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limb traumas are among the most painful and stressful events , that anybody may experience during his or her life .
so long as pain control is concerned , morphine remains the gold standard for analgesia .
it has been the standard analgesic for many years , and the effects of newer analgesics are often expressed in comparison with the effect of morphine .
the search for good analgesics , however , should not only focus on analgesia . as far as analgesia is concerned
, morphine is an excellent drug ; but morphine lacks quality of an ideal analgesia due to its side effects .
these side effects include sedation , respiratory suppression , nausea and vomiting and pruritus , which may be avoided by substituting other drugs or combinations with the same effects and lower or no adverse effects such as ketamine with or without midazolam .
first synthesized in 1963 during the search for the ideal anesthetic , ket - amine was so named because it is a
derivative of an amine . and compared with the r ( - ) isomer , the s ( + ) isomer has a fourfold greater affinity for the nmda receptor , twice the analgesic potency , and fewer psychomimetic effects .
ketamine is useful as a general anesthetic for trauma patients , because it preserves sympathetic reflexes that help support blood pressure in patients who have lost blood . because it does not interfere with respiratory drive , it is also widely used in resource - poor set - tings where intubation and intraoperative mechanical ventilation are unfeasible .
the analgesic action of low , subanesthetic doses of ketamine predominantly de - rives from its activity - dependent , noncompetitive blockade of the glutaminergic nmda - receptor channel complex , through binding at phen - cyclidine ( pcp)-binding sites in the ion channel .
experimental and clinical evidence indicates that ketamine reduces opioid - induced tolerance and hyperalgesia ; however , the mechanisms involved are only partially understood .
low - dose ketamine decreased morphine - resistant pain , reduced dosage requirements in opioid - tolerant patients , decreased hyperalgesia after remifentanil infusion , and reduced hyperalgesia and allodynia along surgical incisions .
traditionally , they have been considered to lack analgesic action ; however , benzodiazepines reduce the minimum alveolar anesthetic concentration of inhaled anesthetics .
this is of interest that the neurophysiological mechanisms of the effects of benzodiazepines ( i.e. midazolam ) on nociception have been studied in animals , but the conclusions often are conflicting .
according to these studies midazolam may suppress pain pathways of the spinal cord by its specific action and that effect is not due to the action of the drug on supraspinal systems . in this study we had two main objectives : ( 1 ) to compare the efficacy of two analgesic regimens regarding pain control in trauma patients ( closed fractures : defined as fractures with intact skin and soft tissue above the fracture site ) ; ( 2 ) to compare the incidence of adverse events , categorized as respiratory , nausea , and vomiting , and agitation in conjunction with hemodynamic alterations between groups receiving low dose iv ketamine plus midazolam versus iv morphine .
we performed a prospective , randomized , single - blind , non - inferiority clinical trial in the emergency department ( ed ) of a university medical center from december 2011 until february 2013 ( clinicaltrials.gov identifier : nct01807429 ) .
the main reason for which we considered this study as a single blind was the possibility of a physician bias resulting from ketamine - induced nystagmus .
the study was approved by the hospital ethics committee , and written informed consent was obtained from each patient .
the sample size was determined about 236 patients ; considering type 1 error rate as 0.05 , statistical power as 80% and common variance as 1.8 for detecting = 1 as the fixed non - inferiority margin ( pain score in terms of visual analogue score ( vas ) ) .
two hundred and thirty - six patients of both genders sustaining closed fracture of the extremities ( i.e. , long bones ) who were between the ages of 18 and 60 years , and in good health or with only mild systemic diseases ( american society of anesthesiologists grade 1 or 2 ) were recruited for this study as a convenience sample because the availability of such a population in the ed .
patients were eligible for inclusion if they presented a trauma with a severe acute pain defined as a vas score of at least 60/100 ( or 6 ) ; were aged between 18 and 60 years ; and were without acute respiratory , hemodynamic , or neurologic compromise ( respiratory distress signs , systolic blood pressure < 90 mmhg , glasgow coma score < 15 ) .
the patients with a psychiatric history ; chronic respiratory , and acute pulmonary infection ; renal , or hepatic failure ; known ketamine sensitivity ; known opioid allergies ; treatment of chronic pain or treatment with opioids ; incapacity to understand the vas ; the use of drugs that affect the central nervous system ; chemical substance abuse ; chronic pain ; pregnancy ; morbid obesity ; increased intracranial pressure ; cardiovascular , hepatic , renal or ocular pathology ; thyroid disease , and pregnancy were not included in the study .
patients , who had already received an opioid analgesic ( either by self - administration or by another attending physician or emergency medicine service ( ems ) ) , were also not included in our study .
a table of random numbers determined the randomization sequence , using a restricted randomization scheme to ensure roughly equal numbers in each group .
the threshold for administration of analgesics in this study was severe acute pain , defined as a vas of at least 6 .
eligible patients were randomly allocated to receive either morphine ( 0.05 - 0.1 mg / kg ) followed by additional doses of 3 mg every 5 - 10 minutes or ketamine - midazolam ( 300 - 500 mcg / kg ketamine and 0.03 mg / kg midazolam ) . the latter regimen was also repeated as needed , until pain relief was obtained as defined by a vas score not exceeding 30/100 .
the consort flow diagram the patients were assessed at the time of arrival at the ed and every 10 minutes for a total interval of 30 minutes , and the following variables were carefully monitored : visual analogue pain score ( vaps ) , pulse oxymetry ( spo2 ) , respiratory rate ( rr ) , blood pressure ( sbp , dbp ) , heart rate ( hr ) , nausea and vomiting , screaming , cursing , nightmares , and unpleasant hallucinations . pain intensity was verified using a 10 cm ( 100 mm ) vas , anchored by no pain at one end and by worst possible pain at the opposite end .
the vas , after teaching the patient as to determining their pain score visually or numerically , was used to evaluate pain , with the patient attributing a value that corresponded to the level of his or her pain . the threshold for efficient analgesia
the statistically significant analgesia , however , was held to be as a vas score of 30/100 or lower .
respiratory adverse events were defined as oxygen desaturation ( spo2 < 90% ) , apnea ( a minimum 20 seconds transient cessation of breathing ) , or laryngospasm .
thirty minutes after the first injection , patients , physicians , and nurses were queried about their level of satisfaction , from 1 ( least satisfied ) to 5 ( most satisfied ) , with a likert scale .
the responses were categorized as satisfied ( likert scale score of 4 or 5 ) and not satisfied ( score of 1 , 2 , or 3 ) .
primary outcome measure was the percentage of patients with pain relief ( with a vas score of 30/100 or lower ) 30 minutes ( t30 ) after the first injection ( t0 ) .
secondary outcomes included pain score comparisons every 10 minutes within the first 30 minutes and comparison of adverse events as mentioned above .
thirty minutes after initial analgesic dose , if the patient still did not reach a visual analogue score of 30 mm or less , he or she was excluded from the study .
in this situation the patient was considered as having adequate pain relief and was assigned a vas score of 0 . when pain was initially too severe to obtain a vas ( patient refusal ) , it was scored 100 .
quantitative variables were expressed as mean sd and qualitative variables as number ( percentage ) .
two independent samples t - test was used as the main statistical method for comparing the main outcomes . for all main outcomes
the percentage changes from baseline values were calculated and compared between two groups . within group comparisons
chi - square test also was used for comparing the qualitative variables between two studied groups .
we performed a prospective , randomized , single - blind , non - inferiority clinical trial in the emergency department ( ed ) of a university medical center from december 2011 until february 2013 ( clinicaltrials.gov identifier : nct01807429 ) .
the main reason for which we considered this study as a single blind was the possibility of a physician bias resulting from ketamine - induced nystagmus .
the study was approved by the hospital ethics committee , and written informed consent was obtained from each patient .
the sample size was determined about 236 patients ; considering type 1 error rate as 0.05 , statistical power as 80% and common variance as 1.8 for detecting = 1 as the fixed non - inferiority margin ( pain score in terms of visual analogue score ( vas ) ) .
two hundred and thirty - six patients of both genders sustaining closed fracture of the extremities ( i.e. , long bones ) who were between the ages of 18 and 60 years , and in good health or with only mild systemic diseases ( american society of anesthesiologists grade 1 or 2 ) were recruited for this study as a convenience sample because the availability of such a population in the ed .
patients were eligible for inclusion if they presented a trauma with a severe acute pain defined as a vas score of at least 60/100 ( or 6 ) ; were aged between 18 and 60 years ; and were without acute respiratory , hemodynamic , or neurologic compromise ( respiratory distress signs , systolic blood pressure < 90 mmhg , glasgow coma score < 15 ) .
the patients with a psychiatric history ; chronic respiratory , and acute pulmonary infection ; renal , or hepatic failure ; known ketamine sensitivity ; known opioid allergies ; treatment of chronic pain or treatment with opioids ; incapacity to understand the vas ; the use of drugs that affect the central nervous system ; chemical substance abuse ; chronic pain ; pregnancy ; morbid obesity ; increased intracranial pressure ; cardiovascular , hepatic , renal or ocular pathology ; thyroid disease , and pregnancy were not included in the study .
patients , who had already received an opioid analgesic ( either by self - administration or by another attending physician or emergency medicine service ( ems ) ) , were also not included in our study .
a table of random numbers determined the randomization sequence , using a restricted randomization scheme to ensure roughly equal numbers in each group .
the threshold for administration of analgesics in this study was severe acute pain , defined as a vas of at least 6 .
eligible patients were randomly allocated to receive either morphine ( 0.05 - 0.1 mg / kg ) followed by additional doses of 3 mg every 5 - 10 minutes or ketamine - midazolam ( 300 - 500 mcg / kg ketamine and 0.03 mg / kg midazolam ) . the latter regimen was also repeated as needed , until pain relief was obtained as defined by a vas score not exceeding 30/100 .
the consort flow diagram the patients were assessed at the time of arrival at the ed and every 10 minutes for a total interval of 30 minutes , and the following variables were carefully monitored : visual analogue pain score ( vaps ) , pulse oxymetry ( spo2 ) , respiratory rate ( rr ) , blood pressure ( sbp , dbp ) , heart rate ( hr ) , nausea and vomiting , screaming , cursing , nightmares , and unpleasant hallucinations . pain intensity was verified using a 10 cm ( 100 mm ) vas , anchored by no pain at one end and by worst possible pain at the opposite end .
the vas , after teaching the patient as to determining their pain score visually or numerically , was used to evaluate pain , with the patient attributing a value that corresponded to the level of his or her pain . the threshold for efficient analgesia
the statistically significant analgesia , however , was held to be as a vas score of 30/100 or lower .
respiratory adverse events were defined as oxygen desaturation ( spo2 < 90% ) , apnea ( a minimum 20 seconds transient cessation of breathing ) , or laryngospasm .
thirty minutes after the first injection , patients , physicians , and nurses were queried about their level of satisfaction , from 1 ( least satisfied ) to 5 ( most satisfied ) , with a likert scale .
the responses were categorized as satisfied ( likert scale score of 4 or 5 ) and not satisfied ( score of 1 , 2 , or 3 ) .
primary outcome measure was the percentage of patients with pain relief ( with a vas score of 30/100 or lower ) 30 minutes ( t30 ) after the first injection ( t0 ) .
secondary outcomes included pain score comparisons every 10 minutes within the first 30 minutes and comparison of adverse events as mentioned above .
thirty minutes after initial analgesic dose , if the patient still did not reach a visual analogue score of 30 mm or less , he or she was excluded from the study .
in this situation the patient was considered as having adequate pain relief and was assigned a vas score of 0 . when pain was initially too severe to obtain a vas ( patient refusal ) , it was scored 100 .
we performed a prospective , randomized , single - blind , non - inferiority clinical trial in the emergency department ( ed ) of a university medical center from december 2011 until february 2013 ( clinicaltrials.gov identifier : nct01807429 ) .
the main reason for which we considered this study as a single blind was the possibility of a physician bias resulting from ketamine - induced nystagmus .
the study was approved by the hospital ethics committee , and written informed consent was obtained from each patient .
the sample size was determined about 236 patients ; considering type 1 error rate as 0.05 , statistical power as 80% and common variance as 1.8 for detecting = 1 as the fixed non - inferiority margin ( pain score in terms of visual analogue score ( vas ) ) .
two hundred and thirty - six patients of both genders sustaining closed fracture of the extremities ( i.e. , long bones ) who were between the ages of 18 and 60 years , and in good health or with only mild systemic diseases ( american society of anesthesiologists grade 1 or 2 ) were recruited for this study as a convenience sample because the availability of such a population in the ed .
patients were eligible for inclusion if they presented a trauma with a severe acute pain defined as a vas score of at least 60/100 ( or 6 ) ; were aged between 18 and 60 years ; and were without acute respiratory , hemodynamic , or neurologic compromise ( respiratory distress signs , systolic blood pressure < 90 mmhg , glasgow coma score < 15 ) .
the patients with a psychiatric history ; chronic respiratory , and acute pulmonary infection ; renal , or hepatic failure ; known ketamine sensitivity ; known opioid allergies ; treatment of chronic pain or treatment with opioids ; incapacity to understand the vas ; the use of drugs that affect the central nervous system ; chemical substance abuse ; chronic pain ; pregnancy ; morbid obesity ; increased intracranial pressure ; cardiovascular , hepatic , renal or ocular pathology ; thyroid disease , and pregnancy were not included in the study .
patients , who had already received an opioid analgesic ( either by self - administration or by another attending physician or emergency medicine service ( ems ) ) , were also not included in our study .
a table of random numbers determined the randomization sequence , using a restricted randomization scheme to ensure roughly equal numbers in each group .
the threshold for administration of analgesics in this study was severe acute pain , defined as a vas of at least 6 .
eligible patients were randomly allocated to receive either morphine ( 0.05 - 0.1 mg / kg ) followed by additional doses of 3 mg every 5 - 10 minutes or ketamine - midazolam ( 300 - 500 mcg / kg ketamine and 0.03 mg / kg midazolam ) . the latter regimen was also repeated as needed , until pain relief was obtained as defined by a vas score not exceeding 30/100 .
the consort flow diagram the patients were assessed at the time of arrival at the ed and every 10 minutes for a total interval of 30 minutes , and the following variables were carefully monitored : visual analogue pain score ( vaps ) , pulse oxymetry ( spo2 ) , respiratory rate ( rr ) , blood pressure ( sbp , dbp ) , heart rate ( hr ) , nausea and vomiting , screaming , cursing , nightmares , and unpleasant hallucinations . pain intensity was verified using a 10 cm ( 100 mm ) vas , anchored by no pain at one end and by worst possible pain at the opposite end .
the vas , after teaching the patient as to determining their pain score visually or numerically , was used to evaluate pain , with the patient attributing a value that corresponded to the level of his or her pain . the threshold for efficient analgesia
the statistically significant analgesia , however , was held to be as a vas score of 30/100 or lower .
respiratory adverse events were defined as oxygen desaturation ( spo2 < 90% ) , apnea ( a minimum 20 seconds transient cessation of breathing ) , or laryngospasm .
thirty minutes after the first injection , patients , physicians , and nurses were queried about their level of satisfaction , from 1 ( least satisfied ) to 5 ( most satisfied ) , with a likert scale .
the responses were categorized as satisfied ( likert scale score of 4 or 5 ) and not satisfied ( score of 1 , 2 , or 3 ) .
primary outcome measure was the percentage of patients with pain relief ( with a vas score of 30/100 or lower ) 30 minutes ( t30 ) after the first injection ( t0 ) .
secondary outcomes included pain score comparisons every 10 minutes within the first 30 minutes and comparison of adverse events as mentioned above .
thirty minutes after initial analgesic dose , if the patient still did not reach a visual analogue score of 30 mm or less , he or she was excluded from the study .
in this situation the patient was considered as having adequate pain relief and was assigned a vas score of 0 . when pain was initially too severe to obtain a vas ( patient refusal ) , it was scored 100 .
quantitative variables were expressed as mean sd and qualitative variables as number ( percentage ) .
two independent samples t - test was used as the main statistical method for comparing the main outcomes . for all main outcomes
the percentage changes from baseline values were calculated and compared between two groups . within group comparisons
chi - square test also was used for comparing the qualitative variables between two studied groups .
two hundred and thirty - six patients were selected , among whom were 207 males ( 87.3% ) , and 29 females ( 12.2% ) .
the average age was 32.6 12.8 with extremes of 60 years and 18 years .
the patients were divided into two groups : g1 : 116 patients receiving ketamine - midazolam ( 33.8 14.1 ) and g2 : 120 patients receiving morphine alone ( 31.5 11.4 ) .
the median for body weight among g1 patients was 69 kg , and among g2 patients it was 70 kg [ table 1 ] .
demographic characteristics of two studied groups the vas score at t30 was significantly decreased compared with vas score at t0 , in both groups ( p < 0.0001 ) .
no statistically significant difference , however , was observed between two groups ( p < 0.16 ) .
the mean value of the vaps between two groups showed no meaningful difference ; in other words the efficacy of both regimens was the same in terms of pain control .
the mean value of dbp revealed no significant difference in both groups ; whereas regarding the mean value of rr and spo2 a meaningful difference was encountered between two groups .
furthermore , the mean value of the sbp and hr depicted a meaningful difference ; this means that sbp and hr mean values increased 30 minutes after taking ketamine - midazolam but with morphine these values were decreased [ table 2 ] .
nausea , vomiting , agitation , or hallucination was not noted in both groups . with reference to satisfaction from pain control process
, no significant difference was seen between two groups [ table 3 ] . comparing the mean of analgesic in two groups in terms of main studied outcome variables satisfaction rates among physicians , nurses , and patients
the most significant finding achieved in this study is that there is no meaningful difference between low - dose ketamine - midazolam and morphine with respect to pain control in patients sustaining closed limb fracture(s ) .
we found that hypoventilation and increased heart rate / blood pressure were more prominent in group morphine and group ketamine plus midazolam , respectively .
the changes noted in cardiopulmonary system , however , were congruent with what we already knew according to the previous evidence - based researches .
the emergency atmosphere and ed are somehow stressful per se ; so ketamine - midazolam regimen could be a better choice in terms of pain control in limb trauma patients , while it imposes a minimal risk on cardiopulmonary systems ( like respiratory depression and apnea ) .
