a retrospective cohort study of 320000 american adults with 15 and 35 years of follow - up described a strong relationship between the risk of developing advanced chronic kidney disease ( ckd ) and an increased bmi , especially for subjects with a bmi of 25 kg / m , regardless of age , sex and race , and the presence of underlying renal disease , diabetes or hypertension . similar results were published 3 years earlier in an epidemiological study of 9000 american adults who participated in the national health and nutrition examination survey ( nhanes ii ) . in that study physical inactivity , smoking and morbid obesity were found to be risk factors for ckd . additional studies have shown that obesity can exacerbate the progression of pre - existing renal disease . although the absolute individual risk of developing ckd is very low for obese individuals , there has been increasing interest in obesity as a risk factor for the development and progression of ckd , considering the prevalence of obesity in this patient population . because obesity is a preventable risk factor for ckd andbecause obesity , particularly morbid obesity , is currently an important health problem in europe , it is necessary to develop therapeutic and preventive strategies . studies of patients with differing degrees of obesity have recognized obesity - related glomerulopathy ( org ) as its own entity and have defined it as a secondary form of focal segmental glomerulosclerosis ( fsgs ) . our working group first described the presence of early stages of org in morbidly obese ( mo ) patients without overt clinical renal manifestations who were undergoing open bariatric surgery . the findings indicated that structural changes primarily involving the glomerular compartment may be observed in mo patients before they begin to exhibit significant proteinuria and / or renal failure . in most patients , glomerulomegaly was accompanied by other glomerular lesions . however , in six patients , glomerulomegaly was the only lesion observed . in addition , there were high prevalences of increased mesangial matrix , podocyte hypertrophy , glomerular sclerosis and mesangial cell proliferation . despite the lack of clinical manifestations , five of the study patients had already developed fsgs . the presence of these renal lesions was only associated with the bmi , and no association with hypertension or hyperglycaemia was detected , further demonstrating the correlation between morbid obesity and kidney disease . these findings clarify that glomerular hypertrophy in patients with morbid obesity is likely the initial lesion that stimulates podocyte effacement and triggers the inflammatory response eventually resulting in focal segmental glomerulosclerosis . it is therefore important to identify at - risk patients to prevent or precociously treat obesity - related nephropathy at an early stage and thereby prevent the development of irreversible ckd . hyperfiltration theory is also thought to be involved in the progression to end - stage renal disease , although in the presence of normal renal mass this mechanism is not completely understood . however , not all mo patients develop org , implicating the importance of genetic susceptibility and environmental conditions in its development . apparently , it seems to be a subgroup of obese patients with a unique phenotype , the metabolically healthy obesity , that does not associate higher risk of incident ckd . although the incidence of org is unknown due to a lack of data in the literature , d'agathi and co - workers observed an alarming increase in its incidence in a retrospective study of patients with proteinuria or proteinuria and renal failure performed between 1986 and 2000 . recent data from the same group showed further rise in the incidence of org between 2001 and 2015 ( from 2 to 2.7 % ) . these findings are consistent with the increasing prevalence of obesity in the general population during this period . the degree of kidney function in obesity nephropathy depends on the time of its determination . it is not uncommon to detect glomerular hyperfiltration at the time of onset of renal injury as occurs in patients with diabetes mellitus . once renal injury occurs , glomerular hyperfiltration can be observed in addition to apparently normal renal function or renal function deterioration . the initial clinical feature of renal injury is the presence of albuminuria or proteinuria . both of these conditions may precede a decrease in renal function by several years , as occurs in diabetes . proteinuria and albuminuria develop in 1041 % and in 1243 % of obese patients , respectively . in addition , some studies have described the presence of microhaematuria in 526 % of patients with differing degrees of obesity . in contrast , proteinuria in obese patients can be of low grade or have levels of nephrotic range and it is not usually accompanied by oedema , hypoalbuminaemia or severe hyperlipidaemia . the renal evolution of patients with org and clinical proteinuria or renal failure who have not been treated is unfavourable in those with fsgs and in those with glomerulomegaly alone . different studies have reported variable renal survival rates , a rate of 60 % at 8 years of follow - up has been reported in a study by kambham et al . and rates of 77 and 51 % at 5 and 10 years , respectively , have been described in a study by praga et al . . nevertheless , a comparison of the survival curves between idiopathic fsgs and fsgs secondary to obesity revealed that the latter was associated with better prognosis . in our experience , the long - term renal outcome of patients with org with normal renal function or with or without proteinuria is very good ( 10 years ) if they undergo bariatric surgery and drastic weight loss . adipose tissue is not inert ; rather , it is considered a true endocrine organ that produces bioactive substances that directly influence insulin resistance and vascular injury . the dysregulation of these factors mediates the pathogenesis of obesity comorbidities . in addition , the identification of some genes responsible for obesity has increased the understanding of how the body deals with disturbances in the energy balance . leptin is a product of the ob gene , and it is synthesized mainly in adipose tissue of obese patients in whom the plasma level is elevated so that these increased leptin levels are proportional to the amount of adipose tissue . thus , when there is an increase in intake accompanied by a decrease in energy expenditure , adipocyte size increases , resulting in increases in both the synthesis and release of leptin . despite these increased levels , obese patients typically exhibit resistance to leptin ; however , the mechanisms through which this occurs are unknown . furthermore , the kidneys contain a leptin receptor that is present mainly in the renal medulla . because this receptor belongs to the family of class i cytokine receptors , it is thought that leptin may have an important role in inflammatory kidney disorders such as obesity . although the functions of leptin receptor in the kidneys are unknown , experimental studies have demonstrated that leptin exerts a fibrogenic effect by increasing the expression of glomerular transforming growth factor - 1 , and that this effect is associated with the appearance of proteinuria . in addition , leptin acts on the renal tubules by increasing the tubular reabsorption of sodium , which promotes an increase in glomerular filtration through tubuloglomerular feedback . this glomerular hyperfiltration mechanism has also been implicated for other molecules , such as insulin , angiotensin ii and aldosterone . although leptin and adiponectin exert beneficial effects on energy balance by promoting sensitivity to insulin , increased leptin levels and decreased adiponectin levels may have deleterious effects on the kidneys . obesity is associated with hypoadiponectinaemia , which has been linked to insulin resistance , cardiovascular disease and glomerular injury . reduction in adiponectin levels appears to be regulated by fetuin - a , which is a glycoprotein synthesized in the liver that promotes insulin resistance , among other functions . obese individuals have increased levels of fetuin - a , which promotes a down - regulation of adiponectin synthesis by the adipocytes . both excess caloric intake and decreased adiponectin reduce the activation of an energy sensor that is present in liver cells and podocytes ( 5 - amp activated protein kinase ) , thereby promoting podocyte effacement and albuminuria . experimental studies have demonstrated that adiponectin deficiency in mice is associated with podocyte effacement and fusion , as has been observed in some patients with obesity and morbid obesity . these changes are accompanied by albuminuria and do not occur in mice with no such deficit . the administration of adiponectin to mice reduces podocyte damage and leads to the partial resolution of albuminuria . in our previous study , we found that patients with morbid obesity and early stages of org had an increased leptin level and a decreased adiponectin level compared with normal - weight controls . the drastic weight loss that occurred in patients who underwent bariatric surgery helped to reduce leptin levels and increase adiponectin levels , which were accompanied by a decreased albuminuria . therefore , all of the mechanisms , including weight loss , that contributed to decreasing leptin levels and increasing adiponectin levels helped to prevent or improve obesity - related renal injury . this increase can occur independently or as part of the renin angiotensin axis and may contribute to the development of org through two mechanisms : by promoting glomerular hyperfiltration via tubuloglomerular feedback ( similar to leptin ) or by direct injury of podocytes due to the production of reactive oxygen species . spontaneously hypertensive rats with a spontaneous mutation in the gene encoding leptin receptor were compared with a group of rats without this mutation . in the spontaneous evolution of the mutated rats , they developed obesity , which did not occur in the rats without the mutation . when an inhibitor of aldosterone ( eplerenone ) was administered , reduction in podocyte damage was observed , accompanied by decreased proteinuria . in patients with obesity , central fatis associated with increased risks of morbidity and mortality , especially in men . in fact , central obesity is the most important factor that predisposes individuals to insulin resistance and hyperinsulinaemia , thus favouring the development of type 2 diabetes mellitus . notably , fontana et al . published an interesting study on 25 mo patients . high levels of adipokines were observed in the portal vein , and these levels were compared with those in the peripheral blood . the findings suggested that visceral adipose tissue is the largest producer of interleukin - 6 ( il - 6 ) , thus confirming the association between visceral fat and systemic inflammation in patients with morbid obesity . in a study conducted by our group with mo patients with normal renal function and early stages of orghowever , we did not observe any relationships between the plasma levels of inflammatory mediators and glomerular lesions . many other factors related to inflammation in obesity have been studied recently . despite various attempts to elucidate the pathogenic mechanisms of renal disease in obesity , most of which have been experimental , there is still a lack of knowledge on this subject , and further investigation is needed . only a few studies have reported associations among obesity , renal injury and inflammatory hormones . insulin - like growth hormone - 1 ( igf - 1 ) levels are decreased in obesity . we have recently identified a link between a low igf - 1 hormone level and the presence of renal injury in mo patients with early stages of org . additionally , igf - 1 gene expression has been shown to be decreased in kidney biopsies from mo patients with early stages of org compared with those from a normal - weight control group ( m. navarro , unpublished data ) , whereas expression of the proinflammatory genes il - 6 and glucose transporter - 1 was increased ( m. navarro , unpublished data ) . wu et al . have previously demonstrated the differential expression of genes related to inflammatory cytokines , lipid metabolism and insulin resistance in kidney biopsies from obese patients with proteinuria and org . effect relationship