Experiences of preparing children for a death of an important adult during the COVID-19 pandemic: a mixed methods study.
The objectives of this study were to investigate how families prepared children for the death of a significant adult, and how health and social care professionals provided psychosocial support to families about a relative's death during the COVID-19 pandemic. A mixed methods design; an observational survey with health and social care professionals and relatives bereaved during the COVID-19 pandemic in the UK, and in-depth interviews with bereaved relatives and professionals were conducted. Data were analysed thematically. A total of 623 participants completed the survey and interviews were conducted with 19 bereaved relatives and 16 professionals. Many children were not prepared for a death of an important adult during the pandemic. Obstacles to preparing children included families' lack of understanding about their relative's declining health; parental belief that not telling children was protecting them from becoming upset; and parents' uncertainty about how best to prepare their children for the death. Only 10.2% (n=11) of relatives reported professionals asked them about their deceased relative's relationships with children. This contrasts with 68.5% (n=72) of professionals who reported that the healthcare team asked about patient's relationships with children. Professionals did not provide families with psychosocial support to facilitate preparation, and resources were less available or inappropriate for families during the pandemic. Three themes were identified: (1) obstacles to telling children a significant adult is going to die, (2) professionals' role in helping families to prepare children for the death of a significant adult during the pandemic, and (3) how families prepare children for the death of a significant adult. Professionals need to: provide clear and honest communication about a poor prognosis; start a conversation with families about the dying patient's significant relationships with children; and reassure families that telling children someone close to them is dying is beneficial for their longer term psychological adjustment.


Childbirth fear and related factors among pregnant and postpartum women in Malawi.
Childbirth fear is a health concern in women living in high-income countries; however, little is known about childbirth fear among women living in low-income countries like Malawi. In this study, we explored childbirth fear and associated factors among pregnant and postpartum women in Malawi. A cross-sectional study of 152 pregnant and 153 postpartum women was conducted at a district hospital in Malawi. Participants were assessed for childbirth fear using the Wijma Delivery Expectancy/Experience Questionnaire (WDEQ). Demographic and obstetric variables were collected using a structured questionnaire. The Multidimensional Scale of Perceived Social Support (MSPSS) was used to measure social support. Using a multinomial logistic regression, factors related to childbirth fears were examined, namely demographic and obstetric characteristics, and social support. The mean age of participants was 26 (standard deviation: 6.4) years. During pregnancy, 39% women reported a low level of fear, 41% reported moderate fear, and 20% reported high fear; while after birth, 49, 41, and 10% women reported low, moderate, and high fear, respectively. Pregnant women who were illiterate (odds ratio (OR): 5.0, p < 0.01) or unemployed (OR: 12.6, p < 0.01) were more likely to report moderate and high fear. Postpartum mothers who were illiterate (OR: 4.2, p < 0.01) or unemployed (OR: 11.8, p < 0.01) were more likely to have moderate and high fear. Furthermore, postpartum women who sustained perineal tears had significantly higher odds of experiencing moderate (OR: 5.3, p < 0.01) or high (OR: 19.9, p < 0.01) fear than their counterparts. Childbirth fear is common in Malawi, and pregnant women are more likely to experience high levels of fear than postpartum women. This study highlighted the connection between childbirth fear with mother's education, employment, and perineal tears during delivery. Identifying and developing interventions for women with these associated characteristics is of clinical importance for the reduction of childbirth fear before and after childbirth in Malawi.


The guilty but mentally ill verdict: a review and conceptual analysis of intent and impact.
The purpose of this article is to review the law and literature involving the guilty but mentally ill (GBMI) verdict to provide a clear conceptual examination of the actual intent and impact of the verdict. Such an examination may help to clarify continuing debates and confusion about the nature of GBMI and its success in addressing perceived problems with insanity acquittals. This review suggests that the actual intentions of the GBMI verdict are associated with minimal and largely unsuccessful results. In addition, the typical absence of treatment for defendants found GBMI appears unsurprising given that the provision of treatment for mentally ill offenders is not a legal intention of the GBMI verdict. Finally, the introduction of the GBMI verdict has had unintended negative consequences that include increased confusion among jurors and the legal profession and possible increased occurrence of inappropriate verdicts. In conclusion, significant problems can be noted with regard to both the intent and impact of the GBMI verdict.


Misdiagnosis and pitfalls in Panayiotopoulos syndrome.
Panayiotopoulos syndrome (PS) is a frequent (6% among children of 1-15 years) and benign epileptic syndrome, characterized by predominantly autonomic symptoms (emesis, pallor, flushing, cyanosis, mydriasis/miosis, cardiorespiratory and thermoregulatory alterations, incontinence of urine and/or feces, hypersalivation, and modifications of intestinal motility) associated with simple motor focal seizures, which can be followed by secondary generalization. Panayiotopoulos syndrome can be extremely insidious, because it can mimic several condition, such as gastroenteritis, gastroesophageal reflux disease, encephalitis, syncope, migraine, sleep disorders, or even metabolic diseases. This peculiar pleiotropism should be kept in mind by child neurologists and pediatricians and general practitioners, because a wrong diagnosis may lead to inappropriate interventions. The consequences are high morbidity, costly mismanagement, and stress for children and their parents. The availability of electroencephalography (EEG) recording in pediatric Emergency Departments might be useful for a prompt and not-cost-consuming diagnosis. On the other hand, it is important to be aware of the possible, multifaceted, clinical presentations of PS and its clinical, radiological, and neurophysiological features in order to improve both recognition and management.


Intelligence Assessment Instruments in Adult Prison Populations: A Systematic Review.
Detection of intellectual disability (ID) in the penitentiary system is important for the following reasons: (a) to provide assistance to people with ID in understanding their legal rights and court proceedings; (b) to facilitate rehabilitation programs tailored to ID patients, which improves the enhancement of their quality of life and reduces their risk of reoffending; and (c) to provide a reliable estimate of the risk of offence recidivism. It requires a short assessment instrument that provides a reliable estimation of a person's intellectual functioning at the earliest possible stage of this process. The aim of this systematic review is (a) to provide an overview of recent short assessment instruments that provide a full-scale IQ score in adult prison populations and (b) to achieve a quality measurement of the validation studies regarding these instruments to determine which tests are most feasible in this target population. The Preferred Reporting Items for Systematic reviews and Meta-Analyses Statement is used to ensure reliability. The Satz-Mögel, an item-reduction short form of the Wechsler Adult Intelligence Scale, shows the highest correlation with the golden standard and is described to be most reliable. Nevertheless, when it comes to applicability in prison populations, the shorter and less verbal Quick Test can be preferred over others. Without affecting these conclusions, major limitations emerge from the present systematic review, which give rise to several important recommendations for further research.


Thoracic meningioma masquerading as chronic abdominal pain.
Chronic abdominal pain without a structural or metabolic gastroenterological etiology can be extremely challenging to diagnose. Patients presenting with an associated radicular pattern of pain may alert the clinician to a possible structural neurological cause of the symptoms. We present the case of a 70-year-old woman who presented to our institution with an 18-month history of right upper quadrant abdominal pain. She had no associated symptoms or provoking factors. She underwent an extensive gastroenterology evaluation, including colonoscopy that was unrevealing. Ultrasound demonstrated gallstones and she was evaluated for cholecystectomy. She subsequently developed right costal margin pain. Her symptoms remained stable over the course of the next year. Follow-up general surgical evaluation was still unconvincing that the gallstones were the etiology of her symptoms. A thoracic spinal MR demonstrated a large intradural extramedullary mass at T8. The patient's neurological exam was normal. She underwent a thoracic laminectomy and resection of meningioma with intraoperative electrophysiological monitoring. Her abdominal pain resolved. Patients can present with months to years of elusive abdominal symptoms only to be eventually found to be harboring an undiagnosed spinal tumor. We discuss the case and review the literature reports of spinal tumors masquerading as chronic abdominal pain.


The impact of increasing medical school class size on clinical clerkships: a national survey of internal medicine clerkship directors.
To determine the impact of increasing medical school class size on the internal medicine clerkship. In 2006, the Clerkship Directors in Internal Medicine surveyed its 110 institutional members to discover whether their medical school class size had increased (or would increase) and the impact of increasing class size on number of students per teaching site, number of clerkship sites needed, and resources needed. Respondents rated their agreement or disagreement with statements about increasing class size, and they provided free-text responses. Analyses included descriptive statistics and qualitative analysis. Response rate was 76% (83/110). In the three years preceding the survey, one medical school decreased class size; 43% increased by a mean of 14 students per year (10%). Most respondents (51%) expected class size to increase by a mean of 17 students per year (12%) through 2009; none expected class size to decrease. Increasing class size by 15% would mean adding 3.7 (standard deviation = 2.2) students per inpatient site, 2.9 (2.9) new inpatient sites, 3.0 (2.2) students per ambulatory site, and 4.9 (5.5) ambulatory sites. Respondents disagreed with the questionnaire statements that they would have more resources, teachers, and protected time; they agreed with statements that recruiting teachers would be harder as class size increases. Free-text responses to the challenges of increasing class size revealed two themes: strain on resources (space, time, faculty), and the impact on the educational experience. Internal medicine clerkship directors believe increasing medical school class size will dramatically increase resources needed during clerkships and may adversely impact education.