it also makes itself a reasonable choice in opium - addicted patients , in group ketamine - midazolam inflicted with drug tolerance because of its morphine - sparing effects . regarding the effects of ketamine and morphine on pain on the one hand and their interaction , on the other
, so many studies have been yet accomplished . in 2003 , fj et al published an article as to comparing the quality of intravenous patient controlled analgesia ( pcia ) of low - dose morphine plus ketamine with morphine in a group of patients scheduled for elective abdominal hysterectomy .
contrary to our research , this study compared morphine consumption and morphine sparing effect of ketamine .
they concluded that morphine plus ketamine pcia , in doses used in this study ( 7 mg / kg morphine plus 14 mg / kg ketamine as a bolus ) provided analgesia inferior to that of morphine pcia , but may improve the respiratory side effect profile of morphine .
one reason for this conclusion , of course , could be the ultra - low dose of ketamine .
laeben et al reported a study about low - dose ketamine for analgesia in the emergency department ( ed ) .
however , there was concern about the patient group in this study which may interfere with their conclusion when applied to the general population .
compared to our study , the majority of the patients in this research had the record of chronic pain medication use or illicit drug abuse .
tolerance or dependence of opioids or opioid - like agents was frequently seen in these patients , which make them become a drug seeker in the ed , and thus , analgesia or so - called improvement of pain for them is more complicated . in our study , however , anybody with history of chronic drug abuse was excluded .
galinski assessed management of severe acute pain in emergency settings in an article titled as
the aim of the study was to compare in emergency settings two analgesic regimens , morphine with ketamine ( k group ) or morphine with placebo ( p group ) , for severe acute pain in trauma patients . at t30 ,
the main problem with this study , nonetheless , seems to be possible ketamine - induced nystagmus , and a resultant bias pursued , which we tried to resolve it , as mentioned earlier .
similarly , babak garaei and coworkers in iran did a randomized , placebo - controlled clinical trial , in opioid abusers based on their daily opioid consumption .
lithotripsy was performed under moderate sedation with intermittent bolus doses of remifentanil ( 0.2 g / kg ) to alleviate pain .
the incidences of bradypnea , apnea , nausea , vomiting , and hemodynamic changes were not statistically different between the ketamine and placebo groups .
they concluded that preemptive low - dose ketamine ( 0.1 mg / kg ) as a bolus has opioid - sparing effects in opioid abusers undergoing moderate sedation .
what has not been studied in the above mentioned researches , however , is the comparison of morphine versus ketamine regarding ed pain control .
they all used placebo in their studies but this intervention did not necessarily create an unethical issue in these studies , because all the patients received analgesic irrespective of taking ketamine . regarding midazolam , our goals were to decrease pain as toshinobu sumida et al followed in their study , beside its already known effects on anxiety and ketamine induced agitation , known as
emergence phenomenon. of course , probable analgesic effects of midazolam are yet to be investigated by more precise , double - blind studies in the future . another issue that makes our sample more different from its predecessors is that it is a noninferiority trial . the term
noninferiority trial is commonly used to refer to a randomized clinical trial in which a new test treatment is compared with a standard active treatment rather than a placebo or untreated control group .
one starting principle is that no patient is denied a known effective treatment by entering a clinical trial . in our study
we noted no adverse pulmonary effects like hypoventilation as caused by morphine , in group ketamine - midazolam .
the effect of ketamine on respiratory rate is in accordance with the findings of presson et al .
alfentanil induced a decrease in respiratory rate , without affecting tidal volume and respiratory drive .
firstly , ketamine caused subjective side effects in all subjects ( e.g. , strange feeling , body feels tight , arms and legs strange , body feels heavy , etc ) that might have caused general arousal , thereby stimulating respiration indirectly . secondly ,
being an nmda receptor antagonist , ketamine may antagonize the effect of opioids on ventilation as the effect of opioids on the control of breathing may be through inhibition of glutaminergic transmission .
the ketamine dose was , therefore , high enough to have an analgesic effect , but lower than a dose that causes hallucinations .
finally , we recommend more extensive , double - blinded studies with lower therapeutic range of ketamine , in the future which may clarify more exactly the real effect and safety of ketamine plus midazolam compared with morphine .
we studied only adults between the ages of 18 and 60 years , and thus our data can not apply to elderly patients who are perhaps more likely to experience the sympathomimetic effects of ketamine . furthermore , according to the available data and medical textbooks , the incidence of the closed fractures of the extremities tends to be more at the extremes of ages ( e.g. , femoral head , intertrochanteric or distal radius fractures in the elderly and suprachondylar humeral fractures in children , both of them not involved in the study ) .
closed limb fracture because of its low - energy nature ( vas of less than 6 ) , most of the times does not need to be managed with analgesics ; and if a patient who has been probably a drug seeker would apply for analgesic or declared that his pain score was above 6 .
we could not , unfortunately , trust his or her real intent , despite receiving analgesics and being assigned for this study .
another limitation was the ketamine induced nystagmus that made us perform this study as a single - blind trial , in fear for the probable physician bias while monitoring the patients .
we studied only adults between the ages of 18 and 60 years , and thus our data can not apply to elderly patients who are perhaps more likely to experience the sympathomimetic effects of ketamine .
furthermore , according to the available data and medical textbooks , the incidence of the closed fractures of the extremities tends to be more at the extremes of ages ( e.g. , femoral head , intertrochanteric or distal radius fractures in the elderly and suprachondylar humeral fractures in children , both of them not involved in the study ) .
closed limb fracture because of its low - energy nature ( vas of less than 6 ) , most of the times does not need to be managed with analgesics ; and if a patient who has been probably a drug seeker would apply for analgesic or declared that his pain score was above 6 .
we could not , unfortunately , trust his or her real intent , despite receiving analgesics and being assigned for this study .
another limitation was the ketamine induced nystagmus that made us perform this study as a single - blind trial , in fear for the probable physician bias while monitoring the patients .
we concluded that low - dose iv ketamine - midazolam has the same analgesic effects as iv morphine concerning pain control in adult patients sustaining closed limb fracture(s ) , with less pulmonary adverse events . whether midazolam has significant analgesic effects , however
mehdi nasr isfahani , awat feizi : substantial contributions to the conception or design of the work ; or the acquisition , analysis , or interpretation of data for the work .
mehdi nasr isfahani : drafting the work or revising it critically for important intellectual content .
omid ahmadi , mehdi nasr isfahani : final approval of the version to be published .
omid ahmadi , mehdi nasr isfahani : agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved . | background : we assessed the effects of low - dose iv ketamine - midazolam versus morphine on pain control in patients with closed limb fracture(s ) ; and also compared the incidence of adverse events ( cardio - pulmonary ) between two groups.materials and methods : this prospective , single - blind , non - inferiority trial randomized consecutive emergency department ( ed ) patients aged 18 - 60 years to two groups : receiving 300 - 500 mcg / kg ketamine plus 0.03 mg / kg midazolam , or 0.05 - 0.1 mg / kg morphine .
visual analogue score ( vas ) and adverse events were verified during an interval of 30 minutes.results:two hundred and thirty six patients were selected , among whom 207 were males ( 87.3% ) .
the average age was 29 2 , ( range , 18 - 60 years ) .
the vas score at t30 ( i.e. , 30 minutes after initial analgesic dose ) was significantly decreased compared with vas score at t0 , in both groups .
no statistically significant difference , however , was observed between the two groups ( 6.1 1.1 versus 6.2 1.0 ; p = 0.16 ) . with regard to systolic blood pressure and respiratory rate , however ,
a meaningful difference was noted between the two groups ( 1.5 6.4 versus 2.1 6.6 ; p = 0.000 for sbp , and 0.2 1.1 versus 1.1 6.1 ; p = 0.048 for rr).conclusion : low - dose intravenous ketamine plus midazolam has the same analgesic effects as morphine on pain control in trauma patients with closed limb fracture(s ) , in addition to less respiratory adverse events . | INTRODUCTION
MATERIALS AND METHODS
Study procedures and outcome measure
Study design and Patients
Study analysis
RESULTS
DISCUSSION AND CONCLUSIONS
Limitations
CONCLUSIONS
AUTHOR'S CONTRIBUTIONS |
a pregnant 23-year - old female with a six - year history of type 1 diabetes presented with a complaint of increased blur in both eyes for the previous two months .
best corrected visual acuity was 20/40 ou . slit - lamp examination was entirely unremarkable in both eyes .
dilated funduscopic examination was significant for flame - shaped , dot , and blot hemorrhages in the posterior segment , with associated macular edema and exudates bilaterally ( figures 1a and 1b ) .
optical coherence tomography ( oct ) revealed a foveal thickness of 578 5 microns and 667 8 microns in the right and left eye , respectively ( figures 2a and 2b ) .
all oct scans were performed with the stratus optical coherence tomograph ( zeiss - humphrey inc , dublin , ca ) .
examination findings were consistent with bilateral , nonproliferative diabetic retinopathy and clinically significant macular edema . after careful deliberation with the patient and her obstetrician
, a decision was made to treat the bilateral macular edema with intra - vitreal triamcinolone acetonide injection .
the patient received 0.05 ml of triamcinolone acetonide 40 mg / ml in the left eye initially and in the right eye one week later .
best - corrected visual acuity was 20/20 and 20/25 in the right and left eye , respectively .
repeat oct revealed a foveal thickness of 159 5 microns and 202 6 microns in the right and left eye , respectively ( figures 3a and 3b ) .
slit - lamp examination and goldman applanation tonometry did not reveal any intraocular hypertension or significant lenticular changes at this visit or at any point after triamcinolone injection .
the patient delivered a full - term , healthy baby boy weeks prior to this examination .
progression of diabetic retinopathy during pregnancy has been described previously by several authors.1,2 visual impairment in these cases can result from both proliferative ( eg , vitreous hemorrhage , retinal detachment ) and nonproliferative etiologies ( eg , retinal hemorrhage , papillopathy , macular edema).1 although macular edema may regress in some cases after delivery , in other cases edema can persist and can be associated with severe and persistent visual dysfunction.1 data from large , randomized clinical trials have established the benefits of argon laser photocoagulation for clinically significant macular edema.3 focal laser photocoagulation of actively leaking blood vessels or grid laser for areas of diffuse permeability can decrease clinically significant edema . however , laser photocoagulation in close proximity to the fovea increases the risk of inducing iatrogenic central scotoma as a result of thermal injury to the tissues , or subsequent glial proliferation .
there are many reports of off - label use of intravitreal triamcinolone in cases of persistent and refractory diabetic macular edema.4 improved visual acuity and decreased foveal thickness have been documented by serial oct after a single injection .
however , these effects do not appear to persist beyond 34 months without repeated administration.5 a medline search using keywords pregnancy
revealed no case reports or case series documenting the treatment of clinically significant macular edema with intravitreal corticosteroids in a pregnant patient .
side effects of systemic corticosteroid administration are well known . major ophthalmic complications of intravitreal corticosteroid injection include , but are not limited to , cataract formation and increased intraocular pressure .
although corticosteroid equivalents can be measured in the aqueous three months after a single intravitreal injection , it is not known how much corticosteroid is released into the systemic circulation after a single intravitreal injection.6 thus , it is hard to estimate the systemic effects of intravitreal corticosteroid therapy . to date , there are no reports of teratogenic outcomes with systemic corticosteroid use in pregnant human females .
however , teratogenic effects have been observed in many species receiving equivalent systemic human doses.7 many authors have noted maxillofacial deformity and , in particular , cleft palate in mice which have received corticosteroids early in gestation .
the area of greatest thickening was within the fovea of both the right and left eyes , with little edema observed in the extrafoveal area .
laser photocoagulation to this area carried a significant risk of inducing a permanent central scotoma .
given the patient s late stage of pregnancy , we felt that intravitreal steroid posed little risk to either mother or fetus .
we were able to achieve resolution of macular edema and improved visual acuity with a single intravitreal dose to each eye . in conclusion
, we propose that intravitreal triamcinolone injection may be a viable treatment modality for management of clinically significant macular edema in pregnant patients .
the safety profile with administration of this medication is enhanced if the steroid is administered after the first trimester .
we suggest a multidisciplinary approach and consultation with an obstetrician whenever using corticosteroid therapy in pregnant patients . | we present a case of diabetic macular edema in a pregnant patient treated with a single intravitreal injection of triamcinolone acetonomide .
initial presentation and serial examinations after treatment included visual acuity , slit - lamp examination , indirect ophthalmoscopy , and optical coherence tomography .
resolution of visual acuity and macular edema were present six weeks after injection and persisted throughout the duration of the pregnancy without further intervention .
no adverse outcomes for either mother or fetus were noted . to our knowledge , this is the first report of intravitreal triamcinolone administration in this patient population to be published in the medical literature . | Case report
Discussion |
it is the most frequent cause of acute liver failure when acetaminophen overdose is included and is therefore medically relevant , exhibiting a high morbidity and mortality .
it is also of economic importance and represents the second most frequent cause for drug withdrawal from the pharmaceutical market .
many agents , for example , anti - infectives , neurologic , cholesterol - lowering or pain - modifying substances , can act as hepatotoxins ( table 1 ) .
they can either damage the liver directly in a dose - dependent and therefore predictable fashion , or idiosyncratically by immunologic mechanisms or metabolic activation independent of the dose .
the latter is unpredictable , but unfortunately the more common event , if serious liver injury caused by acetaminophen / paracetamol ( apap ) overdose is not accounted for .
symptoms of affected patients are non - specific and include nausea , discomfort in the right upper abdominal quadrant , dark urine , or fatigue .
alt , alanine aminotransferase ; alp , alkaline phosphatase ; r , ratio ; uln , upper limit normal . to substantiate the relationship between an administered drug and liver injury , other causes of acute hepatocellular injury need to be excluded .
these comprise viral hepatitis ( hepatitis a virus [ hav ] , hepatitis b virus [ hbv ] , hepatitis c virus [ hcv ] , hepatitis e virus [ hev ] , epstein - barr virus [ ebv ] , cytomegalovirus [ cmv ] ) , ischemic liver injury , autoimmune hepatitis , budd - chiari syndrome , wilson 's disease and , in cases of cholestatic liver injury , other causes of extrahepatic or intrahepatic cholestasis , such as choledocholithiasis , malignancy , primary biliary cirrhosis , or sclerosing cholangitis .
after exclusion of these differential diagnoses , physicians have to consider dili in patients with an unexplained increase in liver enzymes .
currently dili is categorized into hepatocellular ( r - value [ alt / uln alp / uln ] [ alanine aminotransferase / upper limit of normal alkaline phosphatase / upper limit of normal ] 5 ) , cholestatic ( r - value 2 ) , or mixed - type injury ( r - value 2 - 5 ) by the respective enzyme pattern in blood ( table 1 ) .
the temporal relation to the administration of a potential hepatotoxin and the exclusion of other differential causes are the cornerstones for establishing a diagnosis of dili . for causality assessment , different tools such as
. however , new diagnostic biomarkers for liver injury are currently under investigation in various mechanistic and pre - clinical models and also in large clinical trials .
several consortia are dedicated to evaluating new biomarkers in the diagnosis and management of dili .
although the objectives of the various endeavours differ , the translation of preclinical mechanism - based findings into clinical liver safety assessment offers a unique opportunity to move the field forward . the us drug - induced liver injury network ( dilin ) recruits patients with idiosyncratic dili in both retrospective and prospective study registries .
the international drug - induced liver injury consortium ( idilic ) is a multinational scientific group coordinated by the university of newcastle and university of nottingham .
predicting dili by genetic risk factors and identifying potential hepatotoxins before they lead to severe liver injury are the primary goals of investigation . for this purpose ,
dna isolated from patients with dili is analysed , for example , in genome - wide association studies ( gwas ) .
genetic associations have been shown for flucloxacillin - induced dili and the human leukocyte antigen ( hla)-b*5701 allele . with this predisposition , an 80-fold increase in the risk of developing dili
pharmacogenetic testing of hla - b*5701 is mandatory in patients scheduled to receive abacavir to prevent hypersensitivity .
donaldson and co - workers identified hla class ii genotypes in association with amoxicillin / clavulanate associated dili . for lumiracoxib ,
a cyclooxygenase-2 ( cox-2 ) selective inhibitor , hla - dr and hla - dq genotypes were found to be predictive for dili .
lapatinib , a tyrosine kinase inhibitor , has been associated with dili in carriers of the hla allele dqa*02:01 .
an association between dili caused by ximelagatran , a direct thrombin inhibitor , and hla - drb1 * 0701 and hla - dqa1 * 02 was reported . in the case of alt elevations caused by ximelagatran ,
colony - stimulating factor 1 receptor ( csf1r ) , the receptor for the respective cytokine , was increased significantly in plasma , leading to a new quest for early identification tools .
the safe - t consortium ( safer and faster evidence - based translation ) is focused on the identification of new biomarkers for dili .
funded by the innovative medicines initiative ( imi ) the consortium aims to identify new tools to predict , detect and monitor drug - induced organ toxicity in a more specific , sensitive and predictive manner .
academic centres , pharmaceutical companies and small- to medium - sized enterprises collaborate to promote a personalized medicine approach in the prediction and management of dili .
toxicities to other organs of interest are analysed in drug - induced kidney injury ( diki ) and drug - induced vascular injury ( divi ) work packages .
another imi project , called mip - dili ( mechanism - based integrated systems for the prediction of drug - induced liver injury ) , focuses on the development of preclinical test systems that integrate multiple preclinical data types to improve prediction of dili in man .
the predictive safety testing consortium ( pstc ) was created by the critical path institute and aims to qualify new biomarkers for the detection and monitoring of drug - induced toxicity in preclinical and clinical studies . in this respect , pstc is the preclinical counterpart of the safe - t consortium , since both aim to qualify biomarkers that allow the separation of patients with a self - limiting course of dili from those that progress to severe dili and ultimately liver failure .
this prognostic assessment is currently performed by use of hy 's law that predicts a 10% risk of fatality in cases in which a 3-fold elevation of alt above the upper limit of normal ( uln ) is accompanied by a 2-fold elevation of bilirubin .