of lipid dysmetabolism , insulin resistance and activation of an inflammatory process with the development of obesity - related glomerulopathy . the application of modern techniques , such as genomic techniques , might be useful to open new avenues for further investigation . it is justifiable to consider that if obesity is a modifiable risk factor for kidney disease , then developing the first therapeutic intervention to prevent obesity , given its high prevalence , should be a public health priority . by preventing obesity , a high percentage of all ckd cases in industrialized countriesmight be prevented . for patients who are already obese , an effective treatment should be established to promote weight loss and thus prevent or treat its comorbidities , such as ckd . there is increasing evidence that weight loss not only helps to reduce glomerular hyperfiltration and proteinuria but also attenuates metabolic disorders associated with obesity , such as hypertension , altered lipid metabolism , insulin resistance and inflammation . few studies have investigated the fundamental pathophysiological effects that lead to improvement of renal disease in obese patients on low - calorie diets . ix and sharma investigated the effect of a low - calorie diet on ampk pathway activation and found that it reduced the fetuin - a level , which led to an increase in the adiponectin level and subsequently prevented the occurrence of podocyte injury . the effects of dietary modification on other adipokines and on the secretion of fatty acids are additional areas of interest in the study of obesity - related kidney disease . however , what is the most effective method for maintaining weight loss over a long period of time ? many clinical trials have demonstrated that low - calorie diets aid in weight loss in obese patients , although these studies have failed to demonstrate the maintenance of this weight loss over time and have reported high dropout rates . the use of anti - obesity agents such as orlistat and sibutramine , which have been recommended in combination with low - calorie diets and exercise , has resulted in modest decreases in weight and may cause significant side effects , especially in patients with cardiovascular disease . the results of different studies examined in two meta - analyses that included 18 studies ( assessing medical and surgical interventions ) and 813 patients with differing degrees of obesity have demonstrated that medical interventions for obesity result in a reduction in proteinuria and glomerular filtration rate stabilization . in contrast , surgery normalizes glomerular hyperfiltration and albuminuria , and encouraging data have been reported indicating improved / stable renal function in some patients with renal insufficiency who have undergone surgery . regarding morbid obesity , both medical treatments and lifestyle changes have limited effects . in these patients , bariatric surgery is the only treatment that has demonstrated efficacy in maintaining long - term weight loss . in a recent study with a median follow - up time of 4.4 years and 985 patients who underwent bariatric surgerythe authors observed that bariatric surgery prevented the decline in renal function in mo patients . in addition , drastic weight loss secondary to bariatric surgery in mo patients with org , normal preoperative renal function and mild proteinuria resulted in excellent outcomes , as normal renal function was maintained , blood pressure was improved and albuminuria was attenuated after 10 years of follow - up . although the surgical approach can reduce morbidity and improve renal parameters in patients with morbid obesity , bariatric surgery is associated with an increased risk of acute renal failure postoperatively . this complication is associated with the appearance of oxalate nephropathy but is rarely observed . angiotensin system have proved useful for improving glomerular hyperfiltration in obese or mo patients with renal disease by reducing the intracapillary glomerular pressure and , consequently , podocyte injury and by enhancing the attenuation of proteinuria . because hyperaldosteronism promotes hyperfiltration and podocyte injury and mediates inflammation , the use of aldosterone inhibitors may be indicated in patients with hyperaldosteronism , such as those with obesity and obesity glomerulopathy . further , the addition of aldosterone inhibitors to angiotensin - converting enzyme inhibitors or angiotensin ii receptor blocker treatments improves proteinuria but does not enhance renal function . given the scientific evidence regarding aldosterone inhibitors , these drugs should be considered as second - line drugs , and more studies demonstrating their efficacy should be conducted . in a comprehensive review of the role of ectopic lipid accumulation in obesity - related kidney disease , de vries et al . suggested that this accumulation could represent a novel pathway of this disease and that this information could facilitate the development of new strategies for its treatment . in experimental models , interventions targeting cellular lipid metabolism have been shown to decrease renal lipid accumulation and reduce glomerular injury ; however , further investigation is needed to fully understand what occurs in humans .\noutput:\n" }, { "from": "agent", "value": "obesity and morbid obesity are modifiable risk factors for the development and progression of kidney disease . obesity has reached epidemic proportions and is currently an important health problem in europe , so it is necessary to develop therapeutic and preventive strategies . the obesity - related glomerulopathy has been defined as a secondary form of focal segmental glomerulosclerosis , and its most characteristic feature is glomerulomegaly . the renal evolution of patients with obesity - related glomerulopathy ( org ) who have not been treated is unfavourable . however , morbidly obese patients with org that underwent bariatric surgery and drastic weight loss had a better outcome . many inflammatory factors have been implicated in the pathogenic mechanism of renal disease in obesity . hypoadiponectinaemia , hyperleptinaemia and hyperaldosteronism have been associated with glomerular injury in obese patients . the application of modern techniques has provided important insights that increase the current understanding of org . however , further investigation is needed ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a type of frequent neurological disability caused by a chronic inflammatory and progressive demyelination of the central nervous system ( cns ) is called multiple sclerosis ( ms ) , afflicting over 2.5 million young adults worldwide . in the past , iran was considered a region with low incidence of ms , but the number of patients has increased over recent decades . at the 10 international congress of ms , the number of ms cases was reportedly 37,655 people ( 49.2 / 100,000 ) with the highest prevalence in isfahan , of about 85.5 people / 100,000 . according to these resultsthe women : men ratio of people affected by ms is 10:3 . the most common time for emergence of the disease is during the second and third decade of a person 's life between the ages of 25 - 30 years . only rarely is ms contracted before puberty . incidence of the disease increases dramatically after puberty , and the sex ratio also increases ; when onset of the disease occurs between the ages of 13 - 18 years old , the female : male ratio reaches 2.2:1 . the question that guided this research was : do events at childbearing age ( including puberty ) , such as using contraceptive drugs , pregnancy at an older age , and multiple pregnancies make women more susceptible to ms ? puberty is a complex biological phenomenon influenced by genetic , nutritional , environmental , economic , and socioeconomic factors . there are also changes in gray matter volume , first an increase and then a decrease over time . gender differences are triggered by sex hormones producing basal immune responses , and thus their important roles in the immune system are corroborated . higher antibody responses to antigens , especially those resulted from more intense activities of t - cells , are caused by higher immunoglobulin levels in women . studies show an increased risk of ms in cases of lower age at menarche and appearance of the first signs of puberty at a younger age . regarding the use of oral contraceptives ( ocs ) , no significant effect was determined on the risk of ms . there was no definitive clinical data to demonstrate the beneficial effect of oc use on the course and progression of ms ; however , possible delay in the onset of clinical symptoms of ms has been observed . regarding the effects of childbirth and pregnancy , the risk of ms among women in their first pregnancy has been reported as upper than in women who have had multiple pregnancies . even though , many studies have reported no association between the risk of ms and pregnancy or childbirth . however , childbirth postpones ms to a later age , and this suggests that it has a protective effect . furthermore , pregnancy in patients with ms is associated with decreased neurological symptoms and improved quality of life ; these changes are more obvious during the third trimester compared with the first trimester of pregnancy . in general , the relationship between reproductive risk factors and ms has not been studied extensively . however , the frequency of infertility is higher in women with ms than among the general population . this may be associated with postponed pregnancy or concerns about the risk of disease transmission . on the assumption that childbearing incidents such as puberty , pregnancy at later age , number of pregnancies , and oc use in women are related to the risk of developing ms , and given that no research has focused on impacts of childbearing age variables such as puberty , use of ocs , pregnancy at later age , and number of pregnancies on incidence of ms in women . given the importance of the high prevalence of ms in isfahan , the aim of this study was to assess correlations of some childbearing age variables with risk factor for ms in patients referred to the ms clinic of isfahan . this analytic case control study was approved by school of health , isfahan university of medical sciences , under project number 393260 and was conducted in al - zahra hospital in 2014 on 400 women ( 200 patients and 200 controls ) . patients who were referred to the ms clinic of the hospital whose disease had been confirmed by diagnostic studies such as magnetic resonance imaging and approved by the neurology committee of the hospital using standard ms were considered for inclusion in the study , and women who were referred to different wards of the hospital ( other than psychiatry , obstetrics , and gynecology to avoid confounding factors ) were selected as the control group . the province was divided into cold and tropical climates , and sampling was conducted from both types . criteria common to both groups in the study were age range of women 1550 years ; all were residents of isfahan province , had consented to give their information , and lack of gynecologic disease . inclusion criteria for patients were as follows : absence of acute conditions , full consciousness , member of isfahan 's multiple sclerosis society and having medical records in this society , and duration of at least 1 year from the time of diagnosis . inclusion criteria for the control group were as follows : lack of ms or any other neurologic / mental disease . information collected in this study included demographic characteristics such as age , marital status , place of residence , disease - related variables , and variables affecting women of childbearing age such as early onset of puberty , use of ocs prior to developing ms , age at the first pregnancy , number of pregnancies prior to ms , family history of ms , other autoimmune disease , and history of a viral disease in childhood . demographic variables were collected from medical records and other variables related to diseases and reproductive age were recorded during interviews with patients . participants were first questioned face - to - face in the presence of their parents who had access to patient information . assessment of age of onset of puberty was made according to tanner classification ( age at breast growth and pubic hair growth ) and age at menarche ( first menstruation ) . criterion for age of start of oc use was