Hidden consequences of living in a wormy world: nematode‐induced immune suppression facilitates tuberculosis invasion in African buffalo.
Most hosts are infected with multiple parasites, and responses of the immune system to co-occurring parasites may influence disease spread. Helminth infection can bias the host immune response toward a T-helper type 2 (Th2) over a type 1 (Th1) response, impairing the host's ability to control concurrent intracellular microparasite infections and potentially modifying disease dynamics. In humans, immune-mediated interactions between helminths and microparasites can alter host susceptibility to diseases such as HIV, tuberculosis (TB), and malaria. However, the extent to which similar processes operate in natural animal populations and influence disease spread remains unknown. We used cross-sectional, experimental, and genetic studies to show that gastrointestinal nematode infection alters immunity to intracellular microparasites in free-ranging African buffalo (Syncerus caffer). Buffalo that were more resistant to nematode infection had weaker Th1 responses, there was significant genotypic variation in nematode resistance, and anthelminthic treatment enhanced Th1 immunity. Using a disease dynamic model parameterized with empirical data, we found that nematode-induced immune suppression can facilitate the invasion of bovine TB in buffalo. In the absence of nematodes, TB failed to invade the system, illustrating the critical role nematodes may play in disease establishment. Our results suggest that helminths, by influencing the likelihood of microparasite invasion, may influence patterns of disease emergence in the wild.


Chemotactic steering of bacteria propelled microbeads.
Flagellated bacteria have been embraced by the micro-robotics community as a highly efficient microscale actuation method, capable of converting chemical energy into mechanical actuation for microsystems that require a small payload and high rate of actuation. Along with being highly motile, Serratia marcescens (S. marcescens), our bacterium species of interest, is a highly agile biomotor capable of being steered via chemotaxis. In this paper, we attached S. marcescens bacteria to polystyrene microbeads towards creating biohybrid that can propel themselves towards an attractive chemical source. Using a three-channel microfluidic device, linear chemical gradients are generated to compare the behavior of bacteria-propelled beads in the presence and absence of a chemoattractant, L-aspartate. We tested and compared the behavior of three different bacteria-attached bead sizes (5, 10 and 20 μm diameter) using a visual particle-tracking algorithm, and noted their behavioral differences. The results indicate that in the presence of a chemoattractant, the S. marcescens-attached polystyrene beads exhibit a clear indication of directionality and steering control through the coordination of the bacteria present on each bead. This directionality is observed in all bead size cases, suggesting potential for targeted payload delivery using such a biohybrid micro-robotic approach.


Sub-acute oral toxicity study with fullerene C60 in rats.
To obtain initial information on the possible repeated-dose oral toxicity of fullerene C60, Crl:CD(SD) rats were administered fullerene C60 by gavage once daily at 0 (vehicle: corn oil), 1, 10, 100, or 1,000 mg/kg/day for 29 days, followed by a 14-day recovery period. No deaths occurred in any groups, and there were no changes from controls in detailed clinical observations, body weights, and food consumption in any treatment groups. Moreover, no treatment-related histopathological changes were found in any organs examined at the end of the administration period and at the end of the recovery period. Blackish feces and black contents of the stomach and large intestine were observed in males and females at 1,000 mg/kg/day in the treatment group. There were no changes from controls in the liver and spleen weights at the end of the administration period, but those weights in males in the 1,000 mg/kg/day group increased at the end of the recovery period. Using liquid chromatography-tandem mass spectrometry, fullerene C60 were not detected in the liver, spleen or kidney at the end of the administration period and also at the end of the recovery period. In conclusion, the present study revealed no toxicological effects of fullerene C60; however, the slight increases in liver and spleen weights after the 14-day recovery period may be because of the influence of fullerene C60 oral administration. In the future, it will be necessary to conduct a long-term examination because the effects of fullerene C60 cannot be ruled out.


Prospective analysis of the relation between DSM-III anxiety disorders and alcohol use disorders.
Cross-sectional studies show a robust association between anxiety disorders and alcohol use disorders (comorbidity); however, this methodology does not allow for the testing of causal models. The authors attempted to overcome this limitation by examining comorbid relationships prospectively. Male and female college students were assessed as freshmen (year 1), and then again at years 4 and 7, for selected 12-month anxiety disorders (generalized anxiety disorder, agoraphobia, and social phobia or panic) diagnosed according to the National Institute of Mental Health Diagnostic Interview Schedule (DIS) and DSM-III and for 12-month DIS/DSM-III alcohol use disorders (alcohol dependence alone and alcohol abuse or dependence). Cross-sectionally, the odds of having either an anxiety disorder or an alcohol use disorder were two- to fivefold greater when the other condition was present. Prospectively, the odds of developing a new alcohol dependence diagnosis at year 7 increased from 3.5 to five times for those diagnosed with an anxiety disorder at years 1 or 4. Conversely, the odds of developing a new anxiety disorder at year 7 increased by about four times for those diagnosed with alcohol dependence at years 1 or 4. When alcohol abuse and dependence were combined, the pattern of findings was similar, albeit weaker. Multivariate path models provide similar results and highlight the reciprocal influence of alcohol use disorders and anxiety disorders. Alcohol use disorders (especially alcohol dependence) and anxiety disorders demonstrate a reciprocal causal relationship over time, with anxiety disorders leading to alcohol dependence and vice versa.


Statewide Longitudinal Hospital Use and Charges for Pediatric and Adolescent Patients With Cancer.
We investigated longitudinal hospitalization outcomes (total charges, hospital days and admissions) among pediatric and adolescent patients with cancer compared with individuals from the general population without cancer using a novel and efficient three-step regression procedure. The statewide Utah Population Database, with linkages to the Utah Cancer Registry, was used to identify 1,651 patients who were diagnosed with cancer from 1996 to 2009 at ages 0 to 21 years. A comparison group of 4,953 same-sex and -age individuals was generated from birth certificates. Claims-based hospitalization data from 1996 to 2012 were retrieved from the Utah Department of Health. Using the regression method, we estimated survival (differences due to survival) and intensity (differences due to resource accumulation) effects of the cancer diagnosis on hospitalization outcomes within 10 years after diagnosis. At 10 years after diagnosis, on average, patients with cancer incurred $51,723 (95% CI, $48,100 to $58,284) more in charges, spent 30 additional days (95% CI, 27.7 to 36.1 days) in the hospital, and had 5.7 (95% CI, 5.4 to 6.4) more admissions than the comparison group. Our analyses showed that the highest hospitalization burden occurred during the first 4 years of diagnosis. Patients with leukemia incurred the greatest hospitalization burden throughout the 10 years from diagnosis. Intensity effects explained the majority of differences in hospital outcomes. Our results suggest that children and adolescents who were diagnosed with cancer in 2014 in the United States will incur over $800 million more in hospital charges than individuals without cancer by 2024. Interventions to reduce this burden should be explored in conjunction with improving health and survival outcomes.


An eight-year study of online lecture use in a medical gross anatomy and embryology course.
Online lectures have been used in lieu of live lectures in our gross anatomy and embryology course for the past eight years. We examined patterns of online lecture use by our students and related that use to academic entry measures, gender and examination performance. Detailed access records identified by student were available from server logs. Total views per page of lecture material increased over the first six years, then decreased markedly between years seven and eight, possibly due to the recent availability of alternate forms of lecture audio. Lecture use peaked in midafternoon and again in the evening, although some use was seen at all hours. Usage was highest at midweek and lowest on Fridays as might be expected. Individual student's use varied widely from rates equivalent to less than one viewing/page to more than three viewings per page. Overall use by male students was greater than that of females and gender-specific differences in the daily pattern were seen. Lecture use was correlated to the Medical College Admission Test(®) (MCAT(®)) Verbal Reasoning and Physical Sciences scores but not to composite MCAT scores or undergraduate grade point average. Overall use appeared to be driven by scheduled team-based learning (TBL) sessions and major examinations. Specific subsets of lecture material were most often viewed before related TBL sessions and again during review for examinations. A small but significant correlation between lecture use and examination and course performance was seen, specifically in the male student population. These findings, along with earlier observations, suggest that varied use of online lectures is attributable to multiple factors.


Assessment of computed tomography derived cricoid cartilage and tracheal dimensions to evaluate degree of cricoid narrowing in brachycephalic dogs.
The aims of this observational, analytical, retrospective study were to (i) obtain computed tomographic (CT) cricoid dimensions (height, width, and transverse-sectional area), (ii) compare the cricoid dimensions between brachycephalic and mesaticephalic breeds, and (iii) compare cricoid cartilage dimensions between dogs without and affected with brachycephalic airway syndrome. The study is important to help to further evaluate and understand the anatomical components of brachycephalic airway syndrome. Measurements were performed in 147 brachycephalic and 59 mesaticephalic dogs. The cricoid cartilage was found to be significantly more oval in Pugs and French Bulldogs compared to mesaticephalic breeds. The cricoid cartilage transverse-sectional area was smallest for the Pug and, after adjusting for weight, significantly smaller for Pugs (P < 0.001), Boston Terriers (P = 0.001), and French Bulldogs (P < 0.001) compared to Jack Russell Terriers. The tracheal transverse-sectional area at C4 of English Bulldogs was significantly smaller than for Jack Russell Terriers (P = 0.005) and Labradors (P < 0.001). The cricoid cartilage transverse-sectional area:weight ratio was significantly lower in brachycephalic breeds compared to mesaticephalic breeds (P < 0.001). The cricoid cartilage:trachea at C4 transverse-sectional area for brachycephalic dogs was significantly larger than for mesaticephalic dogs (<0.001), demonstrating that the trachea was the narrowest part of the airway. No significant differences were found for cricoid dimensions between dogs affected with and without brachycephalic airway syndrome. However, large individual variation was found among the brachycephalic breeds and further studies investigating the relationship between cricoid cartilage size, laryngeal collapse, concurrent tracheal hypoplasia, and/or severity of brachycephalic airway syndrome are warranted.