food and drug administration ( fda ) introduced the edish program ( evaluation of drug - induced serious hepatotoxicity ) in 2004 , which has since been implemented to assess dili in clinical trials .
new biomarkers should improve patient safety and also reduce drug attrition due to toxicity . further investigated and proposed markers for dili include liver injury markers such as micrornas ( mirna ) , mechanistic biomarkers such as hmgb-1and cytokeratin-18 fragments , and metabolites from urine and serum . circulating serum mirnas such as mir-122 and mir-192
are liver - specific and are proposed as potentially sensitive and specific markers of liver injury . with a short half - life
hmgb-1 is a molecular pattern protein marking necrosis : in the acetylated form it indicates immune activation .
ck18 and mirna-122 were evaluated as superior biomarkers compared to alt in terms of sensitivity and specificity in dili . ck18 together with hmgb-1 point towards the mechanism of hepatocellular death in apap overdose , notably the degree of necrosis vs. apoptosis .
the performance of combinations of biomarkers is likely to surpass that of a single biomarker alone , depending on the context of its use .
thus , the balance between apoptosis and necrosis may be indicative of the subsequent course the patient will follow , given that the liver is unique in its ability to activate defence mechanisms against toxic injury .
idiosyncratic dili is usually detected in a late stage of drug development often after drug approval in phase iv studies or pharmacovigilance surveillance .
an understanding of the pathophysiologic processes in this type of hepatotoxicity is of special interest to both pharmaceutical companies and regulatory authorities . in cases of apap hepatotoxicity
, levels of mitochondrial and nuclear dna could differentiate patients who developed acute liver failure , but subsequently recovered , from those who died .
these mechanistic markers could provide further insight into the pathophysiological mechanisms of dili , allowing early detection and outcome prediction . in vitro
generated hepatocytes derived from skin biopsies of patients with an idiosyncratic reaction could be used to study the unique features of the affected individuals ' hepatocytes , as well as the genotype - phenotype correlation in dili .
these new techniques and models hold great promise to improve drug safety with back - translation from bedside to bench .
until now , the management of dili has usually consisted of initial withdrawal of the suspected drug .
targeted therapy with antidotes , such as n - acetylcysteine in paracetamol ( acetaminophen ) overdose , is possible in defined cases .
re - challenge with the causative agent can lead to an augmented adverse effect , especially in immunologically mediated dili , and is therefore not recommended .
preventive or prophylactic measures against dili include patients ' education and alerting health care professionals towards liver enzyme monitoring under therapy with a potentially hepatotoxic drug .
pharmacogenetic tests , including next - generation sequencing , proteomic or metabolomic approaches for preselecting susceptible patient populations , and tailoring drug therapy to individual patients , have not yet been approved for routine clinical practice . to what extent
these new markers will change clinical practice for the prevention of dili remains to be seen .
ongoing efforts aim to overcome the gap between bench and bedside towards the early detection of dili and the identification of patients at risk .
important results from major consortia such as dilin , safe - t , mip - dili , pstc and idilic can be expected in 2015 . | drug - induced liver injury ( dili ) is a potentially fatal adverse event with significant medical and economic impact .
many drugs , especially anti - infective , neurologic or pain - modifying substances , act as hepatotoxins . with cardiovascular toxicity ,
liver toxicity is one of the two leading causes for drug withdrawal from the market .
the liver can be affected directly , in a predictable and dose - dependent manner , or idiosyncratically , independent of the dose and therefore unpredictable.currently dili is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes .
the type of injury is categorized into hepatocellular , cholestatic , or mixed by the respective enzyme pattern of injury .
symptoms of affected patients can mimic any other liver disease.therefore , new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi - centre clinical trials that are conducted by international consortia and other initiatives .
pharmacogenetic testing , next - generation sequencing , proteomics , metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients .
proposed dili indicators that are under investigation include micrornas , cytokeratin-18 ( ck18 ) , high mobility group box protein 1 ( hmgb-1 ) , and several other biomarkers .
these developments can change clinical practice , and improve patients ' safety and management .
however , they have not been translated into clinical practice or approved for routine use yet .
management of dili usually consists of initial withdrawal of the suspected drug and if applicable
administration of specific antidotes , such as n - acetylcysteine .
however , the overall management of dili could change in the near future with the advent of novel diagnostic and prognostic dili markers . | Introduction
Diagnosing DILI: future biomarkers
Management and outlook
Disclosures |
need can be defined as whatever is required for health or comfort ; though there are various ways to look at it as normative , felt , expressed , fundamental , etc .
a person with psychiatric disorder needs all things that anybody needs to lead a good life .
a person 's need at a given point of time is likely to be influenced by different factors including type of illness , stage of illness , response to treatment , age , gender , socioeconomic status , support system , and place of stay . some studies
, however , show that needs of persons with severe mental illness are not related to age , gender and education .
whereas persons recovered from these illnesses may express many needs ; persons with severe negative symptoms may express minimal needs or no needs .
numerous scales and schedules are available to explore rehabilitation needs of persons with psychiatric illness . these include needs for care assessment , camberwell assessment of needs ( can ) , and perceived rehabilitation needs questionnaires for people with schizophrenia . the most commonly used schedule in indian studies for assessing rehabilitation needs are rehabilitation needs assessment scale ( rnas ) and can .
rnas schedule collects purely qualitative information from patients ( on 6 items ) and caregivers ( on 2 items ) , but does not require observer rating .
can is a family of questionnaires to assess needs of persons with mental health problems .
it has clinical practice versions , research version , and short appraisal schedule version ( cansas ) for persons with severe mental illness .
the indian studies have assessed rehabilitation needs in out - patient or in - patient set - up or both .
studies have assessed rehabilitation needs from caregivers of persons with chronic mental illnesses in a community sample and in inpatients .
the patients in these studies were suffering from schizophrenia , chronic psychosis , severe mental illness comprising bipolar disorder , schizophrenia , and psychosis not otherwise specified ( nos ) .
the main needs expressed in these studies were need for employment ( 65% ) and help for family ( 55% ) ; accommodation for in - patients and help for family for outpatients ; social skills ( 80% ) , employment ( 65% ) , providing help to families ( 60% ) ; help for family and modification in families attitude toward them ; attitude modification , employment and help for family and help for family , employment , vocational training and psychosocial modification .
a retrospective case records based study on needs of chronic psychiatric patients admitted in a tertiary hospital , reported the need for the development of community outreach programs , especially in areas where no psychiatric services are available .
( 2010 ) reported that patients expressed the need for welfare benefits , information about condition , money , help for psychotic symptoms and psychological distress .
in the same study , caregivers expressed the need for help in welfare benefits , psychological distress , money , company , and intimate relationships .
caregivers in community sample expressed needs in areas of help for the family , employment and occupation , psychosocial modification and skills training .
caregivers of in - patients with schizophrenia patients reported felt need in managing the behavior and social - vocational problems of patients ; health issues of caregivers ; education about schizophrenia ; rehabilitation ; and managing sexual and marital problems of patients . in a study of 101 patients with schizophrenia , 42 had high unmet needs .
this was associated with poverty , lower education , and persistent psychopathology . in an indian psychiatric society
multicentric study on assessment of health care needs of persons with severe mental illness , patients reported needs in money , welfare benefits , transport , information about the illness and treatment , relief of psychological distress , company , household skills , and intimate relationships .
psychiatric rehabilitation services ( prs ) at the national institute of mental health and neurosciences ( nimhans ) , bengaluru runs a day - care center for in - patients and outpatients . at any given point of time ,
the center has a range of vocational sections including candle making , bakery , bamboo , weaving , plastic molding , tailoring , horticulture , carpentry , leather , printing , crafts , recreation , domestic skills , and computer section .
nine female patients admitted in a closed ward for many years ( 2 - 27 years ) due to difficulty in discharging them attend various sections of their choice during the day .
the current study was planned to assess rehabilitation needs of this special population to help us understand and cater to their needs . to assess the rehabilitation needs of chronic female inpatients attending day - care in prs , nimhans , bengaluru , karnataka , india .
to assess the rehabilitation needs of chronic female inpatients attending day - care in prs , nimhans , bengaluru , karnataka , india .
due to unique needs of this special population , an interview schedule was developed by expert consensus [ box 1 ] . focused group discussion was done among the authors of the paper , after going through available scales / schedules .
the schedule included needs like accommodation , safety , diet , grooming , privacy , illness management , family , relationships , sexual , recreation , education , occupation , vocational training , financial , emotional , spiritual and any other needs .
in addition to whatever facilities you are availing here , do you need anything else ? before applying the interview schedule .
rehabilitation needs of chronic inpatients as the patients resided in the hospital , their interactions were limited to nursing staff , hospital attenders , vocational instructors in day - care and treating team .
the perspectives of nursing staff in patient 's ward , vocational section instructor of the day - care section attended by the patient and treating psychiatrist ( senior resident in psychiatry ) were also independently sought .
nine female inpatients hospitalized for more than 1-year and attending day - care in prs were included in this study .
sociodemographic details were collected using proforma designed for the study . the diagnosis made by the treating unit was noted .
due to unique needs of this special population , an interview schedule was developed by expert consensus [ box 1 ] . focused group discussion was done among the authors of the paper , after going through available scales / schedules .
the schedule included needs like accommodation , safety , diet , grooming , privacy , illness management , family , relationships , sexual , recreation , education , occupation , vocational training , financial , emotional , spiritual and any other needs .
in addition to whatever facilities you are availing here , do you need anything else ? before applying the interview schedule .
rehabilitation needs of chronic inpatients as the patients resided in the hospital , their interactions were limited to nursing staff , hospital attenders , vocational instructors in day - care and treating team .
the perspectives of nursing staff in patient 's ward , vocational section instructor of the day - care section attended by the patient and treating psychiatrist ( senior resident in psychiatry ) were also independently sought .
nine female inpatients hospitalized for more than 1-year and attending day - care in prs were included in this study .
sociodemographic details were collected using proforma designed for the study . the diagnosis made by the treating unit was noted .
four patients were diagnosed with schizophrenia , four patients with bipolar affective disorder and one patient was diagnosed with mental retardation with epilepsy with psychosis nos .
sociodemographic details detailed interview about rehabilitation needs was not possible for the patient with mental retardation with epilepsy with psychosis nos due to her symptomatic status .
hence , rehabilitation needs have been mentioned for eight patients from patient 's perspective [ table 2 ] and nine patients from perspective of nursing staff , treating team and vocational instructors [ tables 35 ] .
rehabilitation needs : patient 's perspective ( n = 8) rehabilitation needs : nursing staff 's perspective for nine patients rehabilitation needs : treating team 's perspective for nine patients rehabilitation needs : vocational instructor 's perspective for nine patients the patients were staying in the closed ward as either they did not have any close family members ( 5 ) or their family was not willing to take them home currently ( 4 ) .
they were attending the following vocational sections : bamboo ( 3 ) , computer ( 2 ) , tailoring ( 1 ) , mat weaving ( 1 ) , leather ( 1 ) , and craft section ( 1 ) . to the question in addition to whatever facilities you are availing here do you need anything else ? 8 out of 9 reported that they did not want anything else .
most of the patients and all hospital staff interviewed felt that the hospital provided the patients safe , clean accommodation , and enough privacy . in terms of food , both patients and hospital staff felt that breakfast was provided early .
the treating doctors felt that more nutritious and less oily food should be provided to these patients ; though one of the doctors felt that the food given here was okay as the patient had never complained .
patients expressed unmet needs in grooming such as talcum powder , soap , paste , shampoo , ornaments , etc . which they required when they went out of the ward for day - care .
patients expressed unmet needs in recreation like listening to music , watching tv , and reading books .
everyone interviewed expressed the need for increasing monthly incentives , which can enable patients to have food of their choice occasionally and buy items for grooming .
treating psychiatrists and vocational section instructors wished that the patients should get more incentives but did not specify any amount .
one of the doctors was not aware about how much incentives patient was getting and could not comment .
the nursing staff felt that only two patients needed to stay in closed ward and rest of them could be placed outside or sent out to work .
some interesting suggestions by the treating doctors were about having facilities of listening to music and beauty - parlor facilities for the patients .
the most commonly expressed rehabilitation needs were more incentive for attending day - care , change in food timing , more variety in food , avenues for recreation and more involvement by family .
five out of nine patients were symptomatic , but were referred to day - care as the treating team felt that they were fit to engage in activities .
the patient who could not be interviewed in detail was highly productive in the section she was attending .
probably they were not asked about the needs previously or they might not have felt the need to express themselves or they did not think that these needs might be fulfilled .
this highlights the fact that patients may not spontaneously come out with their needs and have to be specifically asked about it .
both patient and staff felt that patients had enough privacy , even though they stayed in general wards ( 15 - 20 patients in one ward ) and used common toilets .
the possible reason is that patients may have got used to living in the same environment .
the hospital staff felt that seven of them could be sent for work , but only four among those seven patients expressed interest in working .
others were 40 or more than 40 years of age ( 5 of them in 40s and 2 in 60s ) .
the nursing staff expressed concern regarding the change in societal attitude towards patients , but only three patients expressed the need for change .
patients again might have got used to the environment in the hospital , and their interaction with the society had reduced significantly .
a similar view was not expressed by either treating team or vocational instructors as they might be with the patient for limited time , but nursing staff were observing these patients more closely .
vocational instructors expressed need that patients should get more incentives , have more variety in food and they should be engaged in work .
the patients had material needs like variety and taste of food , some grooming items , and an increase in incentives .
it is possible that patients had got used to living in the current situation with limited needs and were unaware about increasing costs of things in the outside world .
the hospital authorities were sensitized about this , and the incentive has recently been increased to rs .
most of the patients had expressed passive recreation needs ( listening to music , watching tv ) ; they did not express much active recreation ( going out , playing games etc . ) .
this suggests that they might have got used to spend time just sitting in the ward in their free time .
we had included sexual needs in the schedule , but we did not probe it specifically as it was a sensitive issue .
many of the expressed needs could be met if the patients were placed back in the community .
some of them could not adjust in nongovernmental organizations when they were placed outside and came back to the hospital again . in future , careful admissions should be planned to avoid families abandoning patients in the ward . for prolonged admissions where family members can not stay with the patient
, families should make regular visits to meet the patients and should take them out for a short duration . in those with poor family support
, attempts to reintegrate patients back to the community should be pursued at the earliest .
else , patients may become comfortable in the hospital , which may make attempts in community reintegration difficult .
as evidenced in the present study , long - term hospitalization can reduce aspirations for independent living of patients . for chronic patients who are hospitalized due to poor family support , the hospital atmosphere
such patients are in a state of handicaptivity who are left with little options other than accepting the security of a hospital due to lack of better available alternatives .
national human rights commission , india ( 2012 ) recommends that authorities may find some jobs for fully recovered patients on nominal remunerations within the hospital to rehabilitate them .
positive social role models , avenues to take up a career / studies , fulfillment of social milestones ( like getting married , being financially independent , becoming parents ) and support in their pursuits is necessary to help them in their road to recovery .
it is important to develop services like supported housing , supported education and supported employment to cater to their complex needs .
such supported approaches will be helpful in social reintegration , reduce stigma , improve quality life , and reduce disability and dependency on the hospital set - up .
small sample size , interviews were not audio - taped , emotional needs were not asked from patients once the nursing staff expressed about them .
small sample size , interviews were not audio - taped , emotional needs were not asked from patients once the nursing staff expressed about them . | background : female patients hospitalized for a long duration in psychiatric hospitals are a special population with unique needs.aims and objectives : to assess rehabilitation needs of chronic female inpatients attending psychiatric rehabilitation services in a tertiary care psychiatric hospital.materials and methods : rehabilitation needs of nine chronic female inpatients were assessed with an interview schedule developed by expert consensus .
the needs were elicited from the patients .
perspectives of nursing staff , vocational instructors , and treating psychiatrists were also sought.results and conclusion : most patients expressed the need for more incentives for working in day - care , variety in food and grooming items .
the nursing staff felt many patients could be placed outside , and the family members should come more frequently to meet them .
vocational instructors felt that patients need more incentives , variety in food and work . treating psychiatrists said that major barriers in discharging and placing them were nonavailability or poor involvement of family members .
services like supported housing , supported education and supported employment are necessary to cater to their complex needs . | INTRODUCTION
Aim
MATERIALS AND METHODS
Interview schedule
Sample
RESULTS
DISCUSSION
Limitations
CONCLUSION
Financial support and sponsorship
Conflicts of interest |
guidelines would be the syntheses of the best available evidences , in addition to professional judgment and patient preferences , support decision - making by clinicians , managers and policy makers about the organization , delivery and improvement of health care [ 1 - 8 ] . according to the world health organization s ( who ) definition , appropriately developed guidelines , based on the best available evidences , should assist providers and recipients of health care and other shareholders to make informed decisions . recommendations
[ in guidelines ] might relate to clinical interventions , public health activities , or government policies [ 9 - 11 ] .
the first clinical guideline have produced by the uk s national institute for clinical excellence was on schizophrenia , in australia date to the late 1970s , when the state health authority began endorsing guideline booklets [ 12 , 13 ] .
most of the guidelines have established in high - income countries but progress in developing such national programs in low and middle income countries has still been lagging behind .
they have sought for improving the quality of care provided to the patients , reducing variability and containing the health care costs [ 15 , 16 ] .
most organizations were under pressure to produce more guidelines in a shorter time with increasingly limited resources . achieving those goals was difficult , and despite the development of clinical guidelines in many countries , solving the problems of cost and quality as well as variation in care has remained a challenge to health systems .
the who has recognized the need to use more rigorous processes to ensure that health care recommendations have informed by the best available research evidence .
systematic approach to considering the use and/or modification of guideline(s ) produced in one cultural and organizational setting for application in a different context .
customizing evidence - informed guideline recommendations for local application has demanded both methodological expertise and an intimate knowledge of the intended clinical practice environment .
dedicated guideline development bodies might have greater capacity to synthesize evidence but often had limited access to detailed contextual information .
however , the cultural and organizational differences between and within countries could lead to legitimate variation in recommendations , even when the evidence base would be the same .
the means that guidelines produced in one setting might not necessarily be appropriate for another , without careful consideration and/or contextualization .