age of onset of using ocs before developing ms . duration of oc use was recorded in months and determined by the amount of time that a participant had used ocs before the onset of ms . after collecting information , the data analysis was performed by descriptive analysis and logistic regression tests using ( pasw statistics for windows chicago : spss inc ) . logistic regression was used for calculating the odds ratio ( or ) and confidence interval ( ci ) was considered at 95 % . this analytic case control study was approved by school of health , isfahan university of medical sciences , under project number 393260 and was conducted in al - zahra hospital in 2014 on 400 women ( 200 patients and 200 controls ) . patients who were referred to the ms clinic of the hospital whose disease had been confirmed by diagnostic studies such as magnetic resonance imaging and approved by the neurology committee of the hospital using standard ms were considered for inclusion in the study , and women who were referred to different wards of the hospital ( other than psychiatry , obstetrics , and gynecology to avoid confounding factors ) were selected as the control group . the province was divided into cold and tropical climates , and sampling was conducted from both types . criteria common to both groups in the study were age range of women 1550 years ; all were residents of isfahan province , had consented to give their information , and lack of gynecologic disease . inclusion criteria for patients were as follows : absence of acute conditions , full consciousness , member of isfahan 's multiple sclerosis society and having medical records in this society , and duration of at least 1 year from the time of diagnosis . inclusion criteria for the control group were as follows : lack of ms or any other neurologic / mental disease . information collected in this study included demographic characteristics such as age , marital status , place of residence , disease - related variables , and variables affecting women of childbearing age such as early onset of puberty , use of ocs prior to developing ms , age at the first pregnancy , number of pregnancies prior to ms , family history of ms , other autoimmune disease , and history of a viral disease in childhood . demographic variables were collected from medical records and other variables related to diseases and reproductive age were recorded during interviews with patients . participants were first questioned face - to - face in the presence of their parents who had access to patient information . assessment of age of onset of puberty was made according to tanner classification ( age at breast growth and pubic hair growth ) and age at menarche ( first menstruation ) . criterion for age of start of oc use was age of onset of using ocs before developing ms . duration of oc use was recorded in months and determined by the amount of time that a participant had used ocs before the onset of ms . after collecting information , the data analysis was performed by descriptive analysis and logistic regression tests using ( pasw statistics for windows chicago : spss inc ) . logistic regression was used for calculating the odds ratio ( or ) and confidence interval ( ci ) was considered at 95 % . a total of 400 women were enrolled for participation in this study ( 200 patients and 200 controls ) . sixty - eight percent of participants in the patient group and 77 % in the control group were married . the mean age of patients was 31.768.13 years and in the control group , it was 31.538.97 years . the most common type of ms in patients was relapsing / remitting ( rr ) subtype with the highest frequency was 90 % . the most common signs of ms presented in patients were impaired vision ( 46 % ) and numbness ( 38.5 % ) , and mean age of onset of symptoms in the patient group was 267.77 years . seventeen percent of patients and 9.5 % of the control group had a positive family history of ms ; there was a significant association between family history of ms with developing the disease ( p = 0.027 ) . seventy - five percent of patients had a history of viral disease in childhood that was significantly different between the two groups ( p = 0.048 ) . table 2 shows distribution of reproductive age risk factors including mean age , age at menarche , age at the first pregnancy , history , age and duration of use of ocs , and number of pregnancies in the two groups . based on results obtained by the independent t - test , a significant correlation was observed between the age at menarche ( p 0.001 ) , prior use of oc before developing ms ( p = 0.004 ) , history duration of contraceptive use before developing ms ( p = 0.002 ) , and number of pregnancies before ms ( p 0.001 ) [ table 2 ] . frequency ( % ) of some demographic and health condition characteristics among cases and controls frequencies of ms risk factors among cases and controls to determine the association between reproductive age , variables such as age at menarche , age of onset of oc use prior to developing ms , duration of use of ocs prior to ms , age at first pregnancy , number of pregnancies before ms and developing ms in women , 6 logistic regression models were separately fitted . the effects of these variables on the risk of ms were adjusted by entering variables such as age , marital status , place of residence , family history of ms , developing other autoimmune diseases , and history of viral diseases in childhood in these models . the results indicate a significant relationship between age of menarche onset and incidence of ms ( or = 0.780 , ci = 0.6760.899 ) that show an inverse relationship regarding or . the relationship between use of ocs ( or = 0.492 , ci = 0.3140.772 ) and duration of use of ocs were statistically significant with the risk of ms ( or = 0.881 , ci = 0.8030.967 ) . this means that consumption and higher duration of using ocs reduced the risk of ms . the relationship between the number of pregnancies and ms was also statistically significant ( or = 0.586 , ci = 0.4610.745 ) , but there was no significant relationship the age at onset of using ocs ( p = 0.80 ) and age at the first pregnancy ( p = 0.45 ) with ms ; the results are shown in table 3 . the aim of this study was to determine the association between risk factors of reproductive age and the prevalence of ms . consistent with the results of this research , several other studies have considered age at menarche as an effective risk factor for development of ms . the association of lower age at menarche with an increased risk of ms is possibly due to earlier exposure to hormonal changes during puberty that may affect the onset and course of the disease . a higher age at menarche may lead to longer preteenage stage of development and thereby an increased volume of gray matter that increases the storage performance capacity against axonal degeneration levels of estrogen . long exposure to this hormone increases the risk of developing an autoimmune disease such as ms . a wide age range for onset of puberty is seen among people that may be affected by factors such as genetics , race , diet , environmental exposure , and lifestyle . a meta - analysis of data from europe suggests that age at menarche has become dramatically lower and this trend has been evident since the late 1800s and continued until 1950 , but it seems to have leveled from 1960 to 2010 . therefore , a decrease in age at onset of puberty during the past 100 years , especially in women , might be effective in increasing incidence and gender difference in ms . this issue supports the hypothesis of an association between age at menarche and risk of ms . the effect of oc use on ms has been assessed in the current study among patients and control groups in terms of the history of use , duration of oc use , and age of onset of oc use . according to the logistic regression model , the relationship between prior use of ocs with ms ( ci = 0.3140.772 , or = 0.492 ) and duration of use of ocs were statistically significant with the risk of ms ( ci = 0.8030.967 , or = 0.881 ) . this means that consumption and higher duration of use of ocs reduced the risk of ms . inconsistent with the results of this study , research by alonso et al . reported no effect of ocs as a source of exogenous sex hormones on the risk of ms in many women . furthermore , inconsistent with the results of this research were those reported by hernan et al . that suggest an increased risk of developing ms among oc users in the long - term . that determined an association between oc use before the onset of ms at a later age that indicated a protective effect against developing ms . exposure to female hormones at a younger age may have little influence on hormonal balance of androgens is in cns by interacting with hormone receptors or with hormone synthesis or metabolism . currently , no clinical data exists to demonstrate a beneficial effect of oc use on the course and progression of ms , except a possible delay in the onset of clinical signs in cases of ms relapse . these findings are contrary to those of other research that report a protective effect of sex steroids on neurons and oc in the field of autoimmune diseases . however , no significant relationship between age at onset of use of ocs was found ( or = 0.99 , ci = 0.9291.059 ) . in this study , the relationship between the number of pregnancies and ms was statistically significant by logistic regression model ( or = 0.586 , ci = 0.4610.745 , ) , which means that the risk of ms decreased in relation to a greater number of pregnancies . while the results of a study by runmarker and andersen show a upper risk of ms in the first childbirth compared with women who had had multiple pregnancies . some studies have reported no association between the risk of ms and pregnancy or childbirth . study showed an association of number of deliveries with delay in age of onset of ms . study showed a significant reduction in the risk of developing the first demyelination among women that had given birth to more children . this indicates a protective effect of ms and is consistent with the results of this study . in this study , no relationship was determined between woman 's age at the first pregnancy ( or = 1.02 , ci = 0.9631.097 ) with ms , but it should be noted that young women may decide to prevent being pregnant with the onset of the disease and this may have contributed to results in line with those of this current research . according to the available information , a beneficial effect of pregnancy onthe risk of inflammatory demyelination may persist , which is probably indicative of hormonal changes . however , experiments have shown that there is a reconstruction of white matter during pregnancy and that supports the results of this study . although women are considered at higher risk of developing ms than men , women are at lower risk of progression in disease onset , at least during their reproductive age . as far as pathogenesis of progressive degeneration of axons in msis not well - known , its possible mechanisms are speculative . the strengths of this research include lack of a similar study in iran that makes a direct assessment of the relationship between risk factors of reproductive age and ms . the limitations of this study include recall bias , as data of risk factors of reproductive age were collected by a self - reported method . given the casecontrol design of the current study , it is logical that it is associated with recall bias and considering that the age at menarche is related to many years before , information may not be reliable , but it should be considered that menstruation is a unique indicator of the process of puberty and studies have demonstrated a strong relationship ( r = 0.670.79 ) between remembering the age at menarche in middle age and original childhood data , which supports observations that show a real association and not influenced by error . moreover , this study was conducted in a limited area and with a limited number of patients that thus reduces generalizability of the results ; it is therefore suggested that a similar study be done on a larger sample size and in other provinces . the results obtained from this study suggest that among the studied reproductive age risk factors , age at menarche , use of ocs , duration of use of ocs , and number of pregnancies can increase the risk of ms . hence , the results of this research can help to identify causes of the disease and disclose important new insights to prevention of the disease for our community , especially through identification of those at risk . however , it is recommended that further studies be done to evaluate the counter - effect of exposure with risk factors and biological changes around puberty to identify preventive actions against the development and progression of ms .