SBaddon: high performance simulation for the Systems Biology Toolbox for MATLAB.
We present the SBaddon package as an extension to the Systems Biology Toolbox for MATLAB (SBtoolbox). The goal of this extension is to provide the users of the SBtoolbox with important functionality that is needed for parameter estimation applications. While simulation in the SBtoolbox relies on the MATLAB ODE solvers, the SBaddon package provides considerably increased simulation performance through automatic generation of compiled simulation functions. Furthermore, the package contains improved optimization algorithms, forward parameter sensitivity analysis and basic numeric parameter identifiability analysis. The SBaddon package is open source and freely available for non-commercial use. Commercial use of SBaddon is only possible through a specific licensing agreement (contact email@example.com). SBaddon can be obtained from http://www.sbtoolbox.org/SBaddon. The website also contains extensive documentation, and examples.


Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure.
Manganese (Mn) is an essential trace element, but overexposure is characterized by Parkinson's like symptoms in extreme cases. Previous studies have shown that Mn accumulation is exacerbated by dietary iron deficiency (ID) and disturbances in norepinephrine (NE) have been reported. Because behaviors associated with Mn neurotoxicity are complex, the goal of this study was to examine the effects of Mn exposure and ID-associated Mn accumulation on NE uptake in synaptosomes, extracellular NE concentrations, and expression of NE transport and receptor proteins. Sprague-Dawley rats were assigned to four dietary groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn exposure (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn (IDMn). (3)H-NE uptake decreased significantly (R=-0.753, p=0.001) with increased Mn concentration in the locus coeruleus, while decreased Fe was associated with decreased uptake of (3)H-NE in the caudate putamen (R=0.436, p=0.033) and locus coeruleus (R=0.86; p<0.001). Extracellular concentrations of NE in the caudate putamen were significantly decreased in response to Mn exposure and ID (p<0.001). A diverse response of Mn exposure and ID was observed on mRNA and protein expression of NE transporter (NET) and alpha(2) adrenergic receptor. For example, elevated brain Mn and decreased Fe caused an approximate 50% decrease in NET and alpha(2) adrenergic receptor protein expression in several brain regions, with reductions in mRNA expression also observed. These data suggest that Mn exposure results in a decrease in NE uptake and extracellular NE concentrations via altered expression of transport and receptor proteins.


Restorative neurology in movement disorders.
Cell replacement for restoration of neurological functions in patients with movement disorders has been investigated for more than 15 years. Initial attempts used autologous adrenal medulla grafts implanted into the denervated striatum of patients with Parkinson's disease (PD). This approach was soon abandoned in favor of intrastriatal implantation of human embryonic mesencephalic tissue, rich in dopaminergic neurons. Available data from grafted PD patients show long-term (up to 10 years) graft survival and clinical benefits. The pattern and magnitude of symptomatic relief following transplantation, however, are incomplete and the outcome varies among patients. The need for large amounts of human embryonic tissue has to be circumvented and a better understanding of the relationship between graft placement and symptomatic recovery is necessary before this procedure can be offered to larger groups of patients. Clinical trials in Huntington's disease have so far shown inconclusive results. Neural cell replacement therapy is still an experimental procedure, but has the potential to become a future restorative treatment in PD and other movement disorders.


Identifying Children at Very Low Risk for Blunt Intra-Abdominal Injury in Whom CT of the Abdomen Can Be Avoided Safely.
Computed tomography is commonly used to rule out intra-abdominal injury (IAI) in children, despite associated cost and radiation exposure. Our purpose was to derive a prediction rule to identify children at very low risk for IAI after blunt abdominal trauma (BAT) for whom a CT scan of the abdomen would be unnecessary. We prospectively enrolled children younger than 16 years of age who presented after BAT at 14 Level I pediatric trauma centers during 1 year. We excluded patients who presented more than 6 hours after injury or underwent abdominal CT before transfer. We used binary recursive partitioning to derive a prediction rule identifying children at very low risk of IAI and IAI requiring acute intervention (IAI-I) using clinical information available in the trauma bay. We included 2,188 children with a median age of 8 years. There were 261 patients with IAI (11.9%) and 62 patients with IAI-I (2.8%). The prediction rule consisted of (in descending order of significance): aspartate aminotransferase >200 U/L, abnormal abdominal examination, abnormal chest x-ray, report of abdominal pain, and abnormal pancreatic enzymes. The rule had a negative predictive value of 99.4% for IAI and 100.0% for IAI-I in patients with none of the prediction rule variables present. The very-low-risk population consisted of 34% of the patients and 23% received a CT scan. Computed tomography frequency ranged from 4% to 96% by center. A prediction rule using history and physical examination, chest x-ray, and laboratory evaluation at the time of presentation after BAT identifies children at very low risk for IAI for whom CT can be avoided.


Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know.
Coronavirus disease 2019 is an emerging disease with a rapid increase in cases and deaths since its first identification in Wuhan, China, in December 2019. Limited data are available about coronavirus disease 2019 during pregnancy; however, information on illnesses associated with other highly pathogenic coronaviruses (ie, severe acute respiratory syndrome and the Middle East respiratory syndrome) might provide insights into coronavirus disease 2019's effects during pregnancy. Coronaviruses cause illness ranging in severity from the common cold to severe respiratory illness and death. Currently the primary epidemiologic risk factors for coronavirus disease 2019 include travel from mainland China (especially Hubei Province) or close contact with infected individuals within 14 days of symptom onset. Data suggest an incubation period of ∼5 days (range, 2-14 days). Average age of hospitalized patients has been 49-56 years, with a third to half with an underlying illness. Children have been rarely reported. Men were more frequent among hospitalized cases (54-73%). Frequent manifestations include fever, cough, myalgia, headache, and diarrhea. Abnormal testing includes abnormalities on chest radiographic imaging, lymphopenia, leukopenia, and thrombocytopenia. Initial reports suggest that acute respiratory distress syndrome develops in 17-29% of hospitalized patients. Overall case fatality rate appears to be ∼1%; however, early data may overestimate this rate. In 2 reports describing 18 pregnancies with coronavirus disease 2019, all were infected in the third trimester, and clinical findings were similar to those in nonpregnant adults. Fetal distress and preterm delivery were seen in some cases. All but 2 pregnancies were cesarean deliveries and no evidence of in utero transmission was seen. Data on severe acute respiratory syndrome and Middle East respiratory syndrome in pregnancy are sparse. For severe acute respiratory syndrome, the largest series of 12 pregnancies had a case-fatality rate of 25%. Complications included acute respiratory distress syndrome in 4, disseminated intravascular coagulopathy in 3, renal failure in 3, secondary bacterial pneumonia in 2, and sepsis in 2 patients. Mechanical ventilation was 3 times more likely among pregnant compared with nonpregnant women. Among 7 first-trimester infections, 4 ended in spontaneous abortion. Four of 5 women with severe acute respiratory syndrome after 24 weeks' gestation delivered preterm. For Middle East respiratory syndrome, there were 13 case reports in pregnant women, of which 2 were asymptomatic, identified as part of a contact investigation; 3 patients (23%) died. Two pregnancies ended in fetal demise and 2 were born preterm. No evidence of in utero transmission was seen in severe acute respiratory syndrome or Middle East respiratory syndrome. Currently no coronavirus-specific treatments have been approved by the US Food and Drug Administration. Because coronavirus disease 2019 might increase the risk for pregnancy complications, management should optimally be in a health care facility with close maternal and fetal monitoring. Principles of management of coronavirus disease 2019 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), laboratory testing for the virus and coinfection, fetal and uterine contraction monitoring, early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations. Information on coronavirus disease 2019 is increasing rapidly. Clinicians should continue to follow the Centers for Disease Control and Prevention website to stay up to date with the latest information (https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html).


Enzyme activities in the oral fluids of patients suffering from bulimia: a controlled clinical trial.
Patients with bulimia nervosa are at high risk for dental erosion. However, not all bulimic patients suffer from erosion, irrespective of the severity of their eating disorder. It is often speculated that differences in the saliva are important, however, little is known about salivary parameters in bulimic patients, particularly directly after vomiting. The aim of the clinical trial was to compare different salivary parameters of subjects suffering from bulimia with those of healthy controls. Twenty-eight subjects participated (14 patients with bulimia nervosa, 7 of them with erosion; 14 matched healthy controls). Resting and stimulated saliva of all participants was analysed as well as saliva collected from bulimic patients directly and 30 min after vomiting. Parameters under investigation were flow rate, pH, buffering capacity and the enzyme activities of proteases in general, collagenase, pepsin, trypsin, amylase, peroxidase, and lysozyme. Regarding flow rate, pH and buffering capacity only small differences were found between groups; buffering capacity directly after vomiting was significantly lower in bulimic subjects with erosion than in subjects without erosion. Differences in enzymatic activities were more pronounced. Activities of proteases, collagenase and pepsin in resting and proteases in stimulated saliva were significantly higher in bulimic participants with erosion than in controls. Peroxidase activity was significantly decreased by regular vomiting. Proteolytic enzymes seem to be relevant for the initiation and progression of dental erosion directly after vomiting, maybe by both hydrolysis of demineralized dentine structures as well as modulation of the pellicle layer.