guidelines have produced and used in the complex environment of a health care system with its cultural , ethical , economical , legal and other aspects ; these aspects have need to be taken into consideration in each country .
guidance has needed to be transparent , systematic , and adapted to the local contexts .
the first national programs of guideline development have started in the usa in the 1980s .
national programs have also sought with the expectation that it will be easier and more fruitful to implement national guidelines than local or society developed clinical guidelines .
transparent , cost - conscious and patient - centered guidelines based on the best available evidence could help establishing these quality and practice measures
. thus , use of guidelines might be optimized by improving their format and content .
research has shown that guideline format and content influence perceptions about and use of guidelines specifically , these intrinsic guideline qualities have shown to promote greater understanding of how users could apply the recommendations , stimulating confidence in users , ability to practice the recommended behavior , leading to greater intent to use guidelines and actual use [ 13 , 25 - 27 ] . in iran , the authorities already have thought of producing and localizing the knowledge products such as clinical evidence - based practice guidelines .
in addition to legislation , a number of clinical guidelines have also produced and localized .
legislator would be responsible for policymaking , planning and supervising on social , economic , cultural and politic , register and presentation of policies , strategies and activities related to training of employees for medical groups , research , health , treatment and medical services , welfare organization social security organization have defined as ministry of health and medical education ( mohme ) responsibility and the islamic consultative assembly in article number 36 ( section b ) in fifth 5 years development plan , ratified in january 5 , 2011 , policy making , planning and supervision of health sector is the responsibility of mohme and consider it as national priority of islamic republic of iran .
mohme has recognized as policy maker and supreme supervisor of national health based on the article number 38 ( section h ) , which all of the governmental and nongovernmental sectors in health areas should follow and obey its rules and regulations . despite the development of guidelines in many countries , the cultural and organizational differences between countries , the problems of cost and quality and limited resources
guidelines that have produced in one setting might not necessarily would be appropriate for another , our national works have conducted within the context of international and national guidelines in developed countries , which has aimed to harmonize guideline development methods in order to reduce duplication of efforts and to ensure efficient use of resources and produced national health guideline in islamic republic of iran . for improving the quality of care provided to the patients , reducing variability and containing the health care costs
, mohme should provide and distribute the guidelines base on its accountability to legal responsibility .
the development of guideline recommendations in a typical professional society setting has occurred at committee meetings , under the direction of a chairperson .
guideline developers have divided in to 2 groups ( include core and main group ) .
the principal aims of the core group were as below : coordinate and provide technical support on guidelines development , organize training on guideline production for main group , provide administrative support for the work of the guidelines review committee .
collaborate with other organizations and international networks that provided methodological expertise in relation to guideline development , adaptation and implementation .
in addition , for each guideline a technical team which contains of author of guideline and co - workers have designated , who have competency in scientific and literary editing considering cost effectiveness as well as efficacy and equity .
the team has included medical specialists in their respective fields , statistician , public health practitioner and epidemiologist as methodologist . in order to adjust and conform ,
the authors of the guidelines , systematically searched databases of twenty - two international sites which have specifically supported by governments as shown in " table1"with the related keywords to the special subject(s ) .
then they have selected at least five sources of them that were more relevant for each subject .
then key questions have identified for each guideline , and main table prepared for it including blank space for the answers of questions by each resources . in front of each question , there was a space for entering of iranian experts final opinion for each question , there were at least five answers .
gathering and summarizing the replies base on general consensus ( iranian experts ) have considered for the answer of the each question ( making group decision and reaching consensus ) .
sometimes , some of the guidelines have sent to scientific institution or experts of other universities to have more idea in this regard ( respected peers - those who have not been members of the guideline panel but were experts in the same field - should review guidelines for scientific validity .
these outside reviewers should be acknowledged at the end of the guideline document ) . at the end of this process , the authors have organized and finalized local guideline in a unified frame work .
the figure presents an overview of the steps . at the end of this process , national health guidelines have written by team and all of guidelines had an identical framework : name of guideline : in persian and english health professional target groups : in governmental and non - governmental sectors ( private public , cooperative , ngo ) centers , specially family doctors introduction and preface : should have the important points of epidemiology , cost , mortality , incidence , prevalence and burden of disease(s ) in iran and the world . preventive interventions : focusing on preventing risk factors of diseases . for each group of health provider the duties and responsibilities
diagnostic interventions : have pots of history , physical examination , least priorities of laboratory - test and imaging .
proper care interventions : should have appropriate cost effectiveness , following , referring of patients and determine the responsibilities of rehabilitation . implementation : responsibilities of mohme , universities of medical sciences and health services and other organization have defined for executing the guidelines . in purpose of final editing , the guideline has returned to national main team for more investigating .
guidelines have also reviewed by the guidelines review committee for content and format . each guideline group has submitted its final draft to the guidelines committee for approval .
the main authors group has finalized the text and draft has forwarded to the idsa governing council for editing and final approval then for registration by a special i d number . in less than 5 months
, more than 500 authors in whole country have prepared for educating co- workers about guidelines development and approximately 150 guidelines have provided in three volumes of the book published and distributed . at the beginning of each book the law and main national health policies that support the guidelines have notified . according to this supreme documents executing of all the strategies which have approved by mohme in the field of health and treatment areas , including prevention , diagnosis , test requests , medical treatment , surgical interventions , follow - up , record keeping , patient information and health promotion stratification of medical services and
each guideline had a specific 4 components national i d number , containing official automation code , year of publication , and unique guideline code and version code .
guideline should be changed base on new evidences every 3 - 5 years ; the version code all will be updated .
the guideline leader could determine whether the scope of change warranted a full - scale revision of the guideline .
the importance of guidelines as decision - making tools , for promoting evidence - informed practice , and serving as one of the foundations for improving health care efforts , has been shown scientifically .
health systems guidance has shown the potential to improve decision - making and enable more efficient use of resources with consequent improvements in the health of populations . however , such guidance needed rigorous and transparent processes of production and evidence - based approaches to ensure its dissemination and uptake . using clinical practice guidelines , especially when they have prepared by adoption method ,
of course it needed extensive planning and coordination in different parts of the system fortunately promising approaches have been taken in our country in recent years .
the primary target groups have been the health professionals and the main responsibility for developing guidelines should rest with them and their organizations .
other interested parties - patients , funders , and policy makers - could be involved whenever appropriate .
paying attention these objective , guidelines should be based firmly on scientific evidences , interpreted through professional experience and complemented by expert opinion whenever was necessary . in the developing countries such as iran adapting health guidelines in short and medium- term could be a proper way to obtain necessary and enough capacity to design national original ones .
also , several guidelines in each different topic would be available to be modified by our country , but , repetition alone was useless except in epidemic and special diseases .
the revision of original guidelines as an alternative could be beneficial . besides , using the modified guidelines could base on social economy .
international evidences have shown that using national guidelines could increase the quality of care in the health systems and avoid many mistakes and medical errors in developing countries . according to this fact that national guidelines have minded very essential means for policy making in health care
, mohme should provide and distribute the guidelines based on its accountability to legal responsibility .
therefore , for all the governmental and nongovernmental sectors , institutions and organizations execution of them would be mandatory .
in addition , we could consider our modifying and adapting health guidelines experiences as an innovation for developing countries . | backgroundguidelines have produced and used in complex environment of health care system with its ethical , economical , legal and other aspects ; that should be taken into account in any country .
modifying the format and content of guidelines might facilitate their usage and lead to improved quality of care and cost containment .
we have produced this tool for explained above purpose.methodsa coordinating national team has settled at the office of minster of health and medical education , supported by a guideline review committee . an innovative and appropriate approach for adapting national health guidelines
has consisted of eight steps , have defined for preparing the draft of each guideline a technical team which , including main author , her / his co - workers have nominated .
the authors of each topic have systematically searched databases of the proposed twenty - two international sites , and then have selected at least five sources of them that were more relevant .
the final recommendations have proposed by agreement of technical team and guideline review committee.resultsin less than 5 months , more than 500 authors in whole country have selected to prepare guidelines and , approximately 150 guidelines have provided in three volumes of the published and distributed book .
each guideline had a national i d number , constant forever ; all topics should be reviewed every 3 - 5 years.conclusionnational health guideline(s ) would be essential means for policy making in health system and increased the cost containment and quality of care .
ministry of health and medical education should provide and distribute the guidelines based on its accountability to legal responsibility . | Introduction
Materials and Methods
Results
Discussion
Conclusion |
orthognathic surgery can affect the oropharyngeal airway through skeletal displacement and changes in the positions of the hyoid bone and tongue1 .
the main concern regarding pharyngeal dimensional changes caused by orthognathic surgery is patient sleep quality1 .
up to 25% of adults suffer from obstructive sleep apnea ( osa ) ( apnea - hypopnea index [ ahi ] 5/h ) , and 10% of patients have moderate to severe osa ( ahi 15/hr)23 .
maxillomandibular advancement surgery has been shown to safely and effectively treat osa4 , but the efficacy of other kinds of orthognathic surgery on the upper airway is not well understood .
two - dimensional ( 2d ) radiograph - based evaluations of the upper airway have revealed that mandibular setback surgery narrows the pharyngeal airway , whereas bimaxillary surgery has a milder or non - narrowing effect156 .
one study reported a significant decrease in the pharyngeal airway six months after bimaxillary surgery7 .
others used computed tomography ( ct ) to evaluate the effect of bimaxillary surgery on class iii patients and found no significant decrease in the pharyngeal airway89 .
cone - beam ct ( cbct ) is an accurate and reliable tool for upper - airway evaluation10 . in this study
, we aimed to assess changes in the upper airway space following bimaxillary orthognathic surgery to correct skeletal class iii malocclusion and to determine whether changes in 2d measurements correlate with three - dimensional ( 3d ) measurements on cbct images .
this was a prospective cohort study conducted at mashhad university of medical sciences ( mashhad , iran ) from april to june 2012 .
all study activities were performed in accordance with the ethical guidelines set by the ethical committee of mashhad university of medical sciences , which conform to the declaration of helsinki . the aims and procedures of the study
we included healthy subjects with no previous medical problems , anteroposterior discrepancy > 10 mm , and a need for bimaxillary orthognathic surgery to correct a class iii malocclusion .
patients were excluded if they had any previous craniofacial syndrome or dentofacial trauma or if they did not require maxillary impaction as part of their surgical plan .
twelve patients participated in the study ( five males and seven females ) with an age range of 16 - 35 years ( mean age , 20.4 years ) and normal body mass index ( bmi ) of 18 - 25 kg / m .
two patients were excluded during the experiment because one did not complete follow - up , and the medical documents of the other were lost ( one male and one female ) .
all patients underwent bimaxillary orthognathic surgery ( maxillary advancement by lefort i osteotomy and mandibular setback by bilateral sagittal split ramus osteotomy [ bssro ] ) and rigid fixation with titanium miniplates and screws .
the mean amounts of maxillary advancement and mandibular setback were 4.4 mm and 6.55 mm , respectively .
maxillomandibular fixation was applied for a two - week period for all patients and was followed by elastic therapy to establish optimal occlusion .
two upper airway cbct scans were performed for all patients one week before and two to four months after surgery .
all cbcts were performed by the same technician at the same clinic , using the same machine and the same settings ( 80 kvp with 6 ma and 0.32 mm slice thickness , planmeca promax 3d s ; planmeca oy , helsinki , finland ) . to provide a reproducible cbct image before and after surgery
all cbct segmentations and measurements were performed with the same workstation ( hp xw9400 ; hewlett - packard , palo alto , ca , usa ) and same software ( planmeca romexis 2.8.1.r ; planmeca oy ) .
the anterior boundaries of the volume space of interest were the vomer bone , soft palate , base of the tongue , and anterior wall of the pharynx .
the posterior , lateral , superior , and inferior boundaries were the posterior wall of the pharynx , the lateral walls of the pharynx , the roof of the nasopharynx , and the plane crossing the vallecula perpendicular to the posterior wall of the pharynx , respectively .
1 , table 1 ) using the mid - sagittal plane view , a mid - sagittal slice was selected and used as a 2d measurement reference ; the landmarks , which are described in fig .
2 and table 2 , were used to perform 2d measurements as previously described by jakobsone et al.9 the wilcoxon one - sample test was used to compare the mean measurements of the airway pre- and post - surgery .
spearman 's rank correlation coefficient was used to test associations between cbct volumetric and linear measurements .
this was a prospective cohort study conducted at mashhad university of medical sciences ( mashhad , iran ) from april to june 2012 .
all study activities were performed in accordance with the ethical guidelines set by the ethical committee of mashhad university of medical sciences , which conform to the declaration of helsinki . the aims and procedures of the study
we included healthy subjects with no previous medical problems , anteroposterior discrepancy > 10 mm , and a need for bimaxillary orthognathic surgery to correct a class iii malocclusion .
patients were excluded if they had any previous craniofacial syndrome or dentofacial trauma or if they did not require maxillary impaction as part of their surgical plan .
twelve patients participated in the study ( five males and seven females ) with an age range of 16 - 35 years ( mean age , 20.4 years ) and normal body mass index ( bmi ) of 18 - 25 kg / m .
two patients were excluded during the experiment because one did not complete follow - up , and the medical documents of the other were lost ( one male and one female ) .
all patients underwent bimaxillary orthognathic surgery ( maxillary advancement by lefort i osteotomy and mandibular setback by bilateral sagittal split ramus osteotomy [ bssro ] ) and rigid fixation with titanium miniplates and screws .
the mean amounts of maxillary advancement and mandibular setback were 4.4 mm and 6.55 mm , respectively .
maxillomandibular fixation was applied for a two - week period for all patients and was followed by elastic therapy to establish optimal occlusion .
two upper airway cbct scans were performed for all patients one week before and two to four months after surgery .
all cbcts were performed by the same technician at the same clinic , using the same machine and the same settings ( 80 kvp with 6 ma and 0.32 mm slice thickness , planmeca promax 3d s ; planmeca oy , helsinki , finland ) . to provide a reproducible cbct image before and after surgery
all cbct segmentations and measurements were performed with the same workstation ( hp xw9400 ; hewlett - packard , palo alto , ca , usa ) and same software ( planmeca romexis 2.8.1.r ; planmeca oy ) .
the anterior boundaries of the volume space of interest were the vomer bone , soft palate , base of the tongue , and anterior wall of the pharynx .
the posterior , lateral , superior , and inferior boundaries were the posterior wall of the pharynx , the lateral walls of the pharynx , the roof of the nasopharynx , and the plane crossing the vallecula perpendicular to the posterior wall of the pharynx , respectively .
1 , table 1 ) using the mid - sagittal plane view , a mid - sagittal slice was selected and used as a 2d measurement reference ; the landmarks , which are described in fig .
2 and table 2 , were used to perform 2d measurements as previously described by jakobsone et al.9
the wilcoxon one - sample test was used to compare the mean measurements of the airway pre- and post - surgery .
spearman 's rank correlation coefficient was used to test associations between cbct volumetric and linear measurements .
the 2d measurements showed no significant decrease in airway space , whereas there was a significant increase in distance between posterior nasal spine ( pns ) and the posterior wall of the pharynx ( p=0.004 ) .
the volumetric measurements of the upper airway space increased in total volume , but the change was not statistically significant .
hypopharyngeal and oropharyngeal areas decreased , and nasopharyngeal area increased , but none of these changes were significant .
we found that 2d and 3d measurements were significantly correlated with changes in u - mpw ( distance between the uvula [ u ] and the middle pharyngeal wall [ mpw ] , which represents the oropharyngeal airway space ) and oropharyngeal volume ( opv ) ( r=0.83 , p=0.004 ) , as well as with changes in p - upw and degree of maxillary advancement ( r=0.72 , p=0.02 ) .
the 2d and 3d changes in the upper airway space that were estimated from cbct scans are shown in tables 3 and 4 .
our results indicated that there were no significant decreases in the upper airway , but a significant increase in pns - upw ( distance between the pns and the upw , which represents the nasopharyngeal airway space ) in 2d measurements was noted . although total and oropharyngeal volumes increased , and nasopharyngeal and hypopharyngeal volumes decreased , these changes were not significant .
we found correlations between changes in u - mpw and opv ( r=0.83 , p=0.004 ) as well as between changes in p - upw and amount of maxillary advancement ( r=0.72 , p=0.02 ) .
one of the advantages of ct scanning is that it offers better delineation between soft tissue and air based on different hounsfield unit ( hu ) densities9 , allowing more accurate measurement of the upper airway .
herein , we used the categorizations and boundaries of upper airway levels described by jakobsone et al.9 and lowe et al.11 .
our upper airway volume calculations were performed automatically using software that calculated airway volume in a segmented manner based on hu density differences .
several authors have demonstrated the feasibility of automatic segmentation and dimension estimation from cbct images for upper airway volume measurement12 .
other researchers have used ct , cbct , and cephalometric imaging techniques to assess correlations between 2d and 3d measures and volumetric measurements , but they did not find any statistically significant results913 .
the cephalograms were taken in an upright position , and no special measures were performed to obtain standardized radiographs in relation to respiration phase9 . in all cases , the acquisition time for the ct scans was too long for patients to hold their breath .
the cephalograms were performed with the patient in an upright position , while ct scans were performed in a supine position9 .
several studies found that changes in posterior airway space are associated with changes in body position among osa patients1415 and healthy individuals1516 .
furthermore muto et al.17 showed that a 10-degree increase in craniocervical inclination enlarged the posterior airway space by approximately 4 mm .
therefore , any increase in craniocervical inclination following mandibular setback17 should be considered during cephalometric imaging with a natural head position .
our study was not affected by these limitations because all 2d and 3d measurements were conducted on cbct scans that were performed by the same radiologist , using the same machine , with the patients in the same position .
however , the main limitation of our study was the small number of patients . although the only procedure we performed on the mandible for this study was bssro , another common procedure in other studies is intraoral vertical ramus osteotomy ( ivro ) , which has been evaluated for its effect on the upper airway .
kawamata et al.18 did not find significant differences between the effects of bssro and ivro on posterior airway space .
the only significant change in the 2d measurements was the distance between the pns and the upper pharyngeal wall , which was consistent with previous studies919 .