\noutput:\n" }, { "from": "agent", "value": "background : multiple sclerosis ( ms ) is an autoimmune disease of the central nervous system . etiology of the disease is not well understood ; however , it is more common in women than in men and occurs mainly during reproductive age . the aim of this study was to evaluate some risk factors in women of childbearing age with ms in isfahan province.methods : this analytic case control study was conducted in ms clinic in isfahan , 2014 . the study was done on 200 patients with ms and 200 nonpatients ( matched controls ) that were randomly selected for inclusion in the study . the data collection tool was a researcher - designed questionnaire consisting of three parts : demographics , disease characteristics , and some risk factors related to reproductive age . data were analyzed by spss version 20 , using descriptive and inferential statistics.results : the results showed that risk of ms had a significant relationship with age at menarche ( p < 0.001 ) , prior use of oral contraceptives ( ocs ) ( p = 0.002 ) , duration of use of ocs ( p = 0.008 ) , and number of pregnancies ( p < 0.001 ) . however , there was no significant relationship between age of onset of use of ocs ( p = 0.80 ) and age at the first pregnancy ( p = 0.45 ) with the risk of ms.conclusions : results of this research determined that the following risk factors were associated with developing ms , age at menarche , history , and duration of use of ocs and number of pregnancies ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the inflammatory bowel diseases ( ibds ) are a heterogeneous group of disorders which have two major phenotypic forms , crohn 's disease and ulcerative colitis , characterized by chronic relapsing and remitting intestinal inflammation 14 . ulcerative colitis is the most common of the ibds 5 and is characterized by a continuous pattern of inflammation beginning in the rectum and extending progressively further into the colon with increasing disease severity . by contrast , crohn 's disease patients frequently develop a discontinuous pattern of inflammation which can occur anywhere in the gastrointestinal tract , although the distal small intestine and colon are the most common locations 6 . in ulcerativecolitis , inflammatory infiltrates are confined to the mucosa and consist primarily of lymphocytes and plasma cells plus granulocytes in crypt abscesses and present in the mucosa during disease flares . ulceration is common during active disease and colonic epithelial cell changes such as goblet cell depletion , distorted crypt architecture , and epithelial dysplasia are associated with chronic disease 7 . transmural inflammation is a characteristic feature of crohn 's disease and this deeper tissue involvement in the inflammatory process appears to be responsible for many of the serious complications associated with crohn 's disease such as fibrostenotic disease , abscesses , and fistula formation 8,9 . epithelioid granulomas are also associated with crohn 's disease and provide diagnostic differentiation from ulcerative colitis when identified histologically . epithelioid cells , so named for a resemblance to epithelial cells , are activated histiocytes with homogeneous eosinophilic cytoplasm , and a working definition of an epithelioid granuloma is a collection of at least five epithelioid cells with or without accompanying multinucleate giant cells 10 . however , these granulomas are found in only about 2040 % of biopsies and 60 % of surgical resection specimens 11 and , when present , must be differentiated from those associated with infectious diseases such as tuberculosis . when crohn 's disease inflammation is confined to the mucosa andno granulomatous lesions are present , it can not be definitively differentiated from ulcerative colitis by histological evaluation . a subset of patients present with clinical and histological features of disease which do not clearly segregate into one of the established phenotypic forms . . some of these patients will eventually develop lesions more characteristic of one of the major forms of ibd . accurately determining the prevalence of inflammatory bowel disease is a challenging proposition given that ibd is not a reportable disease and that patients can have a multi - decade disease course . prevalence estimates have been drawn based on either in - depth regional data 14 or administrative data from health plan databases 15,16 . based on these data , there are between 1 and 1.5 million individuals with ulcerative colitis or crohn 's disease in the united states alone . clinical manifestations of disease develop during childhood in up to 25 % of patients 2 , and disease prevalence in children under 20 years of age is 43 per 100000 for crohn 's disease and 28 per 100000 for ulcerative colitis 16 . as expected with a chronic disease , the prevalence increases with age to about 201 per 100000 for crohn 's disease and 238 per 100000 for ulcerative colitis . the incidence of crohn 's disease and ulcerative colitis in the united states increased after 1940 ; however , those rates appear to have stabilized over the past few decades 14 . despite some uncertainty about the total number of ibd patients , it is clear that large numbers of patients exist and that many of these patients can anticipate the need for treatment over a span of decades . while the advent of biological therapies has improved the clinical situation , ibd remains a major unmet medical need . current models hypothesize that ibd arises from and is sustained by interactions between genetically susceptible hosts and the gut microflora as well as , potentially , other environmental triggers . while the pathogenesis of ibd remains incompletely understood , it is clear that dysfunction of the mucosal immune system plays an important role . dendritic cells are a key player in the mucosal immune system , serving as a bridge between the innate and the adaptive immune response 17 . in this review , we will discuss the evidence for dendritic cells in ibd pathogenesis with emphasis on genetics and microbial interactions . the innate immune system is emerging as a potentially attractive therapeutic target in ibd and we will review some of the current information in this area . it is well established that host genetic susceptibility plays an important role in ibd pathogenesis . the first crohn 's disease susceptibility gene , nucleotide oligomerization domain receptor 2 ( nod2 ) , which is encoded by the card15 gene , was identified in 200118,19 . in the intervening years , tremendous progress has been made using genome - wide linkage and association studies to reveal additional genetic polymorphisms associated with susceptibility to ulcerative colitis or crohn 's disease . a number of susceptibility genes are shared between ulcerative colitis and crohn 's disease 21,22 , suggesting the presence of shared or interlinking pathways in inflammatory bowel disease pathogenesis . while the functional role of many loci or specific single nucleotide polymorphisms ( snps ) is incompletely understood , many of the genes are associated with aspects of mucosal immunity including innate immune response to microbial pathogens 20 ( figure 1 ) . polymorphisms in ibd susceptibility genes in dendritic cells can be broadly categorized as either inhibiting the ability to effectively clear pathogens or contributing to excessive immune response . snps associated with this pathway , including nod2 and atg16l1 , can contribute to failure to deal with pathogens . additionally , dectin - 1 is important for the clearance of fungal pathogens by enabling dendritic cell recognition of -1,3-glucans in fungal cell walls . a number of ibd susceptibility genes are linked to the excessive immune response which is characteristic of both crohn 's disease and ulcerative colitis . nod2 in dendritic cells is upstream of mapk and nf - b , which are important regulators of pro - inflammatory cytokines . impaired regulation of the inflammatory response caused by polymorphisms in nod2 , il12b or tnfsf15 may result in excessive and prolonged pro - inflammatory t - cell responses . in addition , dendritic cells regulate the immune response through production of the anti - inflammatory cytokine il - 10 . snps in il - 10 may result in loss of regulatory t cells , leading to excessive immune response . the importance of microbial recognition and the response of the innate immune system is underscored by the association between crohn 's disease and nod2 , which is a member of the nlr ( nod , leucine - rich repeat - containing protein ) family of intracellular pathogen - associated molecular recognition receptors ( prrs ) 23,24 . this association includes three nod2 polymorphisms which occur with greatest frequency in individuals of european descent but are not found in asian populations 25 . approximately 30 % of patients of european ancestry will have one or more of these mutations and these patients are at increased risk for ileal involvement and fibrostenotic disease 26 . individuals heterozygous for a nod2 polymorphism have an increased crohn 's disease risk of 2.4-fold , while homozygous individuals have a 17.1-fold increase 25 . nod2 is expressed by a variety of immune and non - immune cell types including dendritic cells and is upstream of the nuclear factor - b ( nf - b ) and mitogen - activated protein ( map ) kinase signalling pathways which drive pro - inflammatory cytokine production 27 . it encodes an intracellular sensor of peptidoglycan , a component of bacterial cell walls , and crohn 's disease - associated mutations are mainly located in the leucine - rich repeat region which interacts with the peptidoglycan muramyl dipeptide ( mdp ) motif , leading to altered bacterial recognition 28,29 . how nod2 polymorphisms predispose to crohn 's disease development remains incompletely understood , despite significant research effort in this field . because the intestinal tract has continuous bacterial exposure , chronic activation of nod2 signalling should result in immune cell hyporesponsiveness to subsequent nod2 or toll - like receptor ( tlr ) ligand stimulation 30,31 . while the nod2 - mediated mechanisms which down - regulate pro - inflammatory cytokines during exposure to commensal bacteria are not fully characterized , it is clear that the process is defective in patients with crohn 's disease - associated nod polymorphisms 31 . one hypothesis is that nod2 normally acts to attenuate tlr signalling , resulting in reduced activation of nf - b , and thereby prevents excessive activation of dendritic cells and subsequent pathogenic t - cell response 32 . there is increasing evidence that prr signals intersect with other pathways that coordinate bacterial responses . autophagy is the process by which cytoplasmic components are sequestered into double membrane vacuoles which then fuse with lysosomes , and this process is important in microbial defence processes such as capture of intracellular bacteria during phagocytosis , antigen presentation , and inflammasome activation 35 . atg16l1 encodes an autophagy protein which is part of a complex responsible for proper subcellular localization of the autophagy machinery 36,37 . the atg16l1 polymorphism is associated with an increased risk of crohn 's disease 38 and similar to nod2 , shows an association with terminal ileal disease 38,39 . interestingly , the affected domain of atg16l1 is non - conserved and is not required for all of its functions 40 . in human dendritic cells , autophagy is induced through nod2 stimulation , and dendritic cells isolated from crohn 's disease patients with atg16l1 and / or nod2 polymorphisms have defective autophagy induction in addition to altered antigen presentation and bacterial handling 33 ( figure 1 ) . interestingly , promoter polymorphism in the autophagy gene irgm has also been associated with increased risk of developing crohn 's disease 41 , although characterization of the specific effects on dendritic cells is still preliminary . in aggregate , these data suggest that autophagy may be an attractive drug target area for modifying dendritic cell function in the treatment