Density-dependent male mating harassment, female resistance, and male mimicry.
Genetic variation in female resistance and tolerance to male mating harassment can affect the outcome of sexually antagonistic mating interactions. We investigated female mating rates and male mating harassment in natural populations of a damselfly (Ischnura elegans). This damselfly species has a heritable sex-limited polymorphism in females, where one of the morphs is a male mimic (androchrome females). The three female morphs differ in mating rates, and these differences are stable across populations and years. However, the degree of premating resistance toward male mating attempts varied across generations and populations. Male mating harassment of the female morphs changed in a density-dependent fashion, suggesting that male mate preferences are plastic and vary with the different morph densities. We quantified morph differences in male mating harassment and female fecundity, using path analysis and structural equation modeling. We found variation between the morphs in the fitness consequences of mating, with the fecundity of one of the nonmimetic morphs declining with increasing male mating harassment. However, androchrome females had lower overall fecundity, presumably reflecting a cost of male mimicry. Density-dependent male mating harassment on the morphs and fecundity costs of male mimicry are thus likely to contribute to the maintenance of this female polymorphism.


Hydroxychloroquine and Coronavirus Disease 2019: A Systematic Review of a Scientific Failure.
Hydroxychloroquine (HCQ) emerged early in the course of the coronavirus disease 2019 (COVID-19) pandemic as a possible drug with potential therapeutic and prophylactic benefits. It was quickly adopted in China, Europe, and the USA. We systematically reviewed the existing clinical evidence of HCQ use for the prevention and treatment of COVID-19. We screened for clinical studies describing HCQ administration to treat or prevent COVID-19 in PubMed. We included randomized controlled trials (RCTs), non-randomized comparative cohorts, and case series studies that had all undergone peer review. A total of 623 studies were screened; 17 studies evaluating HCQ treatment were included. A total of 13 were observational studies, and 4 were RCTs. In terms of effect on mortality rates, observational studies provided conflicting results. As a whole, RCTs, including one large British RCT that has not yet been published, showed no significant effect of HCQ on mortality rates, clinical cure, and virologic response. The use of HCQ as a post-exposure prophylactic agent was found to be ineffective in one RCT. There is no evidence supporting HCQ for prophylaxis or treatment of COVID-19. Many observational trials were methodologically flawed. Scientific efforts have been disappointingly fragmented, and well-conducted trials have only recently been completed, more than 7 months and 600,000 deaths into the pandemic.


Comparing the Efficacy of Peritonsillar Injection of Tramadol With Honey in Controlling Post-Tonsillectomy Pain in Adults.
The authors investigated the effect of honey on post-tonsillectomy pain and compare its efficacy with tramadol. This clinical trial was performed on 60 patients with American Society of Anesthesia I and II aged between 18 and 55 years and underwent tonsillectomy. Induction of anesthesia was carried out using 2 mg/kg propofol and 0.5 atracurium following 1.5 μg/kg fentanyl administration. Group B was given tramadol at dose of 2 mg/kg and with volume of 4 mL and Group A was given normal saline with the same volume 2 mL of medications were injected using needle (25) into tonsil bed and anterior old of each tonsil by an anesthesiologist. Three minutes after injection, the surgery was performed by the same ENT residents for all patients. In the recovery room Group B received antibiotics and oral acetaminophen. Group A was given antibiotics, oral acetaminophen, and honey dissolved in 40 mL warm water every 6 hours from when the patient was fully awake. Patients in Group A were told to eat honey 3 times a day 7 days postoperatively. Pain was scored using Numeric Rating Scale at the time points of 2, 6, 12, and 24 hours as well as 3 and 7 days postoperatively. Moreover, the healing status and epithelialization degree of tonsillar bed were considered on 1 and 7 days after the surgery by ENT specialist. The mean of pain score was significantly higher in Group A within 24 hours postoperatively as compared with Group B (P < 0.01). The mean of pain score was lower in Group B after 3 and 7 days but this difference was not statistically significant (P > 0.05). Considering restoration status and epithelialization degree of tonsillar bed on the 1st and 7th days, there was no statistically significant difference between 2 groups; however, tonsillar bed healing process was better in Group B on the 7th day. The current investigation confirmed the positive impact of tramadol on post-tonsillectomy pain relief in adults. The authors also found that honey can be used as a complementary treatment along with acetaminophen and other analgesics for reducing post-tonsillectomy pain. Considering honey impact on wound healing and its anti-inflammatory effect, it is suggested for relieving complications after surgery.


Substandard, falsified and unregistered medicines in Latin America, 2017-2018.
To assess all the incidents of substandard, falsified and unregistered medicines in 2017 and 2018 in Latin America, determining the types of products affected, stages of the supply chain in which incidents were detected, quality deviations identified in tested samples, and regulatory measures taken by authorities. A comprehensive search of the websites of the Latin American national regulatory authorities was conducted, identifying all eligible incidents during 2017-2018. Standardized values were collected from each incident for pre-determined variables: country, year, type of incident, therapeutic group, supply chain, regulatory measures and laboratory data. A total of 596 incidents in 13 countries were included (236 substandard, 239 falsified, 116 unregistered and 5 stolen). The therapeutic categories with the highest incidents were: anti-infectives, medicines for pain/palliative care, hormones/contraceptives, medicines for the respiratory tract, and medicines for mental/behavioural disorders. The most common places where incidents were detected were commercial establishments, pharmacies, health services and manufacturers. The most recurrent quality deviations were failure in parameters (appearance or physicochemical), incorrect labelling, different quantity of active pharmaceutical ingredient, presence of unknown particles, and microbiological contamination. The most frequent regulatory measures identified were alerts, withdrawals, seizures, and prohibition of marketing/distribution/use. In Latin America, substandard, falsified and unregistered medicines persist as a highly prevalent problem. An advanced degree of regulatory development in countries is associated with higher incident detection/reporting rates and a more comprehensive set of measures. The pharmaceutical supply chain is more vulnerable in its final node. Quality deviations identified in tested samples pose serious risks to public health.


Temperature effects in AgGaS2 nonlinear devices.
Refractive indices of AgGaS2 crystal are measured at different temperatures using the classical minimum deviation technique and are fitted in appropriate dispersion relations. The variation of pump laser wavelength for noncritical upconversion of signal at 10.6 microm with the change in crystal temperature has been verified using the above data. Temperature tunable infrared generation by noncritically phase-matched difference- frequency mixing has been predicted from 3 to 18 microm.


Gravitational Mechanisms to Self-Tune the Cosmological Constant: Obstructions and Ways Forward.
Gravitational models of self-tuning are those in which vacuum energy has no observable effect on spacetime curvature, even though it is a priori unsuppressed below the cutoff. We complement Weinberg's no-go theorem by studying field-theoretic completions of self-adjustment allowing for broken translations as well as other generalizations, and identify new obstructions. Our analysis uses a very general Källén-Lehmann spectral representation of the exchange amplitude for conserved sources of energy-momentum and exploits unitarity and Lorentz invariance to show that a transition from self-tuning of long wavelength sources to near general relativity (GR) on shorter scales is generically not possible. We search for novel ways around our obstructions and highlight two interesting possibilities. The first is an example of a unitary field configuration on anti-de Sitter space with the desired transition from self-tuning to GR. A second example is motivated by vacuum energy sequestering.


Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.
Alzheimer's disease (AD) is characterized by deposition of beta-amyloid (Abeta) in diffuse and senile plaques, and variably in vessels. Mutations in the Abeta-encoding region of the amyloid precursor protein (APP) gene are frequently associated with very severe forms of vascular Abeta deposition, sometimes also accompanied by AD pathology. We earlier described a Flemish APP (A692G) mutation causing a form of early-onset AD with a prominent cerebral amyloid angiopathy and unusually large senile plaque cores. The pathogenic basis of Flemish AD is unknown. By image and mass spectrometric Abeta analyses, we demonstrated that in contrast to other familial AD cases with predominant brain Abeta42, Flemish AD patients predominantly deposit Abeta40. On serial histological section analysis we further showed that the neuritic senile plaques in APP692 brains were centered on vessels. Of a total of 2400 senile plaque cores studied from various brain regions from three patients, 68% enclosed a vessel, whereas the remainder were associated with vascular walls. These observations were confirmed by electron microscopy coupled with examination of serial semi-thin plastic sections, as well as three-dimensional observations by confocal microscopy. Diffuse plaques did not associate with vessels, or with neuritic or inflammatory pathology. Together with earlier in vitro data on APP692, our analyses suggest that the altered biological properties of the Flemish APP and Abeta facilitate progressive Abeta deposition in vascular walls that in addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish variant of AD.