the volumetric measurements showed increases in total and oropharyngeal volumes and decreases in nasopharyngeal and hypopharyngeal volumes , but none of these changes were significant .
these findings are in contrast with those of kim et al.20 , who found a significant decrease in total pharyngeal airway volume after bimaxillary surgery in class iii patients .
this discrepancy can be attributed to the surgery procedure , in which they performed posterior maxillary impaction and rotated the occlusal plane . however , our results supported the findings of jakobsone et al.9 because of the similar boundaries and areas used to measure the volumes .
we found a correlation between change in pns - upw and the amount of maxillary advancement in 2d measurements .
the only significant correlation between 2d and volumetric measurements was between changes in u - mpw and oropharyngeal volume .
kim et al.20 found correlation between hyoid bone position and airway volume and between changes in palatal plane angle and decrease in total airway space .
postoperative pharyngeal airway space ( pas ) values should be compared with osa development values in order to assess osa risk , particularly among patients with osa syndrome9 . a cephalometric - based study conducted by kollias and
krogstad21 reported that the normal range of pas values was 14.84.4 mm for males and 12.13.7 mm for females .
pas values < 5 mm were reported to correlate with a high apnea index , independent of bmi22 .
only one patient , whose preoperative pas minimum was 7.37 mm , had a pas < 5 mm ( 4.58 mm ) three months after surgery , which might be clinically important .
there are few studies on the evaluation of polysomnographic value changes after orthognathic surgery for treatment of class iii patients , and the findings from these studies are controversial232425 .
gokce et al.23 reported an improvement in sleep quality among class iii patients after bimaxillary orthognathic surgery for treatment .
in contrast , hasebe et al.24 reported two cases of mild osa after mandibular setback surgery , and foltn et al.25 concluded that bimaxillary surgery for correction of class iii malocclusion increased upper airway resistance .
upper airway changes are not statistically significant but are nevertheless clinically important in some patients because of their associated risk with osa . | objectivesany change in maxilla and mandible position can alter the upper airway , and any decrease in the upper airway can cause sleep disorders .
thus , it is necessary to assess airway changes after repositioning of the maxilla and mandible during orthognathic surgery .
the purpose of this study was to evaluate linear and volumetric changes in the upper airway after bimaxillary surgery to correct class iii malocclusion via cone - beam computed tomography ( cbct ) and to identify correlations between linear and volumetric changes.materials and methodsthis was a prospective cohort study .
cbcts from 10 class iii patients were evaluated before surgery and three months after .
the wilcoxon one - sample test was used to evaluate the differences in measurements before and after surgery .
spearman 's rank correlation coefficient was used to test the correlation between linear and volumetric changes.resultsthe results show that the nasopharyngeal space increased significantly , and that this increase correlated with degree of maxillary advancement .
no significant changes were found in volumes before and after surgery .
a correlation was found between linear and volumetric oropharyngeal changes.conclusionbimaxillary surgical correction of class iii malocclusion did not cause statistically significant changes in the posterior airway space . | I. Introduction
II. Materials and Methods
1. Participants
2. Inclusion criteria
3. Exclusion criteria
4. Imaging procedure
5. 2D and 3D
6. Data analysis
III. Results
IV. Discussion
V. Conclusion |
palatal tremor is a rare movement disorder characterized by rhythmic contraction of the soft palate .
palatal tremor is most often symptomatic , secondary to brainstem or cerebellar disease and , in rarer cases , is categorized as essential in the absence of documented brain lesions.1 some authors have documented hypertrophic degeneration of the inferior olives in secondary palatal tremor , but its precise role in causing palatal tremor has not yet been clarified and this finding is currently controversial.2 essential palatal tremor generally affects children of both genders , whereas secondary palatal tremor is most commonly observed in adult males . essential palatal tremor is bilateral and usually disappears during sleep , whereas secondary palatal tremor is more frequently unilateral and persists even during sleep .
patients with essential palatal tremor usually have an ear click , which is absent in the symptomatic form .
although essential palatal tremor has a benign course and usually disappears spontaneously , it is very annoying for the patient , so several treatments have been administered , including anticonvulsants and anxiolytics , with varying therapeutic effects . at present
no specific treatment has been established , although successful treatment by botulinum has recently been reported.3 there have also been reports in the literature of cases of palatal tremor which have been described as psychogenic because they were associated with psychological or psychiatric disorders . in this form , known as psychogenic palatal tremor ,
the abnormal movement is intermittent , increases during attention , decreases during distraction , and is under voluntary control.4 we describe the case of a 12-year - old boy with palatal tremor presenting clinical features of symptomatic essential and psychogenic palatal tremor , thus suggesting a neuropsychopathological continuum between the different forms of palatal tremor .
the case was a 12-year - old boy , the only child of unrelated parents .
there was a positive family history of psychiatric disorders , in that the father has a personality with borderline and narcissistic traits , poor impulse control , and multiple motor tics , and the mother had a major , recurrent depressive disorder , and histrionic and paranoid personality traits .
moreover , the emotional climate in this family was characterized by a high level of expressed emotion with over involvement and criticism , and with a very conflictual relationship between the parents.5 the patient was born by elective cesarean delivery at the eighth month of gestation after a pregnancy characterized by gestational diabetes treated with insulin .
he showed mild motor developmental delay and inadequate performance at primary school , and difficulty in relating to peers .
he came to our attention about one year earlier due to the emergence of behavioral disturbances characterized by oppositional defiant behavior and aggression , episodes of psychomotor agitation with dysphoria , and aggression towards others .
about two years before these events , when the patient was 10 years old , his parents had started to hear a clicking sound coming from the boy , but no research was carried out until our observations .
we performed clinical and instrumental assessments , including physical , neurological , and otolaryngological examinations , laboratory tests , audiological and neuroimaging studies , and a psychodiagnostic assessment , including the iq rating scale ( wechsler intelligence scale for children iii ) and interviews administered to the patient and his parents using the child behavior checklist and schedule for affective disorders and schizophrenia for school - age children present and lifetime version .
the neurological examination showed only hypotonia of the facial muscles causing drooling , but no other clinical signs , except for the presence of rhythmical bilateral palatal movements , mainly on the right side , associated with a clicking sound that could easily be heard when listening close to the child s ear .
the patient seemed to be very annoyed and concerned about this ear click , which was present with the mouth both open and closed .
nevertheless , it was under voluntary control , and the patient was able to voluntarily induce it or stop it for a few minutes . moreover , the ear click was less audible or had a changed frequency during the performance of complex motor and cognitive tasks .
otolaryngological examination with fibroscopy detected a bilateral palatal tremor at a frequency of 80 cycles per minute .
laboratory tests , including a complete blood count , antinuclear antibody studies , thyroid tests , plasma copper , ceruloplasmin , plasma amino acids , serum lactate and pyruvate , ammonium , and transaminases , were normal .
audiometry and electroencephalography were also normal , as were brain magnetic resonance imaging , angiographic magnetic resonance imaging , and proton magnetic resonance spectroscopy , focusing particularly on study of the brainstem . during spontaneous observation ,
the patient showed a reduced adaptive and relational capacity , with his relationships being characterized by oppositional behavior that sometimes culminated in episodes of aggression and psychomotor agitation .
his moods and affectivity were extremely unstable , featuring sudden swings and a poor control of emotions and impulses , in particular at moments of frustration and deferral of pleasure .
psychosomatic and anxiety symptoms were also detected . at the wisc - iii test , he obtained an iq of 65 ( verbal iq = 81 , performance iq = 56 ) , expressing mild mental retardation . during the previous year , several therapies had been attempted , including anticonvulsants and antipsychotic drugs , with variable results .
topiramate and valproic acid treatment showed no effect on either the behavioral disturbances or the palatal tremor , and carbamazepine therapy showed a transient effect that disappeared for about two months but then recurred . due to an increased frequency of episodes of agitation ,
chlorpromazine therapy was started , then carbolithium was added , resulting in an improvement of the behavioral disturbances .
treatment with piracetam , the effectiveness of which in essential palatal tremor was recently reported by campistol - plana et al,3 was ineffective .
it was not possible to administer treatment with botulinum toxin due to the patient s limited cooperation .
after six months of treatment with carbolithium , chlorpromazine , and family psychotherapy , the behavioral disturbances were further improved and the ear click was audible only on the right side and had started to fluctuate , disappearing spontaneously for days , reappearing spontaneously in stressful situations . over time , the patient had developed a greater ability to inhibit the palatal tremor voluntarily and to induce it on request or by thinking about it , sometimes to attract attention , thus demonstrating voluntary control .
palatal tremor is an abnormal movement of the soft palate and was previously known as palatal myoclonus but more recently has been renamed palatal tremor because this corresponds better with the electrophysiological characteristics of the rhythmic pattern .
the heterogeneous nature of palatal tremor covers a wide spectrum of clinical pictures , including symptomatic essential and psychogenic forms .
secondary palatal tremor can be a consequence of vascular , infectious , degenerative , traumatic , or neoplastic lesions of the brainstem or cerebellum .
this form is often associated with neurological deficits and , once present , persists throughout life and does not disappear during sleep or even in coma .
most symptomatic cases occur in adulthood , while a few cases have been reported in childhood in the course of krabbe s disease,6 a cerebellar tumor,7 and encephalitis.8 in secondary palatal tremor , abnormal hypertrophy of the inferior olives has been detected , but its precise role in causing palatal tremor is controversial and not yet clearly demonstrated .
recently shaikh et al9,10 have shown , through a mathematical model , that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum . in essential palatal tremor , neurological investigations and brain neuroimaging are normal , while an ear click is present , perceived as objective tinnitus , that does not occur in the symptomatic form .
deuschl et al11 demonstrated that , in secondary palatal tremor , the movement of the soft palate is caused by contraction of the levator veli palatini and in essential palatal tremor , by contraction of the tensor veli palatini which induces secondary closure of the eustachian tubes , causing a clicking sound that is audible by the examiner .
essential palatal tremor is more frequently bilateral , occurs mainly in children , and usually disappears when the patient s mouth is open and during sleep , although in some cases it persists even during sleep .
the pathophysiology of essential palatal tremor remains unclear ; it is generally benign , persists for months or years , and in children it tends to fluctuate and disappear spontaneously .
essential palatal tremor has been observed in monozygotic male twins , in one of whom symptoms developed at the age of 14 years and in the other at 37 years , suggesting a genetic etiology of the disorder.12 fernandez - alvarez13 included essential palatal tremor in the class of transient movement disorders , a heterogeneous group of primary pediatric movement disorders with a limited duration of expression over time , none or mild disability , and a spontaneously fading disorder .
in fact , the abnormal movement can be voluntarily induced or inhibited , and can also be discontinued when the patient is concentrating on motor and cognitive tasks , performing movements , reading , thinking , or doing calculations .
some authors have suggested that voluntary control of essential palatal tremor could be due to a certain degree of cortical control that is otherwise absent in the symptomatic forms , while other authors have suggested that it could be due to a psychogenic origin of the disorder .
this form is often associated with psychopathology , responds to placebo and improves with psychotherapy .
furthermore , the movements have a variable frequency , and unlike the other forms of palatal tremor , increase during attention and decrease when the patient is distracted .
nevertheless , psychiatric symptoms , in particular anxiety disorders , have also been reported in the literature for some cases of essential palatal tremor .
after a review of the literature in relation to different forms of voluntary control , samuel et al14 suggested that rather , than being a uniform pathogenic entity , essential palatal tremor may be a heterogeneous disorder including different forms ; in particular , a form of conversion disorder , a tic disorder , or a series of completely involuntary movements , as described in most patients with essential palatal tremor . moreover , the same authors suggested a correlation between secondary palatal tremor and essential palatal tremor , in view of the fact that functional magnetic resonance imaging studies have shown an activation of the inferior olives during palatal movements in the essential form.15 these studies suggest an involvement of the same structures in essential palatal tremor and secondary palatal tremor .
in addition , in some cases of essential palatal tremor , an association with minor ailments has been reported , including respiratory infections , otitis , tonsillitis , fever , minor head trauma , and headache .
the clinical characteristics of our patient seem to support this hypothesis of a continuum between the different forms of palatal tremor ( table 1 ) .
he has a palatal tremor with an ear click , audible in both ears , which is usually present in the essential form but is rare in the symptomatic form .
the palatal tremor persisted during sleep , which is common in the symptomatic form but rare in the essential form . furthermore , neuroimaging studies did not document lesions in the brainstem or cerebellum , which are typically present in the symptomatic form .
in addition , in our patient , pre - perinatal risk factors were present , namely a family history of psychiatric disorders , motor developmental delay , mental retardation , hypotonia of the facial muscles , and behavioral disturbances .
even if voluntary modulation of palatal tremor has been reported in literature in some cases of essential palatal tremor , our patient has developed possible voluntary control , suggesting the acquisition of special motor skills rather than an inhibition of involuntary movements , and this seems suggestive of a psychogenic etiology.16 limited data are available about psychogenic movement disorders in children , but clinical findings suggesting a psychogenic cause similar to that in adults , including inconsistent character of the movements , exacerbation with stress and while paying attention , and disappearance when distracted , as well as a response to placebo and improvement with psychotherapy .
the underlying psychiatric diagnosis was a conversion disorder in most of the cases described in literature.17 in our patient , the disorder also shared some features of psychogenic movement disorders , such as a discontinuous ear click , association with psychopathological disorders , an increase during periods of attention and disappearance at moments of distraction , as well as voluntary control of the movement . in conclusion ,
the clinical characteristics of our patient suggest that there may be a neuropsychopathological continuum between different forms of palatal tremor , but this hypothesis requires further investigation , especially functional neuroimaging and genetic studies . | palatal tremor is a rare movement disorder characterized by rhythmic contractions of the soft palate .
it is most often symptomatic , secondary to brainstem or cerebellar disease and , in rarer cases , is categorized as essential in the absence of documented brain lesions .
there have also been reports in the literature of cases of palatal tremor described as psychogenic because they were associated with psychological or psychiatric disorders .
we describe the case of a 12-year - old boy with palatal tremor presenting clinical features of symptomatic essential and psychogenic palatal tremor , thus suggesting a neuropsychopathological continuum between the different forms of disease . | Introduction
Case report
Discussion |
clinical clues apparent on examination can expand or narrow the differential diagnosis substantially , even when the patient is seen first for management of a life - threatening condition in the intensive care unit ( icu ) .
we present a female patient with presumed chronic inflammatory demyelinating polyneuropathy ( cidp ) in whom recognition of hypertrichosis , clubbing and papilledema suggested poems ( polyradiculoneuropathy , organomegaly , endocrinopathy , m - protein and skin abnormalities ) syndrome .
a 35-year - old female patient was seen by the icu consult services for management of impending respiratory failure .
she had presented with cough , sputum , worsening limb weakness and orthopnea for one - week .
weakness was symmetrical in all four limbs and she was unable to move any of her limbs across the bed .
she was unable to roll to one side or lift her head off the pillow .
she had presented with insidious progressive weakness of all limbs 7 months prior to the current symptoms to another hospital .
cerebrospinal examination was acellular and showed raised proteins ( 1.3 g / dl ) , without any oligoclonal bands .
human immunodeficiency virus enzyme linked immunosorbent assay ( elisa ) , venereal disease research laboratory antibodies and antinuclear antibodies by elisa were negative .
she was initiated on 2 g / kg intravenous immunoglobulins monthly , along with 0.5 mg / kg steroids , 1.5 mg / kg azathioprine and osteoporosis prevention therapy .
weakness remained static till one - week prior to the time of her current presentation .
she had no previous history of smoking , alcohol or other drug abuse or animal exposure .
there was also no relevant family history . on examination , she was afebrile , normotensive , with a respiratory rate of 40 cycles / min and pulse rate of 106 beats / min .
there was evidence of accessory muscle use , with flaring of alae nasi and paradoxical movement of the diaphragm on inspection .
general examination also showed bilateral pitting pedal edema to the level of the knee , grade 2 pandigital clubbing , diffuse skin hyperpigmentation with mucosal sparing and hypertrichosis [ figure 1 ] .
neurological examination confirmed normal mental status and muscle weakness : power in both lower limbs was graded 1/5 and in the upper limbs was 2/5 , according to the medical research council ( mrc ) scale .
arterial blood gas showed respiratory academia due to acute respiratory acidosis ( ph 7.3 , pao280 mm hg on 4 l / min oxygen , paco250 mm hg , hco328 meq / l ) . computed tomography of the head was normal .
bilateral lower limb venous doppler did not show any evidence of venous thrombosis and quantitative d - dimers ( immunoturbidometry , lister metropolis ) were negative .
she was unable to complete a forced vital capacity maneuver or perform breath hold required for respiratory muscle testing .
sniff measurements and ultrasonography of diaphragmatic muscles were not performed given the obvious paradoxical movements clinically .
composite clinical photographs showing grade 3 clubbing ( left ) , with severe distal weakness and a correctible claw - hand deformity and hypertrichosis ( right ) summary of clinical investigations in the index patient she was initiated on parenteral piperacillin - tazobactam , azithromycin , enoxaparin , oxygen at 4 l / min ( approximate fio20.4 ) with bilevel noninvasive ventilation ( niv ) ( bipap 14/4 cmh2o , resmeds9 vpap auto ) .
plasmapheresis with 2 l exchanges using 5% albumin replacement was started on alternate days for possible worsening of cidp and was continued for six sessions .
the simultaneous features of clubbing , hypertrichosis and papilledema along with progression of weakness despite treatment prompted further evaluation .
radiographs of the skull , pelvis , and spine [ figure 2 ] showed osteosclerotic lesions over the right femur and spine .
ultrasound examination showed splenomegaly ; there was no evidence of hepatomegaly , enlarged nodes or ascites .
g / l ) with serum albumin levels of 2.43 g / dl ( normal 4 - 6 g / dl ) .
free lambda chain levels were elevated at 29.60 mg / l ( normal , 5.71 - 26.3 mg / dl ) with normal free kappa chain value of 11 mg / l ( normal 3.3 - 19.4 mg / l ) .
serum 2-microglobulin was 3550 ng / ml ( normal 670 - 2143 ng / ml ) .
bone marrow biopsy from the right iliac crest showed normocellular marrow , absence of lymphoid aggregates or plasma cell rimming and megakaryocyte hyperplasia .