of crohn 's disease . preliminary evidence in support of this concept has been generated using rapamycin , an antibiotic which triggers autophagy by forming a complex with fkb12 , which then inhibits mtor and is commonly used to up - regulate autophagy in cell culture 42 . rapamycin has been used successfully to treat a patient with severe refractory crohn 's disease and has also shown protection in a murine colitis model , suggesting that this therapeutic approach may be promising 43,44 . genome - wide association studies ( gwas ) have shown strong associations of polymorphisms in the il23r and il12b gene loci with crohn 's disease and ulcerative colitis 45,46 . il12b encodes the il - 12p40 subunit , which is a component of both the il - 12 and the il - 23 cytokines , while il23r encodes one of two subunits of the il - 23r 47 . il - 23 is induced in dendritic cells ( dcs ) by ppr stimulation and can promote a wide range of pathological responses in the intestine , mediated either through t cells or through excessive innate immune cell activation 48,49 ( figure 1 ) . dc il - 23 production , which is augmented under conditions of endoplasmic reticulum stress and activation of the unfolded protein response ( upr ) , is an important component of anti - microbial defence linking innate and adaptive immune responses 50 . however , excessive or inappropriate dc il - 23 production favours pro - inflammatory t - cell responses including enhanced proliferation of effector t cells , reduced differentiation of forkhead box p3 ( foxp3 ) - positive regulatory t cells , and emergence of the il - 17 - and ifn -- producing cells associated with chronic intestinal inflammation 49 . conversely , il - 23r polymorphisms , which are associated with protection from ibd risk , have been functionally characterized and result in reduced t - cell activation 5153 . studies in mouse colitis models have shown that il - 23 plays an important role in chronic intestinal inflammation 54 . in addition , the anti - il - 12p40 monoclonal antibody ustekinumab has demonstrated some clinical efficacy in a subset of crohn 's disease patients who were resistant to tnf antagonists 55 . some dendritic cell processes linked to ibd genetic susceptibility have been identified as potential therapeutic targets . for example , blocking interactions between dendritic cells and t cells has been proposed as a means of decreasing activity of the il - 23 / il - 17 pro - inflammatory pathway important in ibd pathogenesis 56 . activated dendritic cells express the tnf family cytokine tl1a ( tnfsf15 ) , which interacts with the dr3 receptor ( tnfrsf25 ) on lymphocytes 57,58 ( figure 1 ) . polymorphisms in the tnfsf15 gene have been shown to contribute to the risk of both ulcerative colitis and crohn 's disease 59,60 . increased expression of tl1a has been shown in crohn 's disease tissue 61 , and antibody to tl1a prevents colitis development in mouse models 62 . a role for il - 10 in ibd pathogenesis was first identified in mice deficient in either il - 10 or the il - 10 receptor 2 ( il - 10r2 ) subunit , as these mice develop spontaneous colitis 65,66 . this has more recently been extended into humans , with the association of very early onset ibd with il - 10 or il - 10 receptor ( il - 10r ) deficiencies 6769 . patients with il - 10 / il - 10r loss - of - function mutations present , often in the first 3 months of life , with severe and progressive colitis complicated by perianal disease 70 . while il - 10 and il - 10r deficiencies are fortunately rare , gwas findings suggest that il - 10 may play a broader role in ibd pathogenesis . il - 10 snps have been associated with both ulcerative colitis and crohn 's disease in paediatric and adult populations 7173 . il - 10 is secreted by a variety of immune cell types including dendritic cells 74 and plays an important anti - inflammatory role through interactions with regulatory t cells , leading to inhibition of effector t - cell response 75 ( figure 1 ) . this effect of il - 10 on t cells is mediated primarily by antigen - presenting cells such as dendritic cells and macrophages 76 . this suggests that dendritic cells may be important in the pathogenesis of il - 10 snp - related ibd . il - 10 has been explored as a potential therapeutic in inflammatory bowel disease with limited success 77 and is currently of most interest in association with probiotic therapeutic strategies 78 . recently , an association has been identified between polymorphism in the dectin - 1 gene ( clec7a ) and severe ulcerative colitis 79 . the risk haplotype was strongly associated with the development of medically refractory ulcerative colitis and overrepresented in patients requiring colectomy . dectin - 1 is a c - type lectin receptor expressed by dendritic cells and macrophages which recognizes -1,3-glucans found in fungal cell walls 80 . dectin - 1 deficiency had previously been associated with increased susceptibility to fungal disease in humans and mice 81,82 . the mechanisms by which dectin - 1 influences fungal control and ibd pathogenesis are still being delineated , but evidence is emerging that it may be necessary to enable dendritic cell antigen presentation to t cells 83 . therapeutic strategies for enhancing the control of microflora in ibd , except for antibiotics and probiotics , are largely unexplored . intestinal microbes represent the largest microbial community in the body , where up to 100 trillion ( 10 ) microbes may exist in a commensal relationship with the human host 8486 . this relationship is facilitated by the intestinal mucus layer which creates a physical boundary between the host and microbe , by specific characteristics of the microbial community which reduce their immune cell - activating properties , and by direct influence on the immune cells . the intestinal microflora develops in early life and then the composition remains largely stable under healthy conditions 8790 . despite the large number of individual organisms , the number of bacterial species is estimated to be about 1000 per individual and represents only a small fraction of the existing phyla , which supports the idea that the commensal relationship is the product of a tight co - evolutionary history between the host and microbiota 86 . shifts in the bacterial makeup on human intestinal microflora have been documented in ibd using 16s rrna sequencing . these studies show that a subset of crohn 's disease and ulcerative colitis patients have depletion of commensal bacteria , especially members of the phyla firmicutes and bacteroidetes 91 . overall bacterial burden is typically lower in patients with crohn 's disease than in those with ulcerative colitis but both are lower than healthy control individuals 92 . even within the same patient , bacterial diversity is reduced in inflamed regions when compared with non - inflamed regions . these data suggest that not only is the host inflammatory response likely contributing to the loss of diversity characteristic of ibd patients but it is also providing a selective advantage to the subset of microbiota which have an increased presence in the disease state 93 . a role for microflora in ibd pathogenesis is supported by studies showing that exposure to the faecal stream is required for endoscopic and histological disease manifestations 9496 and that faecal transplants from healthy individuals can also have therapeutic benefit 97,98 . in addition , antibiotic therapy has shown some efficacy in clinical trials , with predominantly symptomatic improvement but also some endoscopic improvement and induction of remission , depending on the antibiotic and on the trial design 99101 . experimental colitis models also support the contention that microflora is a key component , as most mouse models of ibd require the presence of intestinal microbiota for colitis to develop 102,103 . dendritic cells discriminate between pathogenic and commensal bacteria by utilizing prrs which recognize specific pathogen - associated molecular patterns . these include the toll - like receptors ( tlrs ) and c - type lectins such as mannose receptor and dendritic cell - specific intercellular adhesion molecule 3 - grabbing non - integrin ( dc - sign ) 104 . the microbial environment encountered by an immature dendritic cell can determine the ability of the mature dendritic cell to drive t - cell differentiation towards t helper 1 ( th1 ) , t helper 2 ( th2 ) or regulatory polarization 105110 . this makes the dendritic cell a key player in determining whether a tolerant or protective immune response is mounted at the mucosal surface in response to specific microflora 111 . for example , probiotics might help to restore normal microbial populations in the intestine 112 ; however , to date , these efforts have not generated consistently promising results in ibd , particularly in crohn 's disease 113115 . therefore , many investigators have turned to investigating the immunomodulatory effects of specific bacteria or bacterial components in murine models to identify promising candidates . there is emerging evidence that alterations of cell surface components of lactobacilli can alter the immunoregulatory responses of dendritic cells , and this might provide a better defined therapeutic pathway in inflammatory diseases of the gastrointestinal tract 116 . the feasibility of utilizing genetically modified bacteria as a therapeutic agent has been established 117 . the innate immune system exists to provide a rapid initial response to pathogens but it must also identify and minimize immune response to commensal microflora . initiation of the gut mucosal immune response takes place following antigen uptake by dendritic cells and presentation to adaptive immune effector cells . however , in the absence of pathogen recognition , mucosal dendritic cells primarily function to regulate immune responsiveness 118 . while there is general consensus that dendritic cells from a healthy intestinal tract are hyporesponsive to commensal bacterial components , the mechanisms by which this is achievedone example of this is the evolving understanding of the role of cd103 dendritic cells in mucosal homeostasis . dendritic cell subsets are typically defined based on expression of surface markers , especially cd11b ( integrin m ) and cd103 ( e integrin ) . the majority of this work has been done in mice and dendritic cell subsets are not identical between mice and humans . cd103 dendritic cells comprise a substantial subset of murine mucosal dendritic cells and develop from classical precursors 119,120 . tolerogenic dcs in mice 121 , which are believed to be important in initiating t - cell responses including induction of foxp3 regulatory t cells ( tregs ) , and in the establishment of oral tolerance 122 . while cd103 dendritic cells have been credited with a major role in the maintenance of mucosal hyporesponsiveness , in part due to their ability to produce retinoic acid necessary for the development of foxp3 tregs 123 , there remains some controversy on this point . recently , batf3 ko mice that lack a cd103 dc subset have been reported to have normal treg populations in the lamina propria 124 , suggesting that other dendritic subsets have the potential to support treg development . also , recent work has shown that cd103 dendritic cells are capable of directly sampling , transporting , and presenting luminal antigens , and therefore are not restricted to a purely immunoregulatory role in the mucosa 125,126 . moreover , cd103 mucosal dendritic cell populations are heterogeneous and can be further subdivided into two major populations of cd11b and cd11b subsets , which vary in terms of transcription factors required for their development as well as in geographical distribution within the intestinal mucosa 127,128 . cd103 dendritic cells have been identified in the human colon 129 but , unlike in mice , these cells do not constitute the dominant mucosal subset . this suggests that other distinct dendritic cell subsets may contribute to the tolerogenic intestinal mucosal environment . therefore , although the data suggest that a subset of cd103 dendritic cells may be very important for maintaining mucosal immune hyporesponsiveness in normal individuals , the scientific understanding of these aspects of dendritic cell biology is still evolving . as noted previously , dendritic cells are implicated in ibd pathogenesis by both genetics and their central role in the control of microbial interactions . activated dendritic cells accumulate at sites of intestinal inflammation in human ibd and in murine models of intestinal inflammation 130132 . these cells express increased levels of a variety of activation markers , enhanced tlr responsiveness , and are phenotypically distinct from the hyporesponsive dendritic cells which help to mediate mucosal homeostasis 119,120,133135 . these activated dendritic cells likely contribute to intestinal pathology and may prove to be valuable therapeutic targets in ibd . as our understanding of dendritic cell biology continues to grow and withincreasing definition of mechanistic pathways , we expect to see the emergence of new dendritic cell - related drug targets .