Sensitization of hypoxic tumour cells--clinical experience.
There is substantial evidence for the presence of hypoxia in human tumours. This is documented by histopathological demonstration of vascular insufficiency, direct oxygen measurements in tumours, as well as by physiological imaging and mapping of hypoxic areas. As a consequence, clinical trials have focused on the hypoxia problem for more than 30 years. This includes the use of hyperbaric oxygen, hypoxic cell radiosensitizers, and, more recently, modification of the oxygen-unloading capacity of haemoglobin. Agents directed towards destruction of hypoxic cells have also been applied, such as hyperthermia and bio-reductive drugs. Despite decades of clinical trials, the results are still inconclusive, and although some trials have shown significant benefit, it has become apparent that hypoxia is a complex problem. Hypoxia appears to be especially a problem in certain tumour types (e.g. squamous cell carcinoma), but even within tumours of the same type, site, and stage, hypoxia does not occur to the same extent. Furthermore, there are increasing suggestions that hypoxia may occur in two principally different ways, namely acutely and chronically, yielding varying responses to modifying agents. Although improvement in hypoxic cell radiosensitizers and other agents is under way, a definitive solution to the hypoxia problem will not be found until the tumours in which hypoxia occurs can be identified. This will require detailed analysis of individual tumours and patients' parameters, and better knowledge of the mechanisms of reoxygenation in clonogenic tumour cells.


Zinc intake, zinc status and growth in a longitudinal study of healthy Danish infants.
Mild, growth-limiting zinc deficiency might be prevalent in otherwise healthy infants according to recent studies. We examined zinc intake and status in 91 healthy term infants from birth to 12 months, as part of the Copenhagen Cohort Study on Infant Nutrition and Growth. Zinc intake was recorded monthly and the amount of zinc absorbed was estimated. These estimates were below recently published FAO/WHO/IAEA values for basal requirements in 68%, 62% and 14% of the infants at 2, 4 and 9 months of age, respectively. Serum zinc decreased significantly (p < 0.01) from 10.6 mumol/l at 6 months to 8.4 mumol/l at 9 months of age (normal range 10-18 mumol/l). Erythrocyte metallothionein values, a tentative indicator of long-term zinc status, decreased significantly from 2 to 6 months (p < 0.001) and from 6 to 9 months (p < 0.01). Serum zinc at 9 months was positively associated with growth velocity during the period from 6 to 9 months (weight: p = 0.05; knee-heel length: p = 0.002). The results provide descriptive data on zinc intake and zinc status in healthy Danish infants. Although some of our data suggest suboptimal zinc status during late infancy, evidence for this can only be obtained through a randomized intervention study.


Comparative effects of 2 aqua exercise programs on physical function, balance, and perceived quality of life in older adults with osteoarthritis.
Osteoarthritis (OA) is a degenerative joint disease, which affects a large number of older adults. Many older adults with OA are physically inactive, which can contribute to reduced functional capability, quality of life, and an increased risk of falls. Although hydrotherapy is often recommended for older adults with OA, less is known about aqua fitness (AF), a widely available form of aqua-based exercise. To compare the effect of an AF program and a seated aqua-based exercise program on a range of functional measures and quality of life among older adults with OA. Thirty-five older adults with OA were allocated to an AF group or an active control group who performed seated exercises in warm water for 12 weeks. The primary outcome measure was the timed up-and-go (TUG) test; other measures included step test, sit-to-stand (STS) test, handgrip strength test, 400-m walk test, Arthritis Impact Measurement Scale-Short Form (AIMS2-SF), and Falls Efficacy Scale-International (FES-I). FES-I scores improved significantly in the AF group compared with the control group (P=0.04). Within-group analysis indicated both groups significantly improved their 400-m walk time (P=0.04) and that the AF group significantly improved its step test right (P=0.02) and left (P=0.00) and the AIMS2-SF total score (P=0.02). No significant change in TUG, STS, or handgrip strength was observed for either group. Aqua fitness may offer a number of positive functional and psychosocial benefits for older adults with OA, such as a reduced fear of falling and increased ability to perform everyday tasks.


The control of mimicry by eye contact is mediated by medial prefrontal cortex.
Spontaneous mimicry of other people's actions serves an important social function, enhancing affiliation and social interaction. This mimicry can be subtly modulated by different social contexts. We recently found behavioral evidence that direct eye gaze rapidly and specifically enhances mimicry of intransitive hand movements (Wang et al., 2011). Based on past findings linking medial prefrontal cortex (mPFC) to both eye contact and the control of mimicry, we hypothesized that mPFC might be the neural origin of this behavioral effect. The present study aimed to test this hypothesis. During functional magnetic resonance imaging (fMRI) scanning, 20 human participants performed a simple mimicry or no-mimicry task, as previously described (Wang et al., 2011), with direct gaze present on half of the trials. As predicted, fMRI results showed that performing the task activated mirror systems, while direct gaze and inhibition of the natural tendency to mimic both engaged mPFC. Critically, we found an interaction between mimicry and eye contact in mPFC, superior temporal sulcus (STS) and inferior frontal gyrus. We then used dynamic causal modeling to contrast 12 possible models of information processing in this network. Results supported a model in which eye contact controls mimicry by modulating the connection strength from mPFC to STS. This suggests that mPFC is the originator of the gaze-mimicry interaction and that it modulates sensory input to the mirror system. Thus, our results demonstrate how different components of the social brain work together to on-line control mimicry according to the social context.


The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition.
The cation-Cl- cotransporter KCC2, encoded by SLC12A5, is required for the emergence and maintenance of GABAergic fast synaptic inhibition in organisms across evolution. These findings have suggested that KCC2 deficiency might play a role in the pathogenesis human epilepsy, but this has only recently been substantiated by two lines of genetic evidence. The first is the discovery of heterozygous missense polymorphisms in SLC12A5, causing decreased KCC2-dependent Cl- extrusion capacity, in an Australian family with inherited febrile seizures and in a French-Canadian cohort with severe genetic generalized epilepsy (GGE). The second is the discovery of recessive loss-of-function mutations in SLC12A5 in patients with a severe, early-onset Mendelian disease termed "epilepsy of infancy with migrating focal seizures" (EIMFS). These findings collectively support the paradigm that precisely regulated KCC2 activity is required for synaptic inhibition in humans, and that genetically encoded impairment of KCC2 function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence epilepsy phenotypes in patients. Accordingly, KCC2 could be a target for a novel antiepileptic strategies that aims to restore GABA inhibition by facilitating Cl- extrusion. Such drugs could have relevance for pharmaco-resistant epilepsies and possibly other diseases characterized by synaptic hyperexcitability, such as the spectrum autism disorders.


Drosophila suzukii (Diptera: Drosophilidae) Oviposition and Adult Emergence in Six Wine Grape Varieties Grown in Virginia.
Drosophila suzukii (Matsumura) is a pest of small fruits and grapes in the United States and in its home range of Japan. Physiological and morphological laboratory testing was performed on six commonly grown wine grape varieties in Virginia. Skin thickness, penetration force, and ºBrix were analyzed to determine ovipositional preferences. Experiments were performed for three consecutive years from grapes collected at one Virginia vineyard. More eggs were laid in intact Viognier grapes than any other variety. Oviposition into intact grapes was not affected by skin thickness or ºBrix; however, oviposition increased when penetration force decreased. An ovipositional choice test determined no varietal preferences. Survivorship from egg to adulthood using uninjured and injured grapes was also assessed to determine varietal suitability as D. suzukii hosts, with more flies emerging from injured grapes than uninjured. However, D. suzukii adults did emerge from intact grapes and at higher percentages than previously recorded in other wine grape studies. All varieties had eggs oviposited into them when injured. Determining the time at which each grape variety became susceptible to oviposition was determined using a D. suzukii bioassay spanning 12 wk using grapes from the green pea stage until ripe. Susceptibility to D. suzukii oviposition was based upon ripening period and penetration force. Early ripening varieties may be more susceptible to D. suzukii oviposition in the field with later maturing, harder fleshed-varieties which may escape D. suzukii oviposition.


Expression of the cytochrome P450s, CYP6P3 and CYP6M2 are significantly elevated in multiple pyrethroid resistant populations of Anopheles gambiae s.s. from Southern Benin and Nigeria.
Insecticide resistance in Anopheles mosquitoes is threatening the success of malaria control programmes. This is particularly true in Benin where pyrethroid resistance has been linked to the failure of insecticide treated bed nets. The role of mutations in the insecticide target sites in conferring resistance has been clearly established. In this study, the contribution of other potential resistance mechanisms was investigated in Anopheles gambiae s.s. from a number of localities in Southern Benin and Nigeria. The mosquitoes were sampled from a variety of breeding sites in a preliminary attempt to investigate the role of contamination of mosquito breeding sites in selecting for resistance in adult mosquitoes. All mosquitoes sampled belonged to the M form of An. gambiae s.s. There were high levels of permethrin resistance in an agricultural area (Akron) and an urban area (Gbedjromede), low levels of resistance in mosquito samples from an oil contaminated site (Ojoo) and complete susceptibility in the rural Orogun location. The target site mutation kdrW was detected at high levels in two of the populations (Akron f = 0.86 and Gbedjromede f = 0.84) but was not detected in Ojoo or Orogun. Microarray analysis using the Anopheles gambiae detox chip identified two P450s, CYP6P3 and CYP6M2 up regulated in all three populations, the former was expressed at particularly high levels in the Akron (12.4-fold) and Ojoo (7.4-fold) populations compared to the susceptible population. Additional detoxification and redox genes were also over expressed in one or more populations including two cuticular pre-cursor genes which were elevated in two of the three resistant populations. Multiple resistance mechanisms incurred in the different breeding sites contribute to resistance to permethrin in Benin. The cytochrome P450 genes, CYP6P3 and CYP6M2 are upregulated in all three resistant populations analysed. Several additional potential resistance mechanisms were also identified that warrant further investigation. Metabolic genes were over expressed irrespective of the presence of kdr, the latter resistance mechanism being absent in one resistant population. The discovery that mosquitoes collected from different types of breeding sites display differing profiles of metabolic genes at the adult stage may reflect the influence of a range of xenobiotics on selecting for resistance in mosquitoes.


Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?
Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.


Amino acid transporters expression in acinar cells is changed during acute pancreatitis.
Pancreatic acinar cells accumulate amino acids against a marked concentration gradient to synthesize digestive enzymes. Thus, the function of acinar cells depends on amino acid uptake mediated by active transport. Despite the importance of this process, pancreatic amino acid transporter expression and cellular localization is still unclear. We screened mouse pancreas for the expression of genes encoding amino acid transporters. We showed that the most highly expressed transporters, namely sodium dependent SNAT3 (Slc38a3) and SNAT5 (Slc38a5) and sodium independent neutral amino acids transporters LAT1 (Slc7a5) and LAT2 (Slc7a8), are expressed in the basolateral membrane of acinar cells. SNAT3 and SNAT5, LAT1 and LAT2 are expressed in acinar cells. Additional evidence that these transporters are expressed in mature acinar cells was gained using acinar cell culture and acute pancreatitis models. In the acute phase of pancreatic injury, when acinar cell loss occurs, and in an acinar cell culture model, which mimics changes occurring during pancreatitis, SNAT3 and SNAT5 are strongly down-regulated. LAT1 and LAT2 were down-regulated only in the in vitro model. At protein level, SNAT3 and SNAT5 expression was also reduced during pancreatitis. Expression of other amino acid transporters was also modified in both models of pancreatitis. The subset of transporters with differential expression patterns during acute pancreatitis might be involved in the injury/regeneration phases. Further expression, localization and functional studies will follow to better understand changes occurring during acute pancreatitis. These findings provide insight into pancreatic amino acid transport in healthy pancreas and during acute pancreatitis injury.


A topological algorithm for identification of structural domains of proteins.
Identification of the structural domains of proteins is important for our understanding of the organizational principles and mechanisms of protein folding, and for insights into protein function and evolution. Algorithmic methods of dissecting protein of known structure into domains developed so far are based on an examination of multiple geometrical, physical and topological features. Successful as many of these approaches are, they employ a lot of heuristics, and it is not clear whether they illuminate any deep underlying principles of protein domain organization. Other well-performing domain dissection methods rely on comparative sequence analysis. These methods are applicable to sequences with known and unknown structure alike, and their success highlights a fundamental principle of protein modularity, but this does not directly improve our understanding of protein spatial structure. We present a novel graph-theoretical algorithm for the identification of domains in proteins with known three-dimensional structure. We represent the protein structure as an undirected, unweighted and unlabeled graph whose nodes correspond to the secondary structure elements and edges represent physical proximity of at least one pair of alpha carbon atoms from two elements. Domains are identified as constrained partitions of the graph, corresponding to sets of vertices obtained by the maximization of the cycle distributions found in the graph. When a partition is found, the algorithm is iteratively applied to each of the resulting subgraphs. The decision to accept or reject a tentative cut position is based on a specific classifier. The algorithm is applied iteratively to each of the resulting subgraphs and terminates automatically if partitions are no longer accepted. The distribution of cycles is the only type of information on which the decision about protein dissection is based. Despite the barebone simplicity of the approach, our algorithm approaches the best heuristic algorithms in accuracy. Our graph-theoretical algorithm uses only topological information present in the protein structure itself to find the domains and does not rely on any geometrical or physical information about protein molecule. Perhaps unexpectedly, these drastic constraints on resources, which result in a seemingly approximate description of protein structures and leave only a handful of parameters available for analysis, do not lead to any significant deterioration of algorithm accuracy. It appears that protein structures can be rigorously treated as topological rather than geometrical objects and that the majority of information about protein domains can be inferred from the coarse-grained measure of pairwise proximity between elements of secondary structure elements.


Burden among partner caregivers of patients diagnosed with localized prostate cancer within 1 year after diagnosis: an economic perspective.
Informal care plays an important role in the overall care for people with cancer. This study estimates lost productivity and informal caregiving and associated costs among partner caregivers of localized prostate cancer patients within 1 year after diagnosis. We applied data from the Family and Cancer Therapy Selection study, a three-wave self-administered survey among patients diagnosed with localized prostate cancer and their partner caregivers in multiple clinics in the USA. Time spent was measured by the sum of working hours lost, informal caregiving hours performed, and hours spent on household chores. The national median income for women 55 years or older was used to calculate costs associated with the time spent using the opportunity cost method. Descriptive and bivariate analyses were conducted. The average working hours decreased from 14.0 h/week (SD = 17.6) to 10.9 h/week (SD = 15.9), without a significant change in responsibility/intensity at work. The mean annual time spent on informal caregiving and household chores was 65.9 h/year (SD = 172.4) and 76.2 h/year (SD = 193.3), respectively. The mean annual economic burden among partner caregivers was US$6,063 (range US$571-US$47,105) in 2009 dollars accounted for by a mean of 276.2 h (range 26-2,146) in the study sample. The time spent on informal caregiving and household chores varied by patient and caregiver characteristics. Pilot estimates on non-medical economic burden among partner caregivers (spouses) during the initial phase of the treatment provide important information for comprehensive estimation of disease burden and can be used in cost-effectiveness analyses of prostate cancer interventions.


Impact of early rasburicase on incidence of clinical tumor lysis syndrome in lymphoma.
Early administration of rasburicase to enhance uric acid (UA) elimination has been adopted without robust evidence in support of its impact on clinical outcomes in tumor lysis syndrome (TLS), specifically, the prevention of acute kidney injury (AKI). This was a retrospective cohort study of adult lymphoma patients at intermediate or high risk for TLS. Excluded patients had AKI or were on dialysis at hospital admission. The incidence of new AKI in the setting of TLS was described along with predictors of its development, including early rasburicase use. In 383 included patients, the incidence of new-onset AKI during hospitalization was 6%. Predictors included age, history of renal or cardiovascular disease, and UA >8 mg/dL. Rasburicase use did not significantly impact the risk of developing AKI (HR 2.3; p = .11). The UA level at the time of administration did not modify the effect of rasburicase on prevention of AKI (p = .36 for the interaction term).


Hesperidin-3'-o-methylether is more potent than hesperidin in phosphodiesterase inhibition and suppression of ovalbumin-induced airway hyperresponsiveness.
Hesperidin is present in the traditional Chinese medicine, "Chen Pi," and recently was reported to have anti-inflammatory effects. Therefore, we were interested in comparing the effects of hesperidin and hesperidin-3'-O-methylether on phosphodiesterase inhibition and airway hyperresponsiveness (AHR) in a murine model of asthma. In the present results, hesperidin-3'-O-methylether, but not hesperidin, at 30 μmol/kg (p.o.) significantly attenuated the enhanced pause (P(enh)) value, suppressed the increases in numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, suppressed total and OVA-specific immunoglobulin (Ig)E levels in the serum and BALF, and enhanced the level of total IgG(2a) in the serum of sensitized and challenged mice, suggesting that hesperidin-3'-O-methylether is more potent than hesperidin in suppression of AHR and immunoregulation. The different potency between them may be due to their aglycons, because these two flavanone glycosides should be hydrolyzed by β-glucosidase after oral administration. Neither influenced xylazine/ketamine-induced anesthesia, suggesting that they may have few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, hesperidin-3'-O-methylether is more potent in phosphodiesterase inhibition and suppression of AHR and has higher therapeutic (PDE4(H)/PDE4(L)) ratio than hesperidin. Thus, hesperidin-3'-O-methylether may have more potential for use in treating allergic asthma and chronic obstructive pulmonary disease.


Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model.
IDO converts tryptophan to l-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in α-galactosylceramide (α-GalCer)-induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered α-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after α-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-D-tryptophan also exacerbated liver injury in this murine hepatitis model. In α-GalCer-induced hepatitis models, TNF-α is critical in the development of liver injury. The mRNA expression and protein level of TNF-α in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with α-GalCer were analyzed by flow cytometry, and the numbers of CD49b(+) and CD11b(+) cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with α-GalCer, TNF-α secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in α-GalCer-induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-α-producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the α-GalCer-induced hepatitis model.


A calreticulin-like molecule from the human hookworm Necator americanus interacts with C1q and the cytoplasmic signalling domains of some integrins.
Calreticulin was recently identified as a hookworm (Necator americanus) allergen, implying secretion, and contact with cells of the immune system, or significant worm attrition in the tissues of the host. As human calreticulin has been shown to bind to and neutralize the haemolytic activity of the complement component C1q, and to be putatively involved in integrin-mediated intracellular signalling events in platelets, it was of interest to determine whether a calreticulin from a successful nematode parasite of humans, with known immune modulatory and antihaemostatic properties, exhibited a capacity to interfere with complement activation and to interact with integrin domains associated with cell signalling in platelets and other leucocytes. We can now report that recombinant calreticulin failed to demonstrate significant calcium binding capacity, which is a hallmark of calreticulins in general and may indicate inappropriate folding following expression in a prokaryote. Nevertheless, recombinant calreticulin retained sufficient molecular architecture to bind to, and inhibit the haemolytic capacity of, human C1q. Furthermore, recombinant calreticulin reacted in surface plasmon resonance analysis (SPR) with peptides corresponding to cytoplasmic signalling domains of the integrins alphaIIb and alpha5, in a calcium independent manner. SPR was also used to ratify the specificity of a polyclonal antibody to hookworm calreticulin, which was then used to assess the stage specificity of expression of the native molecule (in comparison with reverse transcriptase-polymerase chain reaction), to indicate its apparent secretion, and to purify native calreticulin from worm extracts by affinity chromatography. This development will allow the functional tests described above to be repeated for native calreticulin, to ascertain its role in the host-parasite relationship.