composite radiographs of the pelvis and hips ( left ) showing a sclerotic lesion over the right femur and thoraco - lumbar spine ( right ) , showing another lesion over the lumbar spinous processes ( black arrows )
poems syndrome is a rare paraneoplastic syndrome because of an underlying plasma cell disorder ( pcd ) .
the pathogenesis of poems syndrome involves -chain producing monoclonal plasma cell clone from the sclerotic bony lesions .
vascular endothelial growth factor ( vegf ) levels are high but may not be the sole pathogenic mechanism , as anti - vegf therapy has shown inconsistent results .
the diagnosis of poems syndrome is made by the dispenzieri criteria [ table 2 ] .
the differential diagnosis includes vasculitis , connective tissue disease , monoclonal gammopathy of undetermined significance , smoldering multiple myeloma ( mm ) , mm or solitary plasmacytoma .
the composite clinical and laboratory findings [ table 1 ] differentiates poems syndrome from these other disorders . plasma vegf level of greater than 200 pg / ml has a specificity of 95% and sensitivity of 68% in support of diagnosis of poems syndrome . this entity can be distinguished from other pcds by the prominent neuropathy , minimal to absent renal disease , thrombocytosis and organomegaly .
diagnostic criteria for the poems * syndrome treatment is directed at abolishing the underlying plasma cell clone . in patients without diffuse marrow involvement and/or > 3 skeletal lesions , radiation to the isolated sclerotic lesions
half of nonresponders or progression occurs within 12 months of radiation . in those with disseminated bone marrow involvement , chemotherapy with melphalan - dexamethasone , lenalidomide , and autologous stem cell transplantation
thalidomide and bortezomib have activity in poems syndrome but have potential to worsen the neuropathy .
the index patient presented with findings of advanced peripheral and phrenic nerve neuropathy as a result of the delay of 18 months prior to diagnosis .
she was managed with local radiotherapy to proximal right femur and lumbosacral area ( 40 gy , 2 gy / cycle , total 20 cycles ) , thromboembolism prophylaxis , limb and respiratory rehabilitation , percutaneous gastrostomy feeds and nocturnal bilevel niv .
she improved objectively 6 weeks after completion of radiotherapy with upper limb power improving to 3/5 and lower limb power to 2/5 and absent paradoxical respiratory movements .
she remains on follow - up at 6 months with clinical assessment monitoring the weakness , sensory loss and pulmonary function testing by spirometry . | we present a female patient who was referred for management of respiratory failure . she was being evaluated and managed as worsening chronic inflammatory demyelinating polyneuropathy with type 2 respiratory failure .
initial examination showed hypertrichosis , clubbing and papilledema along with severe distal and proximal motor - predominant weakness with impending respiratory failure .
she was managed with noninvasive ventilation ( niv ) and plasmapheresis awaiting diagnostic investigations .
immunofixation showed an m band and free lambda chain levels were elevated .
radiographs showed the classic osteosclerotic lesions of poems ( polyradiculoneuropathy , organomegaly , endocrinopathy , m - protein and skin abnormalities ) syndrome .
six weeks after commencing radiotherapy to the osteosclerotic lesions , the patient responded favorably and remains off nocturnal niv support . | Introduction
Case Report
Discussion |
however , there are several controversies in the operative indication , surgical approach and the best treatment method .
the gold standard in the treatment of distal radius fracture remains uncertain.1 cast treatment with or without closed reduction has long been considered a viable option for treatment of distal radius fractures .
however , the results are often unsatisfactory with restricted function and disabilities.23 several studies have reported good anatomical and functional results of distal radius fractures treated with external fixation but also described high incidence of pin tract infection , cosmetic deformity , and nerve injury.4 traditional open reduction and internal fixation often results in extensive soft tissue dissection and periosteal injury and may be associated with high rates of infection , delayed union and nonunion.45 fortunately , the technique of minimally invasive plate osteosynthesis ( mipo ) recently emerged and this technique can minimize soft tissue stripping and damage to the vascularity of the bone.6 it can lead to a reduction in complications caused by conventional treatment .
mipo has been widely used in the treatment of the femoral and tibial fractures.78 more recently its use has also been expanded for the fixation of upper extremity fractures.9101112 in 2005 , imatani et al.13 first reported that five patients of distal radius metaphysis comminuted fracture were treated by mipo in which reduction and internal fixation was completed by two longitudinal incisions ( 3 cm ) on the palmar side of distal forearm .
inspired by the report , we designed two kinds of incisions ( 2 cm ) according to the distance between the main fracture line and the wrist for further minimizing soft tissue related complications , such as tendon injury , nerve dysfunction , and vascular compromises.14 besides , mini - incision can offer better cosmetic results.1516 plate fixation of distal radius fractures usually involves two kinds of incisions : palmar and dorsal .
the palmar approach has been demonstrated to be more superior because it can avoid the complications caused by the attrition of the extensor tendon in the dorsal approach.171819 in addition , the cortex on the palmar side of distal radius is wide and flat which benefits the exposure of fracture fragments and placement of the plate , especially for a die - punch type of fracture .
importantly , the operative scar of the wrist is not very obvious , leading to an excellent appearance.20 a palmar locking plate has superior biomechanics compared with traditional dorsal locking plate.21 we reviewed our experience in treating distal radius fractures using the palmar locking plate and two kinds of incisions in the mipo technique , in order to assess the functional outcome and complications following this method .
22 patients with distal radial fractures ( 10 left , 12 right ) were treated by the modified mipo technique with a t - shaped palmar locking plate .
an informed consent was taken from the patients and the approval of the ethics committee of hand surgery hospital was obtained .
our indications for using mipo were type a2 , type a3 , type b1 , type b3 , type c1 and type c2 distal radial fractures .
patients with type a1 , b2 or c3 of distal radius fracture were not included in this study .
patient was placed on a conventional table in the supine position under brachial plexus block .
once a satisfactory reduction was achieved , one or two 1.5 mm kirschner wires were obliquely inserted from the styloid process of radius to the proximal ulnar side to maintain the reduction , sometimes the kirschner wires were inserted from the opposite direction as well .
it is necessary to add another k wire , parallel to the articular surfaces of the distal radius for a type c fracture .
the two skin incisions of 2 cm each were made [ figure 1 ] . for patients with a distance between the main fracture surface and articular surface of distal radius within 1 cm ,
if this distance was more than 1 cm , distal skin incision was made on the radial side along the proximal wrist crease , parallel to flexor carpi radialis .
after cutting the superficial and deep fascia on the radial side of flexor carpi radialis , the flexor carpi radialis and the radial artery were retracted to the radial or ulnar side respectively . then the flexor pollicis longus was retracted to the ulnar side to expose the pronator quadratus .
for a few patients with unsatisfied closed reduction , the incision should be made on the fracture end to help reduction under direct vision .
a suitable , oblique , t - shaped palmar locking plate was inserted through the incision extraperiosteally .
after satisfactory fracture reduction and fixation of the plate , a 2 cm proximal skin incision was made on the radial side of the flexor carpi radialis .
the superficial and deep fascia was cut to retract the radial artery and the flexor pollicis longus was dissected using forceps to expose the proximal end of the locking plate .
intraoperative clinical photographs showing ( a ) one horizontal and one vertical incision were made at the palmar side .
( b ) the locking screws were inserted to fix the plate.(c ) intraoperative x - ray showed the reduction of the fracture on the lateral and anteroposterior view plaster splints were not applied to any patient postoperatively .
we encouraged the patients to exercise their shoulders , elbows , metacarpophalangeal joints , interphalangeal joints 2 or 3 days after operation .
patients were advised to perform extension and flexion movement of the affected wrist joints after 3 - 5 days post surgery .
postoperative x - rays ( a ) anteroposterior ( b ) lateral views at 2 months followup demonstrating a healed distal radius fracture
patient was placed on a conventional table in the supine position under brachial plexus block .
once a satisfactory reduction was achieved , one or two 1.5 mm kirschner wires were obliquely inserted from the styloid process of radius to the proximal ulnar side to maintain the reduction , sometimes the kirschner wires were inserted from the opposite direction as well .
it is necessary to add another k wire , parallel to the articular surfaces of the distal radius for a type c fracture .
the two skin incisions of 2 cm each were made [ figure 1 ] . for patients with a distance between the main fracture surface and articular surface of distal radius within 1 cm
if this distance was more than 1 cm , distal skin incision was made on the radial side along the proximal wrist crease , parallel to flexor carpi radialis .
after cutting the superficial and deep fascia on the radial side of flexor carpi radialis , the flexor carpi radialis and the radial artery were retracted to the radial or ulnar side respectively . then the flexor pollicis longus was retracted to the ulnar side to expose the pronator quadratus .
for a few patients with unsatisfied closed reduction , the incision should be made on the fracture end to help reduction under direct vision .
a suitable , oblique , t - shaped palmar locking plate was inserted through the incision extraperiosteally .
after satisfactory fracture reduction and fixation of the plate , a 2 cm proximal skin incision was made on the radial side of the flexor carpi radialis .
the superficial and deep fascia was cut to retract the radial artery and the flexor pollicis longus was dissected using forceps to expose the proximal end of the locking plate .
intraoperative clinical photographs showing ( a ) one horizontal and one vertical incision were made at the palmar side .
( b ) the locking screws were inserted to fix the plate.(c ) intraoperative x - ray showed the reduction of the fracture on the lateral and anteroposterior view plaster splints were not applied to any patient postoperatively .
we encouraged the patients to exercise their shoulders , elbows , metacarpophalangeal joints , interphalangeal joints 2 or 3 days after operation .
patients were advised to perform extension and flexion movement of the affected wrist joints after 3 - 5 days post surgery .
postoperative x - rays ( a ) anteroposterior ( b ) lateral views at 2 months followup demonstrating a healed distal radius fracture
the average age of the patients was 65 years ( range 37 - 80 years ) .
the mean time from injury to surgery was 7 days ( range 0.5 hour-10 days ) .
they were all closed fracture and were classified according to ao / asif system , including type a2 ( n=5 ) , type a3 ( n=3 ) , type b1 ( n=4 ) , type b3 ( n=7 ) , type c1 ( n=2 ) , and type c2 ( n=1 ) .
all 22 patients were followed up for an average time of 12 months ( range , 10 - 18 months ) . according to wrist function evaluation criteria described by dienst et al.,22 13 patients obtained excellent results , six cases had good results and three patients had moderate results . none of the patients had poor results [ figure 4 ] .
one patient had anesthesia in the thenar eminence and this symptom disappeared after 3 months .
the extension and flexion of the wrist and the supination and pronation of the forearm were all good
since the first mipo techniques were developed for subtrochanteric and distal femoral fractures , these methods were modified and adapted for use in other fracture types as well , including the distal tibia,2324 humeral shaft925 and the foot.26 in this study , we adopted a modified mipo technique that used a palmar locking plate through two small incisions to treat distal radial fractures .
incision length was determined according to the distance between the main fracture line and the articular surface of distal radius . a prospective , randomized study analyzed 90 patients with displaced intraarticular distal radius fractures with an average of 4-year followup to evaluate the functional outcomes of three modes of treatment ( plaster immobilization , external fixation , and open reduction with internal fixation ) .
good or excellent results were achieved in 43% , 80% , and 63% in each group , respectively.4 similarly , another prospective , randomized study reported that good or excellent outcomes of conventional closed reduction and immobilization with or without norian srs ( skeletal repair system ) cement in the management of intra or extraarticular distal radial fractures were 45%.27 it appears that the functional outcome was similar when compared our results with that using external fixation .
pin tract infection was the major complication of external fixation of fractures and the rates of infection ranged from 0.5% to 30%.28 some bacteria , usually staphylococcus aureus and staphylococcus epidermidis , often colonized at the site of external fixation pins28 that resulted in these infection . in our study , there were no infections .
conventional closed reduction using only simple plaster cast immobilization is insufficient to maintain the reduction and cherubino et al . observed a secondary loss of reduction during plaster cast immobilization in 35% of cases.2 a traditional open surgical approach may increase the risk of nonunion , delayed healing and infection due to extensive soft tissue stripping.30 in addition , the complication of nerve injuries are commonly reported after operative treatment of distal radius fractures .
the incidence has been estimated from 0% to 17% , with the median nerve being the most commonly injured followed by the radial and ulnar nerves.31 however , in present study , no damage of radial artery and median nerve occurred in all 22 patients postoperatively since our longitudinal incisions were usually along the radial side of the flexor carpi radialis and our surgery was performed strictly in the safety window area to avoid accidental injury.32 besides , the radial artery and median nerve were not exposed during the operation in current study 27% cases developed complications in our study including anesthesia ( 4.5% ) , delayed healing ( 4.5% ) , pain ( 9% ) and limited extension and rotation ( 9% ) 27% complication rate associated with mipo used in our study for various types of fractures shows that this method is not suitable for all distal radius fractures .
a specific treatment method and selection of individuals will certainly reduce the number of complications . the limitations of this study include the small sample size , the short followup time , and the absence of a control group . in conclusion , two small incisions to implant a palmar locking plate by mipo for distal radius fractures give good functional results .
but further research also should be carried out to explore more suitable treatment for specific individuals .
| background : fractures of distal radius are common injury in all age groups . cast treatment with or without close reduction is a viable option .
however , the results are often unsatisfactory with restricted function .
the open reduction and internal fixation often results in extensive soft tissue dissection and associated high rates of infect and delayed / nonunion .
the distractor / external fixator have reported good functional and anatomical results but the incidence of pin traction infection nerve injury and cosmedic deformity are high .
we introduced a modified operative technique for minimally invasive plate osteosynthesis ( mipo ) for distal radial fracture and evaluated the functional outcomes and complications.materials and methods:22 distal radial fractures ( 10 left , 12 right ) were treated using the mipo technique and two small incisions with a palmar locking plate from august 2009 to august 2010 .
the wrist function was assessed according to dienst wrist rating system , and postoperative complications were recorded.results:according to dienst wrist rating system , 13 patients showed excellent results , 6 cases showed good results and 3 patients had moderate results .
no patient had poor results .
thus , the excellent and good rate was 86.4% .
one patient had anesthesia in the thenar eminence and this symptom disappeared after 3 months .
one patient had delayed healing in the proximal wrist crease .
two patients had mild pain on the ulnar side of the wrist and two patients had limited wrist joint function.conclusion:the mipo technique by using two small palmar incisions is safe and effective for treatment of distal radial fractures . | I
M
Operative procedure
R
D |
insulin plays a critical role in glucose homeostasis by regulating the balance between glucose production by the liver and glucose uptake by muscle and adipose tissues . in adipocytes and myocytes
, insulin regulates glucose transport by controlling the translocation of the glucose transporter , ( glut)4 .
ir has a rather loose definition , but generally refers to the fact that tissues do not respond sufficiently to physiological insulin concentrations .
t2d patients usually have hyperinsulinemia , and poor insulin sensitivity is a common characteristic of obesity and hyperlipidaemia .
insulin initiates its effects by binding to the extracellular -subunit of insulin receptor ( insr ) , resulting in autophosphorylation of the intracellular -subunit . once activated , the insr recruits and phosphorylates intracellular substrates , including insr substrate ( irs ) family proteins and shc . phosphorylated tyrosine residues on irs and shc then recruit downstream signaling molecules containing src homology 2 ( sh2 ) domains , such as the p85 subunit of phosphatidylinositol 3 kinase ( pi3k ) , which activates akt - mediated signaling , and growth factor receptor - binding protein 2 ( grb2 ) , which leads to the activation of mitogen - activated protein kinase ( mapk ) signaling pathway .
in addition to over 20 tyrosine residues , irs proteins contain more than 50 potential serine / threonine phosphorylation sites . in general
, irs serine / threonine phosphorylation inhibits insulin signaling by antagonizing tyrosine phosphorylation . increased serine / threonine phosphorylation of irs-1 accelerates its dissociation from the insr and downstream signaling molecules , induces mislocalization , and accelerates its degradation by the ubiquitin - proteasome pathway .
multiple irs serine kinases are activated during ir , resulting in increased irs serine phosphorylation and impaired insulin signaling . increased irs serine phosphorylation in ir states , including obesity and t2d ,
akt ( akt1 , akt2 , and akt3 ) , also known as pkb ( pkb , pkb , and pkb ) , is a serine / threonine kinase activated by pi3k downstream of growth factors and various cellular stimuli .
many molecules involved in akt signaling are the key therapeutic targets for the treatment of human diseases , including t2d and cancer .
akt mediates the bulk of insulin 's action , including glycogen , lipid , and protein synthesis , cell survival , and the anti - inflammatory response .
akt2 activation is closely correlated to glut4 translocation via insulin - activated pi3k signals in adipocytes , and t2d patients have reduced akt activation in adipocytes and skeletal muscle .
akt2 knockout mice have impaired insulin action in liver and skeletal muscle and develop diabetes with hyperglycemia , hyperinsulinemia , glucose intolerance , and impaired muscle glucose uptake .
in contrast to the decrease in pi3k - akt activity , the mapk pathway is relatively unaffected by ir .
mapk pathway activation by insulin signaling is responsible for gene expression , cell growth , and mitogenesis .
mapk acts as an irs serine kinase in certain conditions ; therefore , inappropriate activation of mapk may worsen ir by increasing serine phosphorylation of irs and interfering with insulin signaling .
insulin , a peptide secreted by pancreatic beta cells , enters the central nervous system by crossing the blood
brain barrier in a regulated and saturable fashion , although de novo synthesis of insulin in the brain is still under debate .
insrs are widely expressed in the brain , including in the olfactory bulb , cerebral cortex , hippocampus , hypothalamus , and amygdala .
insrs are more concentrated in neurons relative to glial cells and are especially high in post - synaptic densities .
brain insulin signaling plays critical roles in the regulation of food intake , body weight , reproduction , and learning and memory .
intranasal insulin administration improves working memory in both human and animal studies , and intrahippocampal delivery of insulin improves hippocampal - dependent spatial working memory .
in addition , insr mrna and protein levels are increased in the hippocampus ca1 region in association with short - term memory formation after a spatial memory task , suggesting that neuronal insulin sensitivity could be enhanced during learning .