\noutput:\n" }, { "from": "agent", "value": "dysfunction of the mucosal immune system plays an important role in inflammatory bowel disease ( ibd ) pathogenesis . dendritic cells are emerging as central players based on both our increasing understanding of how genetic susceptibility impacts the mucosal immune system and the key role of dendritic cells in regulating response to gut microflora . we discuss areas of therapeutic opportunity in this evolving landscape . 2013 the authors . journal of pathology published by john wiley & sons ltd on behalf of pathological society of great britain and ireland ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: tobacco use is a risk factor for several illnesses affecting almost every organ of the human body . they need to be specifically protected , as the tobacco industry is targeting women for initiating the tobacco habit . women generally do not recognize health as a felt need and the other day to day matters take priority . this was also one of the project clusters where our group had recently implemented a cancer screening program for women . during this former program , we had enlisted and enrolled women using any form of tobacco for oral cancer screening . we obtained this list and enrolled only the current tobacco users in the present program . current tobacco users were defined as women using tobacco at the time of enrollment or having used tobacco within 6 months prior to enrollment in the former program . accordingly , 340 women were identified as current tobacco users . amongst these , 25 women could not be contacted as they had shifted their residence outside of the project cluster . furthermore , 36 women had quit tobacco due to the health awareness created during the former program . thus , overall 279 women were eligible as current tobacco users for the present tobacco cessation program . among these ,260 women were available for post - intervention follow - up at the end of 1 - year . the medical social workers ( msws ) went to the house of each eligible woman , explained the program , and invited them to participate . the women , who agreed to participate , signed or put their left thumb impression on the consent form . another woman / family member from the same area was invited to witness the procedure and signed as a witness . meetings were held with the local community leaders to explain the program and their help was garnered in the various program activities . the msws went to the house of participant women and personally interviewed them to record their pre - intervention details on a questionnaire [ figure 1 ] . this included particulars of their tobacco habits , knowledge of cancer , attitudes toward quitting tobacco and any efforts for the same . we involved the family members to encourage the eligible women to participate in the program . personal interviews being conducted at the house of participant woman to collect the pre - intervention data the women in trombay are predominantly housewives or engaged in part - time occupation of selling fish . hence , most of the participant women were available for the counseling interventions . throughout the program , all efforts were made to maximize compliance . in the case of nonavailability of participant women , multiple visits were made to their houses to contact and invite them to participate in the program activities . the objectives of the study were to assess the knowledge , attitudes , and practices ( kap ) of tobacco among women tobacco users residing in urban slums , provide tobacco cessation interventions at the community level enabling them to quit tobacco , identify factors associated with quitting and to evaluate the quit rates at the end of the program . the program was implemented as three intervention sessions spread over 9 months period followed by a post - intervention follow - up conducted at the end of 1 - year to assess the changes in knowledge , attitudes and tobacco practices . the interventions included games , health education , and group counseling motivating people to quit tobacco and enabling them to cope with the challenges of quitting . this paper presents the results with relation to the kap among the tobacco users and its association with various sociodemographic factors . the details of the tobacco cessation interventions and the related outcomes in the form of tobacco quit rates are presented in another paper which will be soon published . the results related to kap of tobacco , common cancers among women in india and the impact of the interventions on kap are discussed here . during the pre - intervention period , majority of women ( 66.53 % ) identified cancer as an important health hazard of tobacco . there was improvement in the post - intervention knowledge with regards to all the parameters as compared to the pre - intervention period [ figure 2 ] . intervention in the form of health education was provided to the tobacco users . as reflected in figure 2 , the tobacco users even in pre - intervention period had a high level of awareness ( 75.40 % ) about it being dangerous to health . this further improved with the educational intervention to 99.60 % in the post - intervention period . however , there was statistically significant improvement in the knowledge of women with regards to certain parameters like poor oral hygiene and tobacco use being the main cause of oral cancer ( p = 0.007 ) , knowledge of ill effects of second hand smoke ( p = 0.0001 ) , knowledge about possibility of early detection of oral cancer ( p = 0.0001 ) , perception of pictorial and written warnings on tobacco products ( p = 0.0001 ) , and availability of help for quitting tobacco ( p = 0.024 ) . comparison of pre and post - intervention knowledge and attitudes about tobacco among women women had mainly seen pictorial warnings in the form of pictures of scorpio and written warnings of tobacco is harmful on tobacco products . only 7.30 % of the women felt health warnings on tobacco products would prevent people from using tobacco . most women ( 68.46 % ) expressed that they gained knowledge of tobacco being injurious to health from the general public and 17.69 % women reported to have obtained this information through media and other hoardings . univariate and multivariate logistic regression analysis [ table 1 ] were conducted to identify the relation of different socio - demographic variables with knowledge of tobacco being injurious to health . the following variables , that is , age , religion , marital status , education , occupation , and income were used in the analysis . according to the results of univariate analysis age , marital status , education , and occupation were significant and hence were included in multivariate analysis . according to the results of multivariate logistic regression analysis , only marital status and education were significantly related to the knowledge about tobacco being injurious to health . the married women had better knowledge than widowed women , and the formally educated women had better knowledge as compared to women who were illiterate and without formal education about tobacco being injurious to health . univariate and multivariate logistic regression analysis identifying the relation of different sociodemographic factors with knowledge of tobacco being injurious to health all participants in this program ( 279 ) used smokeless forms of tobacco . the distribution of use of different forms of tobacco is as shown in figure 3 . among smokeless tobacco users , majority ( 94.23 % ) used masheri burnt tobacco powder used to clean teeth ( 80.38 % of the women used only masheri , while the rest used it in combination with other forms of tobacco ) . the frequency of masheri use was 1 to 3 times / day for majority ( 76.3 % ) of the participants . the median age of starting masheri was 15 years ( range : 4 - 70 ) and the median duration of using the same was 35 years ( range : 1 - 72 ) . most women ( 88.84 % ) used tobacco within half an hour of getting up in the morning . when asked regarding willingness to quit tobacco habits , majority ( 78.46 % ) women expressed their desire to do so . majority of the women ( 61.92 % ) felt it was not difficult to quit tobacco . this study focuses on the kap related to tobacco use and the impact of the interventions on kap among women in urban low socioeconomic strata in mumbai , india . during the pre - intervention phase , majority women in our study ( 66.53 % ) , , 49.6 % , 35.8 % , and 47.3 % of the participant women could correctly identify cancers of the breast , cervix , and oral cavity as common cancers among women in india .73.8 % , 27.0 % , and 1.1 % participant women from delhi study identified breast , cervix , and oral cavity as common cancers among women . this is in contrast to another study from kerala , wherein 42 % of the participants mentioned bad oral hygiene as a risk factor for oral cancer . majority of the women participating in this program ( 64.61 % ) were aware about tobacco being the main cause of oral cancer . in the kerala study , more than 70 % of the women attributed smoking as the cause of oral cancer . few women in the present study , that is , only 9.23 % of the respondents , were aware about the possibility of early detection of oral cancers and had knowledge of oral precancers . this is in contrast to the study conducted in the villages in kerala , where 90 % of the respondents felt early detection of oral cancers was feasible . another study conducted in the general population in gorakhpur revealed better knowledge about certain oral precancerous conditions . majority of the women ( 75.38 % ) had knowledge of tobacco being injurious to health . the kerala study , where literacy rate is highest in the country , 96.6 % of the participants had this knowledge . we see herein , that though over 70 % women participants were aware of tobacco being dangerous , they were still using it . this strengthens the fact that cessation support , in addition to awareness , is important for quitting tobacco . tobacco users require help in quitting because of the addictive nature of the nicotine present in the tobacco . as per the global adult tobacco survey ( gats ) , majority of the women in india are aware about tobacco causing severe health hazards . majority ( 73.46 % ) women in this program could correctly identify at least one health hazard of tobacco . a study conducted in delhi had similar findings , wherein , majority participants consisting of mixed population ( 64.2 % ) , could identify health hazards of smoking . in the present study , only a small proportion of women could identify at least one ill effect of second hand smoking ( 18.07 % ) . this indicates more awareness needs to be created regarding the harms of passive smoking , as women are likely to be exposed to the same in their homes . this is in contrast to a study among rural women in india , wherein the majority of women ( 75.8 % ) were aware about some health hazards of smokeless tobacco use on children . very few participant women in the current program had noticed health warnings on tobacco products at pre - intervention . totally , 10.76 % women had seen pictorial warnings and only 3.84 % women could recollect having seen both pictorial and written warnings . whereas , another study from mumbai revealed that most participants had seen pictorial as well as written health warnings on tobacco products . the message delivered through these health warnings , was , however , not clearly understood by the participants . only a few women ( 8.46 % ) in the present study , at pre - intervention , were aware about the availability of assistance for quitting tobacco . the availability of formal tobacco cessation services in india is still at a very preliminary stage . these services are inadequate to meet