Breakdown of the Static Picture of Defect Energetics in Halide Perovskites: The Case of the Br Vacancy in CsPbBr3.
We consider the Br vacancy in CsPbBr3 as a prototype for the impact of structural dynamics on defect energetics in halide perovskites (HaPs). Using first-principles molecular dynamics based on density functional theory, we find that the static picture of defect energetics breaks down; the energy level associated with a Br vacancy is found to be intrinsically dynamic, oscillating by as much as 1 eV on the picosecond time scale at room temperature. These significant energy fluctuations are correlated with the distance between the neighboring Pb atoms across the vacancy and with the electrostatic potential at these Pb atomic sites. We expect this unusually strong coupling of structural dynamics and defect energetics to bear important implications for both experimental and theoretical analyses of defect characteristics in HaPs. It may also hold significant ramifications for carrier transport and defect tolerance in this class of photovoltaic materials.


Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens.
Physicians typically switch therapies unless clinically relevant thresholds of response are observed, and treatments that produce high-quality responses and that are active in the salvage setting are generally felt to be promising. With the goal of efficiently selecting promising regimens for more advanced trials, we conducted a randomized selection trial of four regimens to identify promising treatments for androgen-independent prostate cancer. Patients without prior exposure to cytotoxic therapy were randomly assigned to one of four regimens (i.e., cyclophosphamide, vincristine, and dexamethasone [CVD]; ketoconazole plus doxorubicin alternating with vinblastine plus estramustine [KA/VE]; weekly paclitaxel, estramustine, and carboplatin [TEC]; paclitaxel, estramustine, and etoposide [TEE]). Patients were evaluated every 8 weeks to assess response and adverse events. Patients who responded continued with the same treatment; those who did not were randomly assigned to one of the other three treatments. Response was assessed by considering tumor-specific symptoms, tumor regression, and prostate-specific antigen (PSA) changes. Treatment was continued until two consecutive courses induced a response (i.e., overall success, the major criterion for which was 80% PSA reduction) or until patients were given two different regimens that failed to induce such a response. Median overall survival from registration among all 150 patients was 22 months (95% confidence interval [CI] = 19 to 26 months). Estimated survival at 3 and 5 years, respectively, was 26% (95% CI = 20% to 35%) and 10% (95% CI = 5% to 16%). Overall success was achieved in 35 patients with the initial treatment (i.e., four treated with CVD, seven with KA/VE, 14 with TEC, and 10 with TEE) and in nine more patients with a second-line regimen (i.e., two with CVD, five with KA/VE, and two with TEC). For all 44 (29%, 95% CI = 23% to 37%) patients with overall success, median survival was 30 months (95% CI = 26 to 40 months); for the other 106 patients, it was 19 months (95% CI = 17 to 22 months). TEC produced the greatest number and proportion of successful courses of treatment, and TEC followed by KA/VE was the most promising two-stage strategy. Some patients responded to particular treatments, and responses to second-line treatments were not rare. We propose that TEC be considered for phase III evaluation.


Exploring the Link Between Daily Relationship Quality, Sexual Desire, and Sexual Activity in Couples.
Current models of sexual responding emphasize the role of contextual and relational factors in shaping sexual behavior. The present study used a prospective diary design to examine the temporal sequence and variability of the link between sexual and relationship variables in a sample of couples. Studying sexual responding in the everyday context of the relationship is necessary to get research more aligned with the complex reality of having sex in a relationship, thereby increasing ecological validity and taking into account the dyadic interplay between partners. Over the course of 21 days, 66 couples reported every day on their sexual desire, sexual activity (every morning), and relationship quality (every evening). In addition, we examined whether the link between these daily variables was moderated by relationship duration, having children, general relationship satisfaction, and sexual functioning. Results showed that the sexual responses of women depended on the relationship context, mainly when having children and being in a longer relationship. Male sexual responding depended less on contextual factors but did vary by level of sexual functioning. Several cross-partner effects were found as well. These results verify that relational and sexual variables feed forward into each other, indicating the need to incorporate interpersonal dynamics into current models of sexual responding and to take into account variability and dyadic influences between partners.


Prevalence of celiac disease among blood donors in São Paulo: the most populated city in Brazil.
Celiac disease is a permanent enteropathy caused by the ingestion of gluten, which leads to an immunemediated inflammation of the small intestine mucosa. The prevalence of celiac disease varies among different nations and ethnic backgrounds, and its diversity is determined by genetic and environmental factors. São Paulo city is one of the largest cities in the world, with a vast population and an important history of internal migratory flow from other Brazilian regions, as well as immigration from other, primarily European, countries, resulting in significant miscegenation. The aim of the present study was to estimate the prevalence of adults with undiagnosed celiac disease among blood donors of São Paulo by collecting information on the ancestry of the population studied. The prevalence of celiac disease was assessed by screening for positive IgA transglutaminase and IgA endomysium antibodies in 4,000 donors (volunteers) in the Fundação Pró-Sangue Blood Center of São Paulo, São Paulo, Brazil. The antibody-positive subjects were asked to undergo a small bowel biopsy. Of the 4,000 subjects, twenty-four had positive tests, although both antibody tests were not always concordant. For example, ten subjects were positive for IgA tissue transglutaminase only. In twenty-one positive patients, duodenal biopsies were performed, and the diagnosis of celiac disease was confirmed in fourteen patients (Marsh criteria modified by Oberhuber). In this group, 67% claimed to have European ancestry, mainly from Italy, Portugal and Spain. The prevalence of celiac disease is at least 1:286 among supposedly healthy blood bank volunteers in São Paulo, Brazil.


Aortic aneurysmal disease: assessment of stent-graft treatment-CT versus conventional angiography.
To compare computed tomographic (CT) angiography and conventional angiography for determining the success of endoluminal stent-graft treatment of aortic aneurysms. Forty patients underwent conventional angiography and CT angiography following treatment of aortoiliac aneurysms with endoluminal stent-grafts. Six additional sets of conventional angiographic-CT angiographic examinations were performed in five patients after placement of additional stent-grafts or coil embolization to treat perigraft leakage. Three faculty CT radiologists who were blinded to patient clinical data and outcome independently interpreted the CT angiograms, and three faculty angiographers, who were not involved in the stent-graft deployment, interpreted the conventional angiograms. Images were assessed for the presence of postdeployment complications. A reference standard was developed by experienced radiologists using all available images and clinical data. Sensitivities, specificities, and kappa values were calculated. Perigraft leakage was the most commonly identified complication. Twenty perigraft leaks were detected in the results of 46 examinations. Sensitivities and specificities for detecting perigraft leakage were 63% and 77% for conventional angiography and 92% and 90% for CT angiography, respectively. The kappa value was 0. 41 for conventional angiography and 0.81 for CT angiography. CT angiography is the preferred method for establishing the presence of perigraft leakage following treatment of aortoiliac aneurysms with stent-grafts.


Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover.
This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42-0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00-4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61-1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.


Sid4: A secreted vertebrate immunoglobulin protein with roles in zebrafish embryogenesis.
The small members of the immunoglobulin superfamily (IGSF) are a molecularly diverse group of proteins composed solely of immunoglobulin domains. They may be secreted or tethered to the cell mebrane via GPI linkages and are proposed to have important functions in vivo. However, very few small IGSFs have been functionally characterized. During an ongoing in situ hybridization analysis of expressed sequence tags in zebrafish we identified secreted immunoglobulin domain 4 (sid4), a gene encoding a soluble vertebrate protein composed solely of four immunoglobulin domains. Throughout development, sid4 is expressed in regions of the embryo undergoing active cell division and migration. Functional analysis using morpholino antisense oligonucleotides demonstrates that timing of gene expression is normal in morphants, but these embryos are smaller and exhibit defects in epiboly and patterning of axial and prechordal mesoderm. Analyses of chordin, pax2, krox20, and dlx2 expression in morphants demonstrate that early brain patterning is normal but later organization of hindbrain neurons and development of cranial neural crest are perturbed. Levels of apoptosis in morphants were normal prior to 90% epiboly, but were elevated after 10 h post-fertilization (hpf). Apoptosis does not account for early patterning defects of axial mesoderm, but likely contributes to overall reduction in embryo size. Phylogenetic analysis demonstrates that Sid4 is strikingly similar to the fibronectin binding Ig domains of Perlecan/HSPG2. Overall, our data demonstrate a fundamental role for sid4, possibly as a co-factor in extracellular matrix (ECM) interactions, in processes underlying tissue patterning and organogenesis in a vertebrate.