disruption of insulin signaling , however , makes neurons more vulnerable to metabolic stress , thus accelerating neuronal dysfunction .
defective insulin signaling is associated with decreased cognitive ability and the development of dementia , including ad .
poor cognitive performance in diabetes and ad are associated with a decrease in insr expression and cerebrospinal fluid ( csf ) insulin levels .
a recent study demonstrated decreases in the phosphorylation of similar insulin signaling molecules in both ad and t2d patient brains , and this decrease was more severe in the brains of the patients with both ad and t2d . decreased insulin signaling , including altered kinase activity and irs expression , in ad gets worse with disease progression , and increased basal irs-1 phosphorylation , a key signature of ir , is evident in the ad brain .
interestingly , the brain regions with the highest densities of insr , such as the hippocampus and temporal lobe , are also the major targets of neurodegeneration in ad .
therefore , impaired insulin signaling caused by ir can have a profound effect on cognitive decline and the development of ad .
multiple studies report that patients with mets have an increased risk of developing ad compared to age- and gender - matched controls , and accumulating evidence suggests that ad is closely related to dysfunction of both insulin signaling and glucose metabolism in the brain , prompting some investigators to refer ad as type 3 diabetes , or an insulin resistant brain state .
the incidence of both t2d and dementia rise in later life , increasing the prevalence of the comorbidity of these age - related diseases .
indeed , t2d predicts cognitive decline in older adults and is related not only to vascular dementia ( vd ) , but also to ad .
one of the pioneering epidemiological studies about the connection between t2d and dementia is the rotterdam study , which demonstrates that t2d almost doubles the risk of dementia ad ; interestingly , people who were insulin - treated ( therefore , with more severe diabetes ) at baseline were at the highest risk .
another study on a japanese - hawaiian cohort further showed a 1.5- , 1.8- , and 2.3-fold increased risk of total dementia , ad , and vd , respectively , for people with diabetes .
the religious order study demonstrated a 65% increased risk of ad among t2d patients . among the diabetes - related factors , higher levels of 2-hour post - load plasma glucose , fasting insulin , and homeostasis model assessment - estimated ir ( homa - ir ) were associated with increased risk for senile plaques after adjustment for age , sex , systolic blood pressure , total cholesterol , bmi , habitual smoking , regular exercise , and cerebrovascular disease .
a detailed analysis of 14 high quality longitudinal studies from medline and embase searches further demonstrates that individuals with t2d have a greater than two - fold increased risk of developing ad compared to individuals without t2d , adjusted for age , sex , education , and vascular risk factors ( including a history of stroke , hypertension , and heart disease ) .
the duration of diabetes is also a risk factor for increased cognitive decline , and this may be related to the length of exposure to high levels of insulin combined with the severity of disease .
the converse is also true , as patients with ad are also more likely to develop diabetes .
the mayo clinic ad patient registry reveals that 80% of ad patients have either t2d or an impaired fasting glucose level .
animal studies also demonstrate the connection between diabetes and ad . we have reported that db / db mice , a model of t2d , exhibit age - dependent increases in tau phosphorylation and cleavage . inducing type 1 diabetes ( t1d ) and ir by streptozotocin ( stz ) treatment or by feeding with a high fat diet ( hfd ) in ad animal models exacerbates both amyloid and tau accumulation .
high - fat and high carbohydrate diet feeding of ad rats significantly increased hyperphosphorylated tau and total tau mrna compared to rats with t2d or ad alone , and there was also a significant difference in spatial memory deficits between ad and ad+t2d groups .
obesity is a pathologic state defined by an excessive accumulation and maintenance of adipose tissue .
bmi is a simple index of weight - for - height that is commonly used to classify overweight and obese adults ( kg m ) .
worldwide , obesity has nearly doubled between 19802008 , with ~35% and ~11% of adults currently overweight or obese , respectively ( http://www.who.int/mediacentre/factsheets/fs311/en/ ) . in the united states ,
the epidemic is even worse ; 35% of adults and 15% of children were obese in 2010 and 80% of obese individuals are insulin resistant .
obesity has been associated with several processes related to the acceleration of aging , including the excessive production of free radicals , oxidation , and inflammation .
visceral adipose tissue is a metabolically active endocrine organ , and dysfunction in this organ is responsible for increased plasma free fatty acids ( ffas ) .
the inappropriate accumulation of lipids in muscle and liver due to abnormal fatty acid metabolism is one of the main features of ir .
visceral fat is also infiltrated with inflammatory cells and secretes proinflammatory cytokines , such as interleukin 6 and tumor necrosis factor- , which are implicated in the development of ir .
furthermore , these proinflammatory cytokines produced by adipocytes can cross the blood - brain barrier ( bbb ) and induce neuroinflammation and subsequent neurodegeneration . increased inflammation induces accelerated a deposition and/or decreased clearance and facilitates the polymerization of tau .
midlife obesity ( measured by bmi ) consistently demonstrates a strong and independent association with late - onset dementia and ad .
in a 30 year longitudinal study involving 6583 members of kaiser permanente of northern california , central obesity ( sagittal abdominal diameter ) alone doubled the risk of dementia after adjusting for age , sex , race , education , marital status , diabetes , hypertension , hyperlipidemia , stroke , heart disease , and medical utilization .
studies examining later onset obesity , however , have generated mixed results . in the cardiovascular health study , which involved people 65 years or older , underweight individuals ( bmi<20 ) had an increased risk of dementia ( hazard ratio [ hr]=1.62 ) , whereas obese individuals ( bmi>30 ) exhibited a reduced risk ( hr=0.63 ) relative to normal bmi controls .
another study found a decreased risk of dementia with higher bmi in subjects over 76 years old , and bmi and dementia further exhibited a u - shaped correlation in individuals younger than 76 years .
rats fed with diets high in saturated or unsaturated fat for 3 months display impairments in learning and memory tasks , and mice fed with a hfd have impaired spatial working memory , as assessed by a t - maze .
furthermore , brains of hfd - fed mice exhibit dysfunctional akt signaling and increased irs serine phosphorylation , a marker of ir , and mice fed with a high fat / high cholesterol diet display increased app c - terminal fragment accumulation and increased tau phosphorylation .
these results suggest that obesity - induced peripheral ir alters central insulin signaling and leads to ad - like cognitive impairment .
dyslipidemia is an important component of ir . because insulin plays a critical role in lipid metabolism by stimulating lipogenesis and suppressing lipolysis , perturbations in insulin signaling lead to accelerated lipolysis and increased production of ffas .
approximately 30% of total body cholesterol is contained in the brain ; therefore , slight changes in lipid metabolism may have profound effects on cognitive function .
cholesterol is the key component of the plasma membrane , and the processing of app into a occurs in the plasma membrane .
the interaction between cholesterol and app in the plasma membrane is critical for a production and clearance . in tg2576 ad mice ,
a high - fat / high - cholesterol diet significantly increased the production of a , and cholesterol lowering drugs reduced this brain amyloid load by more than two - fold .
lowering cholesterol levels in vitro also stimulates non - amyloidogenic processing of app , thereby reducing a production . a meta - analysis of 18 prospective studies ranging from 329 years revealed a consistent association between high midlife total cholesterol and an increased risk of ad and dementia .
interestingly , no evidence was found to support an association between total cholesterol later in life and ad .
cohorts of the seven countries study by a finnish group concluded that high serum total cholesterol is an independent risk factor for ad , while another finnish study further demonstrated that high midlife cholesterol levels are positively connected with an increased risk of ad later in life .
further , a retrospective cohort study of members of the kaiser permanente medical care program of northern california showed that midlife cardiovascular risk factors including smoking , hypertension , high cholesterol , and diabetes are all positively connected with increased dementia in later life , with diabetes and high cholesterol being the strongest risk factors . despite these findings , however ,
the connection between cholesterol and dementia is still complex and inconclusive , as some studies show no correlation , and others even demonstrate a protective role for cholesterol .
abnormal phosphorylation of tau has been implicated as a mechanism of ad pathophysiology since the mid-1980s .
tau is commonly regulated by post - translational modifications , including phosphorylation , glycation , glycosylation , sumoylation , o - glcnacylation , and cleavage . in ad
, tau is abnormally phosphorylated at its over 80 serine / threonine residues , which leads to the aggregation of tau filaments , appearing as nfts , in cell bodies and proximal dendrites .
several kinases , including glycogen synthase kinase-3 beta ( gsk3 ) , cyclin - dependent kinase 5 , mapk , and microtubule affinity - regulating kinases , and phosphatases , such as protein phosphatase 2a , are responsible for tau phosphorylation .
these kinases and phosphatases are the targets of insulin regulation . as in peripheral tissues ,
ir mostly affects pi3k - akt signaling in the brain , and chronic hyperinsulinemia prevents insulin - stimulated akt phosphorylation in cortical neuron cultures .
increased basal akt phosphorylation is also present in the cortex of t2d db / db mice , and ex vivo insulin stimulation could not increase cortical akt phosphorylation as it did in non - diabetic control mouse ( db+ ) .
gsk3 is one of the key signaling molecules downstream of akt and is a major tau kinase .
therefore , the precise regulation of akt signaling is critical for both amyloid and tau neuropathology in ad . impaired glucose metabolism due to ir can affect tau pathology via the dysregulation of o - glcnacylation .
similar to phosphorylation , o - glcnacylation is a dynamic post - translational modification involving the attachment of n - acetyl - d - glucosamine ( glcnac ) moieties to the hydroxyl group of serine and threonine residues .
o - glcnacylation is affected by nutrients in circulation , especially glucose ; therefore , the accumulation of excess energy associated with obesity and ir can result in the dysregulation of o - glcnacylation .
furthermore , in some cases , o - glcnacylation may occur at or near the residues that can also be phosphorylated .
tau has at least 12 o - glcnacylation sites which are mostly inversely correlated with phosphorylation status .
recent reports demonstrate that reduced brain glucose metabolism and o - glcnacylation leads to increased tau phosphorylation in both in vivo and in vitro models .
thus , the failure of proper insulin signaling can promote the accumulation of neurofibrillary tau , disrupt neuronal cytoskeletal networks and axonal transport , and lead to a loss of synaptic connections and progressive neurodegeneration .
a recent study examining 157 human brain autopsies demonstrated that irs-1 serine phosphorylation is increased in multiple sites in ad , and in other tauopathies such as pick 's disease , corticobasal degeneration and progressive supranuclear palsy .
furthermore , increased irs-1 serine phosphorylation was frequently co - expressed with pathologic tau in neurons and dystrophic neurites .
similar results were observed in transgenic ps19 tau mouse brains , where abnormally increased irs-1 serine phosphorylation co - localized with tangle - bearing neurons .
conversely , inducing ir by feeding mice a hfd increased tau phosphorylation and impaired insulin signaling , and high fat - feeding of animal models of ad exacerbated the pathologies .
after 23 wk on hfd , appswe / ps1de9 mice displayed severe hyperinsulinemia along with increased tau phosphorylation , a levels , and amyloid burden .
hfd - feeding from an early age in thy - tau22 mice also potentiated spatial learning deficits and significantly increased tau phosphorylation , and direct disruption of insulin signaling by inducing t1d using stz or irs-2 knockout increased tau pathology .
in addition , stz injections in pr5 tau transgenic mice greatly increased insoluble hyperphosphorylated tau and the later deposition of nfts , features not observed in control pr5 mice .
together , these results suggest that ir accelerates the onset and increases the severity of ad , especially in situations with a predisposition to developing tau pathology .
brain insulin signaling plays a critical role in the regulation of food intake , body weight , reproduction , and learning and memory , and defective insulin signaling is associated with decreased cognitive ability and the development of dementia and ad .
ad is characterized by improper expression and processing of app and the accumulation of insoluble neurotoxic a into subsequent senile plaques .
studies show that insulin signaling regulates multiple steps of the amyloid cascade and affects a aggregation in the brain .
insulin increases the transcription of anti - amyloidogenic proteins , such as the insulin - degrading enzyme ( ide ) and -secretase , and stimulates a clearance . while gsk3 is the major tau kinase , gsk3 increases a production by stimulating -secretase activity .
constitutively active akt inhibits app trafficking and a secretion through feedback inhibition of irs and pi3-k .
app is modified by o - glcnac in a region that may affect its degradation , and a recent report demonstrated that o - glcnacylation of app encourages non - amyloidogenic -secretase processing , thus decreasing a secretion .
conversely , a can affect insulin signaling by competing with or reducing the affinity of insulin binding to its own receptor or by regulating intracellular signaling .
soluble a binds to the insr in hippocampal neurons to inhibit receptor autophosphorylation and subsequent activation of pi3k / akt , and a derived diffusible ligands ( addls ) induce the abnormal expression of insr and interrupt insulin signaling , thereby potentially contributing the development of central ir .
in addition , a inhibits insulin signaling by c - jun n - terminal kinase ( jnk)-mediated increases in irs serine phosphorylation .
intracellularly , a prevents the interaction of pyruvate dehydrogenase lipoamide kinase isozyme 1 ( pdk1 ) with akt to inhibit akt activation .
therefore , a feed - forward interaction between impaired insulin signaling and increased a production exacerbates ad pathology in the presence of ir . in a recent cross - sectional study of the wisconsin registry for alzheimer 's prevention that included187 late middle - aged adults , higher ir levels were connected with increased amyloid deposition , as measured by pittsburgh compound b uptake . inducing ir in rats using fructose - containing water also enhanced a production by increasing the expression of -secretase , stimulating -secretase activity , and decreasing ide levels . in cultured primary cortical neurons , insulin reduced
a buildup by enhancing the conversion of oligomers to monomers and also prevented a oligomer - induced synaptic toxicity at the level of both synapse composition and structure .
in contrast , inhibiting insr activity by transfecting a kinase - dead mutant receptor or a tyrosine kinase inhibitor increased a oligomer aggregation ; similar results were obtained through either insr knock - down or pi3k pathway inhibition .
thus , dysfunctional insulin signaling due to ir accelerates amyloid pathology , both in human and animal models . in summary ,
the resulting impaired insulin signaling , which mainly impacts the pi3k / akt pathway , then increases app processing / a levels and tau phosphorylation .
finally , increased a further disrupts insulin signaling to exacerbate ad pathology and cognitive decline ( figure 1 ) .
given the close correlation between brain ir and cognitive impairment , therapeutic approaches using anti - diabetic drugs to improve insulin levels or signaling have been tested to treat ad . in rats ,
intracerebroventricular ( icv ) administration of insulin improved spatial learning and memory and reversed stz - induced cognitive decline , and intranasal delivery of insulin reduced hfd - induced tau phosphorylation , whereas subcutaneous injection only had a minimal effect . although systemic insulin infusion demonstrated beneficial effects on memory , it is not a viable long - term option for ad patients due to adverse hypoglycemic effects , including cognitive deficits and neuronal death .
intranasal delivery of insulin , however , is a safe and effective alternative to increase csf insulin concentrations without affecting systemic insulin and glucose levels , and studies have demonstrated the beneficial effects of intranasal insulin on memory function .
intranasal insulin delivery for 8 wk improved delayed word recall test in cognitively normal young adults , and a single - dose intranasal insulin administration improved verbal memory in subjects with ad and mild cognitive impairment ( mci ) . in a subsequent study , chronic intranasal insulin for 21 days resulted in enhanced declarative memory and selective attention performance in early ad patients .
intranasal insulin also increased plasma a40/a42 ratios , suggesting decreased amyloid pathology levels . likewise ,
daily intranasal insulin treatment for 4 months in 104 adults with early ad or amnestic mci also improved delayed memory and preserved caregiver - rated ability to carry out daily functions .
these studies provide compelling evidence that intranasal insulin may be a promising novel therapeutic approach for early ad and mci patients ; however , it should also be noted that some studies suggest that intranasal insulin treatment is effective only in individuals with apoe - 4-negative genotypes .
thiazolidinediones ( tzds ) , rosiglitazone , and pioglitazone are ligands for peroxisome proliferator - activated receptors ( ppars ) , a family of nuclear receptors that regulate the transcription of genes involved in lipid and glucose metabolism .
tzds have been used as an anti - diabetic drug since the 1990s due to their beneficial effects on glucose homeostasis , which include increasing insulin sensitivity , reducing blood glucose levels and improving lipid metabolism .
a number of animal and clinical studies further suggest that tzds improve cognitive function by enhancing insulin action .
early treatment with ppar agonists effectively prevented icv - stz - induced neurodegeneration and its associated learning and memory deficits , and rosiglitazone similarly improved learning and memory and reduced ide mrna levels in tg2576 ad mice .
chronic treatment with rosiglitazone also facilitated a clearance , reduced amyloid plaques , decreased tau phosphorylation , and improved cognitive function in ad mouse models , and pioglitazone prevented ir and a overproduction that are associated with fructose - drinking in rats .
some studies , however , show inconsistent results depending on gender and/or genotype of the selected animal models . likewise , there are mixed results from human clinical trials with tzds .
an early study demonstrated that mild ad or amnestic mci patients who received rosiglitazone for 6 months exhibited better delayed recall and selective attention , and rosiglitazone protected cognitive decline in older individuals with both t2d and mci .
similar to intranasal insulin treatment , the effect of rosiglitazone was effective only on the individuals with apoe - 4-negative genotypes .
a multicenter trial proved no effect of rosiglitazone on brain atrophy or cognitive function in ad patients , and two large phase iii clinical trials also demonstrated no evidence of clinically significant efficacy in cognition or global function , regardless of apoe - 4 genotype .
two prospective randomized open - labelled studies demonstrated that pioglitazone induced cognitive and functional improvements and stabilization of the disease in the individuals with mild ad and mci with t2d .
however , another study evaluating the safety of pioglitazone as the primary outcome exhibited no significant treatment effect on cognition after 6 months of treatment in non - diabetic ad patients .
incretins , glucose - dependent insulinotropic peptide ( gip ) and glucagon - like peptide-1 ( glp-1 ) , are a group of gastrointestinal hormones secreted by intestinal epithelial cells in response to food intake that can affect whole body glucose utilization .
glp-1 receptors are widely expressed throughout the body , including in the pancreas , intestines , heart , and lungs , and in both the central and the peripheral nervous system .