the needs of the vast tobacco using population in india . as a result , awareness regarding the availability of quittingparticipant women in the program were aware about tobacco being injurious to health , mainly through information received from the general public . a study from an industry in rural maharashtra reported that employees had received knowledge about harms of tobacco through hoardings , printed media , television , and doctors . in the present study , women with formal education had better knowledge about tobacco being harmful for health . other studies have also indicated knowledge to be positively co - related with education . though the age was not a significant factor in our study , a karachi study among urban squatter settlement , showed higher knowledge of health hazards of tobacco with increasing age and educational level . in the present study , income was not related to the knowledge of tobacco hazards . however , a study from morocco reported lesser knowledge about health hazards of tobacco use among lower income group . a large majority of participant women in this program used masheri . this is similar to another study among women in rural maharashtra , wherein masheri and betel quid were the most common forms of tobacco use . another study from mumbai also revealed that masheri was the most popular form of tobacco use among women , and that majority women used masheri 3 times a day . the average age of initiation for masheri use in the current study was similar to the age of initiation for tobacco use among women in india as per the gats . male tobacco users in a rural industry in maharashtra , india , revealed a little higher age at initiation of tobacco . the average age of smoking initiation among women in five european countries was 18 years . the participants in the current program used tobacco within 30 min of waking , which is consistent with the findings of gats in india . this in contrast to another study from india , wherein only 12 % of tobacco users intended to quit within a month 's duration . as per gats in india , and a survey in kuwait , a little 50 % of the current tobacco users wanted to quit the habit . the participant women in this program ( 61.92 % ) did not perceive quitting tobacco use as being difficult . this is in contrast to another study conducted in france and india , wherein most participants felt quitting tobacco was a challenge . thus , the present study among urban low socioeconomic women in mumbai , india shows high prevalence of smokeless tobacco . the use of masheri is especially popular among these women . though the pre - intervention knowledge on various aspects of tobacco was poor amongst these women , it significantly improved in the post - intervention period . this highlights the importance of health awareness programs and tobacco cessation services focused toward changing the kap . the outcome of different tobacco cessation and education interventions would be greater if it is implemented hand in hand with other strategies such as reducing the easy availability and raising prices of tobacco products thus making it very expensive .\noutput:\n" }, { "from": "agent", "value": "context : tobacco use is an important health issue globally . it is responsible for a large number of diseases and deaths in india . female tobacco users have additional health risks.aims : the aim was to assess changes in pre and post - intervention tobacco - related knowledge , attitudes , and practices among women from urban low socioeconomic strata , after three rounds of interventions.subjects and methods : a structured questionnaire was used to interview women living in low socioeconomic housing clusters in mumbai , regarding their tobacco consumption , attitudes , and practices , by medical social workers . these data were entered into ibm spss statistics , version 20 and analysed . interventions for tobacco cessation were provided 3 times over a span of 9 months , comprising of health education and counseling . post - intervention questionnaire was introduced at 12 months.results : there was statistically significant improvement in the knowledge of women , following the interventions , with particular reference to poor oral hygiene and tobacco use being main cause of oral cancer ( p = 0.007 ) , knowledge of ill effects of second hand smoke ( p = 0.0001 ) , knowledge about possibility of early detection of oral cancer ( p = 0.0001 ) , perception of pictorial and written warnings on tobacco products ( p = 0.0001 ) , and availability of help for quitting tobacco ( p = 0.024 ) . conclusion : the prevalence of smokeless tobacco use is very high among urban women from lower socioeconomic strata . therefore , tobacco awareness programs and tobacco cessation services tailor made for this group of women must be planned and implemented ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: bio - informatic analysis allowed 723 such particles to be identified in 358 species . coronins consist of amino - terminal tryptophan - aspartate residues , containing regions of repeats prior to the unique region of variable length that binds to carboxy - terminal spiral convoluted domains , which are necessary for their oligomerization . a tandem of coronins has also been described , formed of two wd cores , i.e. a large family of proteins , whose key role is to participate in creating protein complexes in almost all eukaryotic cell organelles . the proteins contain repeated regions that do not contain spiral domains . seven coronin genes have been identified in mammals . it has been demonstrated that coronins 1 to 6 present the classic coronin structure , while coronin 7 is a tandem coronin particle without a spiral domain . the best characterized coronin , in terms of both structure and function , is the mammalian coronin 1 . coronins , which are located in the membrane , do not have trans - membrane domains . they only bind to the membrane with the cytoskeleton through interaction with cholesterol . coronins are involved in the regulation of actin dynamics , e.g. coronin a isolated from the lower eukaryote dictyostelium discoideum and coronins 1 and 4 occurring in mammal cells indicate association with f - actin . for coronins 2 and 7 , data point to their binding to f - actin , but there are also data not confirming this . there is a lack of data on potential interaction of coronins 5 and 6 as well as 2 and 3 with f - actin . it was further found that coronin 1 is associated with a complex of proteins associated with actingiven coronin interaction with the f - actin cytoskeleton of cells in the yeast saccharomyces cerevisiae , invertebrates , as well as in mammals , it is suspected that these proteins evolved from actin - binding particles in lower eukaryotes in order to become regulators of various cellular processes in mammals , determining and influencing the activity of the immune system and the immune response in viral and autoimmunological infections . the role of coronins in mammals in the area of immune mechanisms has been demonstrated e.g. in avoidance of the intracellular cidal property of mycobacterium tuberculosis . it is known that most pathogenic microorganisms are effectively eliminated by macrophages by phagocytosis ending with lysosomal destruction . in the case of m. tuberculosis , however , the bacterium stops this phenomenon by actively blocking lysosomal supplies , because m. tuberculosis bacteria undergoing phagocytosis are stuck in phagosomes , where they manage to survive for a longer time . it was found that during mycobacterial infection , a 51 kda protein is recruited and actively stored in the cytoplasmic part containing mycobacteria in macrophage phagosomes . this protein blocks the supply of phagosomes containing mycobacteria to lysosomal organelles , which prevents their destruction . peptide sequencing of the isolated protein and cloning of cdna that codes the protein showed the presence of a large central wd region that is typical for coronins . the region contains tryptophan - aspartate repeats , as well as its homologues of the previously identified p57 protein with unknown function , which were obtained together with phospholipase c from human leucocytes . based on the presence of the wd region and location of the 51 kda macrophage protein around phagosomes containing mycobacteria , the particle has been referred to as taco , namely tryptophan - aspartate - containing coat protein . such facts and identification of several homological taco particles , genes of which were sequenced , have led to the conclusion that taco and p57 are members of a protein family associated with coronins in yeasts and d. discoideum ; hence presently it is assumed that taco is coronin 1 . in mice , based on genetic ablation ( a method involving dna modification to interrupt the production of a specific gene ) , it was determined that coronin 1 is the cause of facilitated survival of mycobacteria in such animals macrophages . it was also evidenced that small rna interruptions limiting regulation of coronin 1 in mice caused drastic reduction of mycobacteria in macrophages as a result of infection . apart from binding to phagosomes containing m. tuberculosis , coronin 1 also places itself near phagosomes containing m. leprae , which can also survive for a longer time in macrophage phagosomes of mice . it is also assumed that helicobacter pylori , like m. tuberculosis and m. leprae , is able to escape the immune response for a longer period of time . this shows that the role of coronin 1 is connected with the prevention of lysosomal supply in mammals infected with m. tuberculosis , m. leprae and h. pylori . it is assumed that macrophages retained coronin 1 expression because of its key role in certain conditions for their function , or because the immune system of vertebrates maintained a store of mycobacteria in a closed subcellular space during evolution to use them as natural agents that allow for a quick immunological response . this hypothesis is supported by the fact that liver macrophages are the only leucocytes with no expression of coronin 1 and due to evolutionary pressure on effective destruction of mycobacteria in the liver . the studies on phagocytic activity of macrophages deprived of coronin 1 revealed that they do not show cytoskeletal defects and preserve their adherence and migration capacity , as well as chemotaxis and absorption capacity , i.e. fundamental phases of phagocytosis . recently , it has been demonstrated that coronin 1 is necessary to activate calcium signalling after the entry of mycobacteria into the macrophages , because absorption of these bacteria is associated with a transient increase in intracellular calcium ion concentration . this activates calcium - dependent calcineurin phosphatase an enzyme of major importance for mycobacterial survival in macrophages . interestingly , the activation of calcium - dependent signalling after the uptake of mycobacteria turned out to be dependent on the expression of coronin 1 . it was also found that if intracellular calcium ions are eliminated using chelating agents , the effect is the same as the removal of coronin 1 . in turn , if the intracellular concentration of calcium ions in coronin 1 - negative macrophages increased , mycobacteria survived again therefore , it appears that the number of m. tuberculosis resistant to macrophage degradation is closely related to coronin 1 - dependent activation of the calciumit was also found that despite the lack of defined coronin species specificity , coronin 1 - deficient mice neutrophils showed no striking change of phenotype compared with wild mice type neutrophils , in the context of their development , migration ability , absorption and the nadph oxidase - dependent killing activity of these cells . increased expression of coronin 1 in neutrophils and dc cells , together with reduced apoptosis of polymorphonuclear ( pmn ) cells , was recorded in human patients with cystic fibrosis . it was also found that antigen processing and presentation by dc cells both to th and tc cells takes place correctly even in the absence of coronin 1 . such data indicate that coronin 1 is redundant for antigen processing and presentation by dendritic cells and that t cell activity depletion , as well as lowered immune status of mice , is combined with coronin 1 deficiency . in the case of mast cells , alsodifferences in their functioning in the absence of coronin 1 were observed , although there are also data that do not