EPO protects Müller cell under high glucose state through BDNF/TrkB pathway.
Neurotrophic factor decreased in the early stage of diabetic retinal nerve cells. Neurons damage brain derived neurotrophic factor (BDNF) and receptor TrkB expression reduced. Erythropoietin (EPO) plays an important role in protecting early diabetic retinopathy. The rats were euthanized at 24 h after EPO vitreous injection and the retina was separated. HE staining was applied to observe the pathological tissue morphology. Immunohistochemistry, immunofluorescence, and Western blot were used to detect BDNF, TrkB, extracellular signal-regulated kinase (ERK), and glial fibrillary acidic portein (GFAP) expression. Retinal structure was clear in group C, while the retinal thickness and RGCs number decreased in group B at 24 w. Retinal thickness in group E was greater than in group B but lower than in group C. GFAP and ERK expression increased in both group B and E, whereas the latter was significantly lower than the former. TrkB protein level was in group E > B > C at 4 w, while it was in group C > group E > group B at 24 w. BDNF expression in group B was higher than in group C at 4 w, whereas it was opposite at 24 w. BDNF expression increased in group E at 4 w, and it was similar in group E compared with group C at 24 w. EPO vitreous injection can increase BDNF and TrkB expression, while reduce GFAP and ERK expression in diabetes rat retina. It could protect Müller cells through BDNF/TrkB pathway to play a role of nerve nutrition.


ELISA Serology for Antibodies Against Chlamydia trachomatis in Crohn's Disease.
Recently we reported IgA anti-Chlamydia antibodies in patients with Crohn's disease (CD), in particular in four patients from a single family of six with CD. We studied sera from four cohorts from the north of France. These were identified as: EPIMAD (80 pediatric onset CD and 20 pediatric onset ulcerative colitis), MINOTOR (148 adult onset sporadic CD and 50 adult onset ulcerative colitis), Grande Famillies (50) and matched controls for the Grande Famillies cohort (49). Sera were tested using commercial anti-Chlamydia trachomatis (LGV2:434) IgG and IgA human enzyme-linked immunosorbent assay (ELISA) kits. Cutoff for positivity was 11.0 standard units. Patients with sporadic CD, unaffected first degree relatives from multiplex families and ulcerative colitis patients had no greater serologic reactivity than controls. However, multiplex families' patients had twice as many positives as the other groups: for IgG 20% vs. 8%; for IgA 20% vs. 10%. Though not attaining statistical significance, the data showed that familial CD patients had greater exposure to C. trachomatis than sporadic CD patients, supporting our earlier results from one family from the north of France. More specific serologic tests based on outer membrane proteins will need to be employed against the various Chlamydia species with zoonotic potential.


High-frequency QRS analysis improves the specificity of exercise ECG testing in women referred for angiography.
Exercise ECG testing in women for the diagnosis of coronary artery disease (CAD) has a higher false-positive rate compared to men. Consequently, women referred for coronary angiography following a positive exercise test often have normal coronary arteries or non-obstructive lesions. Analysis of the high-frequency components of the QRS complexes (HFQRS) has been reported to provide a sensitive means of detecting myocardial ischemia, independent of gender. The aim of the present study was to prospectively test the diagnostic performance of HFQRS and conventional exercise ECG in detecting stress-induced ischemia in women referred for coronary angiography. The study included 113 female patients (age 64 ± 9 years) referred for non-urgent angiography. Patients performed a symptom-limited treadmill exercise test prior to angiography. High-resolution ECG was acquired during the test and used for both HFQRS and conventional ST-segment analyses. HFQRS diagnosis was determined by computerized analysis, measuring the stress-induced reduction in HFQRS intensity. The diagnostic performance of HFQRS, ST-segment analysis and clinical interpretation of the exercise test were compared, using angiography as a gold standard. HFQRS provided sensitivity of 70% and specificity of 80% for detection of angiographically significant coronary obstruction (≥ 70% stenosis in a single vessel or ≥ 50% in the left main artery). HFQRS was more specific than exercise ECG test (80% vs. 55%, P<.005), as well as more accurate (76% vs. 62%, P<.01). The number of ECG leads with ischemic HFQRS response correlated with the severity of CAD. HFQRS was highly specific (93%) in patients who achieved their age-predicted target heart rate, and retained its diagnostic accuracy in subgroups of patients with resting ECG abnormalities or inconclusive exercise ECG. HFQRS analysis, as an adjunct technology to exercise stress testing, may improve the diagnostic value of the ECG, and reduce the number of unnecessary imaging and invasive procedures.


Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.
Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.


Piglet ileal mucus contains protein and glycolipid (galactosylceramide) receptors specific for Escherichia coli K88 fimbriae.
The aim of this study was to characterize the Escherichia coli K88-specific receptors in mucus from the small intestines of 35-day-old piglets with the isogenic strains E. coli K-12(pMK005) (K88+) and E. coli K-12(pMK002) (K88-). These strains differed only in that the latter one cannot produce intact K88 fimbriae because of a deletion in the gene coding for the major fimbrial subunit. Adhesion was studied by incubating 3H-labeled bacteria with crude mucus, pronase-treated whole mucus, mucus fractionated by gel filtration, delipidated mucus, or extracted lipids immobilized in microtiter wells. In addition, E. coli strains were tested for adhesion to glycolipids extracted from mucus by overlaying glycolipid chromatograms with 125I-labeled bacteria. The recently reported finding that K88 fimbriae bind to glycoproteins in mucus from the piglet small intestine was confirmed in two ways. Pronase treatment of immobilized mucus reduced adhesion by 82%, and adhesion to delipidated mucus was 14 times greater for the K88+ than for the K88- strain. E. coli K88+ adhered to several of the fractions collected after gel filtration of crude mucus, including the void volume (M(r), > 250,000). Receptor activity specific for the K88 fimbriae was demonstrated in the lipids extracted from mucus, as the neutral lipids contained six times as much receptor activity as the acidic lipid fraction. Specificity was confirmed by demonstrating that adhesion to the total lipids could be inhibited by pretreatment of the immobilized lipids with K88 fimbriae. Relative to K-12 (K88-), the K-12 (K88+) bacterial cells bound more avidly to galactosylceramide when the neutral lipids were separated on thin-layer chromatography plates. No adhesion to lipids in the acidic fraction separated on thin-layer plates was detected. Relative to adhesion of K-12 (K88-), adhesion of K-12 (K88+) to commercially available galactosylceramide immobilized in microtiter wells confirmed the results with the thin-layer plates. It can be concluded that 35-day-old piglet mucus contains both protein and glycolipid receptors specific for K88 fimbriae, the latter being galactosylceramide.


Surgical data recording in the operating room: a systematic review of modalities and metrics.
Operating room recording, via video, audio and sensor-based recordings, is increasingly common. Yet, surgical data science is a new field without clear guidelines. The purpose of this study is to examine existing published studies of surgical recording modalities to determine which are available for use in the operating room, as a first step towards developing unified standards for this field. Medline, EMBASE, CENTRAL and PubMed databases were systematically searched for articles describing modalities of data collection in the operating room. Search terms included 'video-audio media', 'bio-sensing techniques', 'sound', 'movement', 'operating rooms' and others. Title, abstract and full-text screening were completed to identify relevant articles. Descriptive statistical analysis was performed for included studies. From 3756 citations, 91 studies met inclusion criteria. These studies described 10 unique data-collection modalities for 17 different purposes in the operating room. Data modalities included video, audio, kinematic and eye-tracking among others. Data-collection purposes described included surgical trainee assessment, surgical error, surgical team communication and operating room efficiency. Effective data collection and utilization in the operating room are imperative for the provision of superior surgical care. The future operating room landscape undoubtedly includes multiple modalities of data collection for a plethora of purposes. This review acts as a foundation for employing operating room data in a way that leads to meaningful benefit for patient care.


Arachidonic acid regulation of the cytosolic phospholipase A 2α/cyclooxygenase-2 pathway in mouse endometrial stromal cells.
To investigate the role of arachidonic acid (AA) in mouse endometrial stromal cells. Experimental animal study. University research laboratory. Sexually mature female CD1-strain mice. Primary culture of endometrial stromal cells. Western blot and real-time polymerase chain reaction for gene expression and/or phosphorylation analysis. Luciferase assay for Cox-2 promoter analysis. AA-derived prostaglandins play important roles during embryo implantation and decidualization. However, the function of AA itself in reproduction is largely unknown. In this study, exogenous AA stimulated cPLA(2α) phosphorylation and COX-2 expression, mainly through ERK1/2 in mouse endometrial stromal cells, and p38 inhibitor modestly inhibited cPLA(2α) phosphorylation induced by AA. The induction of COX-2 by AA was diminished by short interfering RNA against C/EBPβ and inhibitory C/EBPβ (LIP). C/EBPβ binding site at -872--864 of Cox-2 promoter contributes to Cox-2 promoter activation induced by C/EBPβ transfection. The expression of C/EBPβ protein induced by AA was inhibited by p38 inhibitor, and the phosphorylation of C/EBPβ induced by AA was inhibited by p38 inhibitor and ERK1/2 inhibitor. A nonmetabolized analogue of AA (ETYA) also enhanced cPLA(2α) phosphorylation and COX-2 expression. The activation of cPLA(2α)/COX-2 by AA was not inhibited by COX inhibitor indomethacin. AA can induce cPLA(2α)/COX-2 pathway activation in mouse endometrial stromal cells.