the activation of glp-1 receptors leads to the facilitation of glucose utilization and antiapoptotic effects in various organs , and two long - lasting glp-1 analogues , exenatide ( byetta ) and liraglutide ( victoza ) , are approved for the treatment of t2d .
more importantly , glp-1 can readily cross the bbb and enhance insulin signaling in the brain .
therefore , glp-1 analogues are an attractive therapeutic approach to improve ir in ad and in t2d because they can activate pathways common to insulin signaling and facilitate brain synaptic plasticity , cognition , and cell survival .
excendin-4 prevented glucose - induced tau hyperphosphorylation or a-mediated toxicity in cultured neurons , and subcutaneous injection of liraglutide for 30 days reduced icv - stz - induced tau hyperphosphorylation and significantly improved learning and memory in mice .
two months of liraglutide injections in app / ps1 mice reduced plaque load , app and a oligomer levels , and overall inflammation and increased ide levels .
furthermore , long - term potentiation was significantly enhanced and liraglutide also improved cognitive function , as measured by novel object recognition and morris water maze tests .
liraglutide not only has a protective effect at an early stage of ad ( 7 mo ) , but it is also able to reverse ad - related changes in older ( 14 mo ) app / ps1 mice .
moreover , liraglutide reduced tau phosphorylation and restored akt and gsk3 phosphorylation in a hfd - induced model of t2d in rats .
other glp-1 analogues demonstrated similar beneficial effects on ad pathologies and cognitive function in ad mouse models .
although the first small clinical trial of liraglutide in ad patients did not lead to any improvement in cognition or changes in a deposition , as measured by pittsburgh compound b pet , a recent clinical trial of exenatide in parkinson 's disease patients demonstrated clinically relevant improvements in motor and cognitive measures .
currently two additional clinical trials are in progress with exenatide ( http://clinicaltrials.gov/ct2/show/nct01255163?term ) and liraglutide ( http://clinicaltrials.gov/ct2/show/nct01843075?term ) in mci and early ad patients , and completion is estimated in 2016 and 2017 , respectively .
recent evidence supports the contention that ad may be a slow - progressing brain metabolic disease , and numerous studies demonstrate an intricate connection between mets and ad . individuals with mets features , such as t2d and obesity , have a higher risk of developing ad , while ad patients often develop hyperglycemia and ir .
ir due to impaired insulin signaling is a common characteristic of both mets and ad , and likely represents the key link between the two diseases .
insulin signaling regulates a and tau , and a has negative effects on insulin signaling ; therefore , dysfunctional insulin signaling can enhance a and tau pathology , and increased a production can further exacerbate ir .
thus , several diabetes treatments that enhance insulin signaling are being tested for therapeutic potential in ad and dementia , and even though the results from the tzd clinical trials were disappointing , intranasal insulin and glp-1 analogues are still being actively pursued as a potential treatments for ad and have exhibited some promising results .
intranasal insulin , however , is only effective in early ad and mci patients , and individuals with the apoe - 4 allele do not respond well .
in addition , exenatide and liraglutide are still in the early stages of therapeutic development , and large clinical trials are currently in progress .
effective ad and mci treatment demands the development of specific biomarkers to support the diagnosis of these conditions as early as possible .
currently , total tau , hyperphosphorylated tau , and a40/a42 ratios in the csf exhibit over 80% specificity as biomarkers of ad . continued research to discover the precise mechanism of how ir contributes to the onset and progression of ad , is also imperative for the development of improved therapeutic interventions . given the current obesity epidemic among all ages and increased life expectancy , there is a critical need to understand the underlying causes of cognitive impairment due to ir , which may be the key link for the increased incidence of ad in individuals with metabolic disorders . | metabolic syndrome ( mets ) is a cluster of cardiovascular risk factors that includes obesity , diabetes , and dyslipidemia .
accumulating evidence implies that mets contributes to the development and progression of alzheimer 's disease ( ad ) ; however , the factors connecting this association have not been determined . insulin resistance ( ir )
is at the core of mets and likely represent the key link between mets and ad . in the central nervous system , insulin plays key roles in learning and memory , and ad patients exhibit impaired insulin signaling that is similar to that observed in mets . as we face an alarming increase in obesity and t2d in all age groups , understanding the relationship between mets and ad is vital for the identification of potential therapeutic targets .
recently , several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in ad and dementia . in this review
, we will discuss mets as a risk factor for ad , focusing on ir and the recent progress and future directions of insulin - based therapies . | Metabolic syndrome and insulin signaling
Insulin signaling in the brain
MetS and AD
IR and tau
IR and A
Insulin signaling as a therapeutic target of AD
Conclusion |
studies that only infuse oxytocin into participants and then make claims about human behavior are suspect .
this approach does not identify what the brain itself is doing during social interactions , including neurochemical promotion and inhibition of oxytocin synthesis and dose - response relationships between oxytocin and behavior .
the key question is whether the brain produces its own oxytocin during the behavior being studied ; if so , the causal relationship between oxytocin and a particular behavior can be demonstrated via an infusion study .
but the reverse is not true : infusing oxytocin or any drug into the brain and observing a change in behavior does not mean that this is how the brain works it simply means that a drug has changed behavior , as many drugs do .
my studies complete the causal circle by measuring what the brain does naturally and then intervening in this system pharmacologically to show that the behavior can be provoked .
after years of experiments , i now consider oxytocin the neurologic substrate for the golden rule : if you treat me well , in most cases my brain will synthesize oxytocin and this will motivate me to treat you well in return .
this is how social creatures such as humans maintain themselves as part of social groups : they play nice most of the time .
( why people do not play nice is a fascinating story we also have studied ; see zak , 2012 for evidence ) .
but i m a skeptic at heart , so i always want to measure the behavioral effects of oxytocin rather than simply ask people s opinions about how they feel . the experience i had watching million dollar baby caused me to wonder if movies , in addition to direct personal interactions , would cause oxytocin release . to test this , my colleague jorge barraza edited a set of a short video clips that we obtained with permission from st .
one version shows a father talking to the camera while his 2-year - old son , ben , who has terminal brain cancer , plays in the background .
the story has a classic dramatic arc in which the father is struggling to connect to and enjoy his son , all the while knowing that the child has only a few months to live .
the clip concludes with the father finding the strength to stay emotionally close to his son until he takes his last breath .
we also developed a video of the same father and son spending a day at the zoo .
this version does not mention cancer or death , but the boy is bald ( from his chemotherapy ) and is called miracle boy once during the clip .
this video lacks the tension induced by the typical story form but includes the same characters .
this version was used as a control story to see what the brain does when any video is being watched . in our first study of narratives , we took blood before and after participants watched one of the two versions of the video.11 we found that the narrative with the dramatic arc caused an increase in cortisol and oxytocin .
tellingly , the change in oxytocin had a positive correlation with participants feeling of empathy for ben and his father . heightened empathy motivated participants to offer money to a stranger who was in the experiment .
flat narrative of ben and his father at the zoo did not increase oxytocin or cortisol , and participants did not report empathy for the story s characters .
these findings suggest that emotionally engaging narratives inspire post - narrative actions in this case , sending money to a stranger .
, we did not know for sure that oxytocin was the reason participants cared about the people in the video , just that oxytocin and empathy were correlated .
our previous study pointed to oxytocin as the biological instrument that puts people in thrall to a story . to assess the causal impact of oxytocin on narrative immersion , we ran a study using public service announcements ( psas ) in which participants received intranasal infusions of synthetic oxytocin or a placebo . this time around , we decided to test a larger set of video narratives .
we wanted stories that most people would not have seen before and ones that could elicit a prosocial action at a cost ( such as a donation ) .
we found a rich trove of public service announcements from the united kingdom that are well - produced and engaging .
the experiment used sixteen psas that ran for thirty or sixty seconds on four topics : smoking , drinking to excess , speeding , and global warming . to incentivize people to pay attention to the videos , each of the participants was paid five dollars if they could correctly answer a factual question about the ad immediately after watching it .
for example , was there a car in the video ? then , our software asked participants if they would like to donate some of the five dollars they had just earned to a charity associated with the cause shown in the psa .
none of the psas solicited donations , they simply told stories about social issues . computer software presented all the videos and post - video questions and we used random participant identifiers so that one s donation behavior was kept private .
forty people received either 40 iu of oxytocin or an equivalent amount of normal saline ( placebo ) .
participants started watching the videos after an hour - long period during which the synthetic oxytocin diffuses from the sinuses into the brain .
we found that those who received oxytocin donated , on average , 56 percent more money to charity compared with participants who received the placebo.12 this confirmed the causal role of oxytocin on post - narrative prosocial behavior .
we discovered that participants who were given oxytocin showed substantially more concern for the characters in the psas .
this increased concern motivated them to want to help by donating money to a charity that could alleviate the suffering these stories depicted .
it is as if the brain is lazy and is using a monkey see , monkey do approach to assess appropriate social behaviors .
( indeed , the brain seeks to conserve energy by using default pathways a kind of laziness . )
the psas seemed to persuade viewers that ( for example ) nowadays the humans are very concerned about drinking too much , so as a human , i , too , should be concerned .
such responses are what social creatures with social brains do . and yet , participants understand that the stories are fictional and are portrayed by professional actors .
the money donated to charity can not help these actors out of their fictional binds .
the money might help prevent the harm depicted in the psas from happening to an unknown other person , but this is a big if .
nevertheless , oxytocin makes people want to help others in costly and tangible ways . in another experiment,12 we sought to replicate our earlier study by taking blood samples before a group of forty - two participants ( who were not in the oxytocin infusion study ) watched one of the uk psas .
we measured the change in oxytocin and in a fast - acting arousal hormone with a long name that is abbreviated acth .
when the psa elicited an increase in both acth and oxytocin , donations were 261 percent higher than when one or both of these biomarkers did not rise .
the change in acth correlated with the amount of attention people paid to the story .
this finding makes sense : if we do not attend to a story , it will not pull us into its narrative arc .
attention is a scarce neural resource because it is metabolically costly to a brain that needs to conserve resources .
if a story does not sustain our attention , then the brain will look for something else more interesting to do .
we also found that the change in oxytocin was associated with concern for the characters in the story , replicating our earlier finding .
if you pay attention to the story and become emotionally engaged with the story s characters , then it is as if you have been transported into the story s world .
this is why your palms sweat when james bond dodges bullets . and why you stifle a sniffle when bambi s mother dies .
narratives that cause us to pay attention and also involve us emotionally are the stories that move us to action .
more generally , stories with a dramatic arc fit the requirements for high - impact narratives .
this structure sustains attention by building suspense while at the same time providing a vehicle for character development .
the climax of the story keeps us on the edge of our neural seats until the tension is relieved at the finish .
theorists including aristotle ( poetics , 335 bce ) , gustav freytag ( die technik des dramas , 1863 ) , and joseph campbell ( the hero with a thousand faces , 1949 ) have contended that the rising and falling tension of dramatic performances facilitate the audience s emotional connection to the characters .
now let s get down to brass tacks : why are there so many dreadful movies ?
humans have known about the three - act structure and mythos , pathos , and ethos for 2,500 years .
department of defense wanted to know why narratives are persuasive and supported our research and that of other labs as well .
attention is easy to measure rapidly , via a quickened heartbeat or sweat coming from eccrine glands in the skin .
nature provided a solution . while we were mostly interested in oxytocin in the brain , the stimulus - induced co - release of oxytocin in the brain and blood meant we could measure changing activity in regions with densities of oxytocin receptors . the vagus nerve ( the longest cranial nerve , which innervates the heart and gut ) is chock - full of oxytocin receptors . with a bit of algorithmic
fiddling , scientists can measure the activity of the vagus using an electrocardiogram ( ecg ) .
we confirmed that the change in oxytocin in blood correlates with changes in vagus nerve activity .
we returned to the story of the dying child ben because it is a reliable way to stimulate oxytocin release .
this time we measured cardiac activity using an ecg and sweat using an electrodermal sensor on the fingers . because we were developing a system that might be used in a war zone , we built in redundancies .
attention was measured using both heart rate and skin conductance changes from sweat on the fingers ; emotional resonance was quantified using two measures of changes in the brain s relaxation response driven by the vagus nerve .
the exciting part was that we could measure both effects up to one thousand times a second with off - the - shelf wireless technologies .
but it is not so simple to isolate the effects of a story from everything else the brain is doing to keep you upright , breathing , and conscious .
all neuroscience studies need to extract the neurologic signal produced by a stimulus during an experiment from the background noise of all other neural activity .
to give you a sense of the scope of this problem , for every thirty people we test for an hour each , we collect a terabyte of peripheral neurologic data .
most of this data is not relevant to understanding why people respond to stories , but the faint traces that are relevant must be extracted and processed with extraordinary care .
once we did all this , the data told us several interesting things.13 first among them is that the brain does not work like the hypothetical story structure known as freytag s pyramid , in which strictly rising action leads to a climax , and then strictly falling action occurs as the story resolves .
even for the one - hundred - second ben video , one s attention waxes and wanes .
the brain is attending to the story and then doing a quick search of the rest of the environment , and then refocusing on the story as the tension rises .
nevertheless , the peak attentional response occurs in the climax , when ben s father reveals that ben is dying . that s a bombshell to which people pay attention .
after about thirty seconds , vagal activity begins to increase as viewers get to know and then begin to empathize with ben and his father .
not only were we able we track what the brain is doing millisecond by millisecond during a story , we used the neurologic data to build a predictive model of donations to a childhood cancer charity our measure of story impact .
the statistical model we built predicts whether a participant would donate money with 82 percent accuracy .
that is , by measuring how your peripheral nervous system responds to a story , we can almost perfectly predict what you ll do before you do it .
the participants who , for whatever reason , either lost interest in the video or did nt form an emotional connection to ben and his father almost never donated money to charity .
the money will not save ben and it wo nt offer relief to his father .
it seems that once we are attentive and emotionally engaged , our brains go into mimic mode and mirror the behaviors that the characters in the story are doing , or might do . as social creatures we are biased toward engaging with others , and effective stories
truth be told , ben s story is as near to a perfect high - impact narrative as there is .
we wondered if neurologic data could identify bad stories , too . and what about stories that may be distasteful but that are still desirable to watch ?
i m glad i did , but i do nt have much desire to watch it again .
our next study tested stories about hot - button issues to see how people reacted to potentially disagreeable topics .
we used first - person narratives from storycorps , a nonprofit that collects and distributes personal stories .
we choose six stories on racism , gun control , and the terrorist attacks of september 11 .
for our narrative impact measure , we invited participants to donate some of their earnings to a charity associated with the topic of the story .
just as in the ben story , we confirmed that stories that sustain attention and generate emotional resonance produce post - narrative donations even stories on difficult topics . to the brain ,
good stories are good stories , whether first - person or third - person , on topics happy or sad , as long as they get us to care about their characters .
psycholinguists have shown that effective stories induce transportation into the narrative.14 transportation happens when one loses oneself in the flow of the story just like i did while watching million dollar baby . to understand the psychological effects of stories
, we included surveys of narrative transportation and concern for story characters in the storycorps study .
this shows why stories affect behavior after the story has ended : we have put ourselves into the narrative .
even a week after the experiment , accurate story recall was predicted by a single measure : narrative transportation .
you may be thinking that we have a money - centric approach to assessing when people are moved by a story .
let s try a different approach : we ll have thousands of people rate stories instead .
the stories we used were tv commercials . conveniently , this is just what usa today asks readers to do on super bowl sunday : vote for the commercials they like the best .
about five thousand people voted for their favorite commercials in 2014 , and the style and content of these short narratives vary from the unusual to poignant to just plain silly .
this gave us a chance to further refine our algorithms and test them against what people say they like .
usa today does not simply provide a ranking of commercials ; it has its readers rate them on a one to ten scale .
my group derived a quantification of narrative engagement using neurologic data so we , too , could rate story quality .
we estimated the relative contribution of attention and emotional resonance on story impact from our corpus of studied stories .
we call this measure a story s zest ( for zak engagement statistic ) . by estimating each super bowl ad s zest
, we could compare the usa today readers ad likability with the zest measure of brain activity .
three days after the 2014 super bowl , sixteen participants watched the top ten super bowl commercials in random order in my lab while we measured their peripheral neurologic activity .
there was no correlation at all between what usa today readers said they liked and a commercial s zest .
so we ran another study using usa today s top ten 2013 super bowl commercials and found exactly the same thing : zero correlation .
these findings suggest that people are unable to articulate what they like and do not like .
perhaps this should not surprise us . in a classic study , psychologist and economics nobel laureate daniel kahneman found that people s preferences for things they have not experienced are largely unformed.15 watching the super bowl commercials myself , i sensed why it is hard to articulate what one likes . the best super bowl commercial in 2014 , according to usa today readers ,
produced for budweiser beer . in the first ten seconds , one sees a puppy nuzzling the nose of a clydesdale horse .
one immediately recognizes the clydesdale as the budweiser icon , and this tells viewers what they can expect from the ad .
the suspense is gone , and our neurologic measures show that people s attention wanders starting fifteen seconds into the commercial . without attention ,
the hoped - for emotional resonance with the ad s characters ( and presumably the brand ) fails to occur . but ask people what they like and , gosh , they see puppies and horses and wide open country and , well , of course we love these images .
the commercial is dull . in all our studies we ruled out effects that might influence zest , including movement , cars , buildings , attractive men and women , and many other factors .
department of defense s funding of the emerging science of narrative jump - started the field.16
17 storytellers have always known that attention and emotion are important to develop during a narrative , but now we have ways to measure these responses directly rather than rely on incohate impressions such as entertaining or fascinating . yet , even with millennia of practice , creating a great story is difficult . the emerging science of narrative can guide the art , but it can not replace it .
the narrator in million dollar baby describes the heroine , maggie s , desire to be a boxer as ... the magic of risking everything for a dream that nobody sees but you . | editor s note : the man behind the discovery of the behavioral effect of a neurochemical in the brain called oxytocin wondered if the molecule might motivate people to engage in cooperative behaviors . in a series of tests using videos
, his lab discovered that compelling narratives cause oxytocin release and have the power to affect our attitudes , beliefs , and behaviors . | Provoking the Brain
Narrative Immersion
Attention-getting
Do We Know a Good Story When We See One? |
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