confirm this observation , which suggests that such cells dependence on coronin 1 may differ depending on the type . the role of this coronin was also found in nk cells , as this protein increases cytotoxicity of such cells through f - actin . if actin polymerisation is distorted by pharmacological inhibitors or its mutation , this results in nk cells dysfunction . in mice without coronin 1 , a low number or absence of t - cells was recorded in peripheral blood , despite their normal growth in the thymus . it was also found that principally absence of coronin 1 affects the pool of naive t - cells , as compared to effector and memory t - cells , both in the aspect of their absolute number and functionality . it is assumed that the engagement of coronin 1 in survival of naive t cells is related to its role in regulating f - actin , because in the absence of such protein , it accumulates in t cells , which is positively correlated with increased apoptosis of these lymphocytes . therefore , it was assumed that the decrease of coronin 1 deficient t - cells occurs as a result of spontaneous apoptosis despite normal production of t - cells in the thymus . it was evidenced that increased mortality of naive t - cells with coronin 1 deficiency is due to f - actin - induced distortions of mitochondrial membrane potential , although there are studies not confirming this . it was also recorded that defects of the cytoskeleton in naive t - cells resulting from deficiency of coronin 1 or caused by mutated coronin 1 are related to f - actin deregulation , although such changes have not been confirmed for b - cells , macrophages or neutrophil granulocytes . it was reported that deficiency of coronin 1 in naive t - cells does not affect their membrane dynamics , formation of immunological synapses and talin polymerisation , or their migration activity . it was , however , evidenced that the function of coronin 1 in naive t - cells is related to calcium signalling and movement of calcium ions , because mobilisation of such ions and calcineurin activation are also the key for signal cascade activation of the t - cell receptor ( tcr ) , and their inhibition promotes apoptosis of such cells . it was reported that , in naive t - cells , mobilisation of calcium ions is greatly reduced if there is no expression of coronin 1 , or if there is expression of mutated coronin 1 . thus , it is assumed that the mobilization of calcium ions and activation of calcineurin provide pro - survival signals for t cells , although it has been demonstrated that coronin 1 deficient t cells have elevated levels of caspase 3 expression , which affects reduction of the level of pro - intravital molecules , as shown in the case of b cell lymphoma 2 . this fact confirms the role of coronin 1 in t - cells in calcium - calcineurin signalling . this hypothesis is additionally supported by the fact that absence of naive t - cells , observed in the absence of coronin 1 , has a similar effect as deletion of a calcineurin in the absence of naive t - cells . it was also evidenced that both calcineurin activation and survival of such cells can be restored by increasing the intracellular concentration of calcium ions in t - cells with coronin 1 deficiency . also , a practical insight into coronin 1 function in naive t - cells was provided by the analysis of shionogi cataract ( cts ) in mice with a major deficiency of t - cells in the peripheral blood , the phenotype of which is very similar to the one in knockout mice deprived of coronin 1 or its e26k mutation . in mice with cts , single positive thymocyteswere observed which also showed distorted migration in the thymus , as well as defective mobilisation of calcium ions , although their survival rate was largely the same . it was also reported that , in the case of coronin 1 , e26k mutants are delocalised in t - cells , which may contribute to their damaged migration capacity . it is assumed that such mutated protein is partially functional , which determines the mobilization and migration of calcium ions and survival of naive t cells . the research has shown that coronin 1 may be part of a signalling platform that requires supporting structures based on f - actin , to which coronin 1 may bind . such activity through this platform may be responsible for the mobilization of calcium ions , which functions as an important stimulus for the survival of naive t lymphocytes . it is also possible that , apart from signalling cascade of tcrs , there is also another coronin 1 - dependent trigger required in order to fully sustain the survival of nave t - cells . it is currently assumed that the role of coronin 1 in t - cell survival is of major importance in reference to naive t - cells , because memory and effector t - cells survive well in the absence of coronin 1 . this assumption correlates with the role of coronin 1 in transmission of signals supporting tcr regulation in naive t - cells , which are proved to be necessary for survival of peripheral naive t - cells . in turn , memory and effector t - cells , as well as regulatory t - cells , can survive even in the absence of peripheral stimulation by mhc particles . such observations also indicate that molecular events underlying the signalling mediated by tcrs can differ in naive t - cells as compared to effector and memory t - cells . for example , in nave t - cell signalling , strengthening signals are usually required to sustain their survival , whereas in the case of effector and memory t - cells , signalling is only required for their formation and survival . in reality , stimulation of tcrs in effector and memory t - cells induces calcium ion mobilisation regardless of the coronin l expression , although the number of regulatory t - cells is normal and they are functional in the absence of coronin 1 . coronin 1 is also required for complete mobilisation of calcium ions upon triggering the b - cell receptor ( bcr ) . it is not , however , required for their survival and activation , probably because co - stimulation of such cell function largely , but not entirely , depends on the presence of coronin 1 . considering the fact that many coronins are co - expressed in leucocytes , there is the question how necessary or unnecessary the presence of coronin 1 is . it has been shown that deletion of ubiquitously expressed coronin 2 , which was considered important for cytoskeleton modulation , did not cause visible results in such cells . furthermore , double knockout mice lacking both coronin 1 and 2 showed no effect on the phenotype , apart from a t - cell signalling defect caused by deletion of coronin 1 . although other known coronins can compensate for the loss of coronins 1 and 2 , it is assumed that the major role of coronin 1 in calcium - calcineurin signalling mediated by tcrs , which is expressed in t - cells , can not be compensated by any of them , as several cases of immunodeficiency associated with only mutations of coronin 1 have been described . it was registered with immunodeficiency in humans , in the case of coronin 1 mutations in the paternal allele coupled with the deletion of the chromosomal mother s allele , although even in this case it must be assessed to what extent the observed defects were a result of coronin 1 dysfunction . the role of coronins was evidenced in mice with coronin 1 deficiency , where t - cell - dependent antiviral immunity was analysed during infection with lymphocytic choriomeningitis virus ( lcmv ) and vesicular stomatitis indiana virus ( vsv ) . it was found that for early control of infection with lcmv , a strong antiviral response of cd8 t - cells is necessary , while in the case of long - term antiviral immunity against lcmv , specific cd4 t - cells and b - cells are required . immunity against such viral infection principally depends on type i interferons and early production of class g neutralising antibodies and the response of cd4 t - cells and b - cells . it was reported that after infecting coronin 1 deficient mice with lcmv , elimination of viruses and induction of virus - specific cd8 t - cells were similar as in wild mice , which suggests a coronin 1 - independent mechanism for t - cell activation , which is necessary to eliminate lcmv . moreover , infection with this virus leads to normalisation of the range of peripheral cd8 + t - cells . also , the response of cd4 + t - cells is significantly weakened as a result of infection with both lcmv and vsv , whereas activity of cd4 + t - cells and induction of b - cells are sufficient to maintain long - term control over infection with lcmv . the authors also revealed that coronin deficient mice are very susceptible to infections with vsv due to the significant delay in the response of neutralising antibodies . the occurrence of nonsense homozygous mutations in coronin 1 has also been found in humans , determining susceptibility to infection with epstein - barr virus ( ebv ) . furthermore , the role of coronin 1 in auto - immunological diseases was observed in coronin 1 - deficient mice immunised with a peptide originating from myelin oligodendrocyte glycoprotein ( own antigen inducing experimental autoimmune encephalomyelitis [ eae ] in wild mice ) . it was observed that deletion of cyclin - dependent kinase 5 ( cdk55 ) in haematopoietic cells of mice causes distorted activation of auto - reactive t - cells after infection with eae , which is attributed to defective coronin 1 phosphorylation after the removal of cdk5 . also , in mice with coronin 1 deficiency , more severe symptoms of eae were recorded after immunization than in the wild mice control group , which points to faulty activation of smad3 ( mothers against decapentaplegic homolog 3 ) in th17 cellsdependent on transforming growth factor tgf . despite these facts , it is not clear whether coronin deficient mice immunity excitation after viral infection is due to the lack of a naive t cell or faulty signalling mediated by the tcr . further proof for the role of coronins in autoimmune diseases is the observation of a mutation in the coronin 1 gene , which inhibited the development of autoimmune disease in a mouse model of systemic lupus erythematosus ( sle ) . in such animals , this was identified as a cytosine transition to thymine 784 in the coronin 1 gene , which led to transformation of a codon from glutamine to a stop codon . therefore mice expressing this coronin 1 mutant did not show any detectable expression of coronin 1 and are characterized by a significant reduction in the number of t cells . also , the population of nave t - cells in mice in the absence of coronin 1 points to a severe defect in calcium ion mobilisation after tcr stimulation . it was also observed that after deletion of coronin 1 , the autoimmune response was distorted , although immunity against foreign antigens remained at a normal level . the authors explained that , despite the fact that conditions of self - immunisation result from the deficiency of nave t - cells in mice deprived of coronin 1 , the antigen - related molecular processes that follow tcr activation can differ from the signals following stimulation by own antigens , which are coronin 1 - dependent . coronins have been proved to play a role in reactivity of immune system cells , as well as in the immunological response to viruses and in autoimmune diseases ; nevertheless , further studies are required to confirm their function in such processes in microorganisms .\noutput:\n" }, { "from": "agent", "value": "coronins are a large family of proteins occurring in many eukaryotes . in mammals , seven coronin genes have been identified , evidencing that coronins 1 to 6 present classic coronin structure , while coronin 7 is a tandem coronin particle , without a spiral domain , although the best characterised coronin , in terms of both structure and function , is the mammalian coronin 1 . it has been proven that they are related to regulation of actin dynamics , e.g. as a result of interaction with the complex of proteins arp2 / 3 . these proteins also modulate the activity of immune system cells , including lymphocyte t and b cells , neutrophils and macrophages . they are involved in bacterial infections with mycobacterium tuberculosis , m. leprae and helicobacter pylori and participate in the response to viral infections , e.g. infections of lymphocytic choriomeningitis virus ( lcmv ) and vesicular stomatitis indiana virus ( vsv ) . also their involvement in autoimmune diseases such as lupus erythematosus has been recorded ." } ]