First Report of Phomopsis Seed Decay of Soybean Caused by Phomopsis longicolla in South China.
Phomopsis seed decay of soybean (Glycine max (L.) Merr.) causes poor seed quality and suppresses yield in most soybean-growing areas in the world. The disease is caused primarily by Phomopsis longicolla Hobbs. During the spring of 2010, soybean seeds without symptoms were planted in the fields but emergence was poor and the emergence rates ranged from 30 to 70% in south China. Approximately 3,000 symptomless seeds were randomly collected from seven fields at three locations in Guangzhou, Nanchang, and Wuhan. Seeds were surface disinfected with 1% sodium hypochlorite for 12 min, rinsed in sterile distilled water three to four times, and placed on 2% agar. Plates were then incubated at 26°C under 16/8-h photoperiod for 3 to 4 days. About 10 to 20% of the seeds produced white hyphae that spread rapidly and covered the whole seed. The hyphae from fungal isolates were transferred to potato dextrose agar (PDA) and incubated at 26°C in the dark. After 3 to 4 weeks, conidia were elliptical with two oil drops at both ends and hyaline (6.2 to 7.2 × 2.6 to 3.2 μm). The cultural and morphological characteristics of the isolates corresponded with the description of P. longicolla (2). Colonies on PDA were floccose, dense, and white. Stromata were large, black, and spreading. To confirm the morphological identification, the ribosomal internal transcribed spacers (ITS1-5.8S-ITS2) from three isolates were sequenced (GenBank Accession Nos. JQ899030, JQ899031, and JQ899032). BLAST analysis indicated that the isolates had 99% nucleotide sequence identity with P. longicolla (GenBank Accession Nos. AY857868.1, EF026104, and HQ130441.1). Pathogenicity tests were conducted on 2-week-old soybean seedlings (3). A mycelial plug (3 mm in diameter) from the margin of 1-week-old PDA culture of the Wuhan isolate was individually placed mycelial side down directly on the top of cut stem 1 to 2 cm above cotyledon node of the soybean seedling. PDA plugs without the fungus was used as the negative control. All seedlings were kept in a growth chamber at 26°C with 92 to 94% relative humidity. After 2 weeks, all inoculated seedlings showed browning, stem wilt, and the lesions were 0.3 to 2.0 cm long. No symptoms were observed in the control plants. P. longicolla was reisolated from the infected seedlings. The pathogenicity test was repeated three times. Soybean stem blight caused by P. longicolla has been reported in northeast China (1). To our knowledge, this is the first report of P. longicolla causing Phomopsis seed decay of soybean in south China. This report will establish a foundation for developing a program for screening germplasm for resistance to this disease in south China. References: (1) Y. L. Cui et al. Plant Pathol. 58:799, 2009. (2) T. W. Hobbs et al. Mycologia 77:535,1985. (3) S. Li et al. Plant Dis. 85:1031, 2001.


Cluster anxiety-related adverse events following immunization (AEFI): An assessment of reports detected in social media and those identified using an online search engine.
Adverse events following immunization (AEFI) arising from anxiety have rarely been reported as a cluster(s) in the setting of a mass vaccination program. Reports of clusters of anxiety-related AEFIs are understudied. Social media and the web may be a resource for public health investigators. We searched Google and Facebook separately from Atlanta and Geneva to identify reports of cluster anxiety-related AEFIs. We reviewed a sample of reports summarizing year, country/setting, vaccine involved, patient symptoms, clinical management, and impact to vaccination programs. We found 39 reports referring to 18 unique cluster events. Some reports were only found based on the geographic location from where the search was performed. The most common vaccine implicated in reports was human papillomavirus (HPV) vaccine (48.7%). The majority of reports (97.4%) involved children and vaccination programs in school settings or as part of national vaccination campaigns. Five vaccination programs were reportedly halted because of these cluster events. In this study, we identified 18 cluster events that were not published in traditional scientific peer-reviewed literature. Social media and online search engines are useful resources for identifying reports of cluster anxiety-related AEFIs and the geographic location of the researcher is an important factor to consider when conducting these studies. Solely relying upon traditional peer-reviewed journals may seriously underestimate the occurrence of such cluster events.


Optically-induced-potential-based image encryption.
We present a technique of nonlinear image encryption by use of virtual optics. The image to be encrypted is superposed on a random intensity image. And this superposed image propagates through a nonlinear medium and a 4-f system with single phase key. The image is encrypted to a stationary white noise. The decryption process is sensitive to the parameters of the encryption system and the phase key in 4-f system. This sensitivity makes attackers hard to access the phase key. In nonlinear medium, optically-induced potentials, which depend on intensity of optical wave, make the superposition principle frustrated. This nonlinearity based on optically induced potentials highly improves the secrecy level of image encryption. Resistance against attacks based on the phase retrieval technique proves that it has the high secrecy level. This nonlinear image encryption based on optically induced potentials is proposed and demonstrated for the first time.


Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer.
Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.


Factors influencing exposure to secondhand smoke in preschool children living with smoking mothers.
The health effects on young children of exposure to secondhand smoke (SHS) are well described. Recent work suggests that over one quarter of school-aged children in Scotland are regularly exposed to SHS in the home. The study was designed to describe SHS exposure in preschool children whose mothers smoked and identify factors that influence exposure. Smoking mothers with at least one child aged 1-5 years were recruited to the Reducing Families' Exposure to Secondhand Smoke in the Home study. Concentrations of airborne particulate matter less than 2.5 μm in size (PM(2.5)) in the home were measured together with child's salivary cotinine. Demographics including age, accommodation type, socioeconomic status, and number of cigarettes smoked at home were recorded. Data were collected from 54 homes. In 89% of the homes, concentrations of PM(2.5) exceeded health-based guidance values at some point of the day. Household PM(2.5) concentrations were highest during the evening hours of 6 p.m. to midnight. Younger children had higher salivary cotinine concentrations than older children, and the geometric mean of salivary cotinine was 2.36 ng/ml. Household smoking restrictions and maternal confidence in enforcing smoking restrictions in their own home were strongly associated with child's SHS exposure. Preschool children's exposure to SHS in homes where the mother smokes is considerable. Interventions and policy development to increase parental awareness of the health effects of SHS and provide parents with the confidence to implement smoke-free households are required to reduce the SHS exposure of preschool age children.


Clinical electrophysiology--a decade of progress.
During the past 14 years there have been major advances in the field of clinical electrophysiology. This progress is a result of a more extensive use of intracardiac electrode catheters with recordings from multiple sites in the right and left cardiac chambers, the introduction of programmed electrical stimulation techniques and the use of antiarrhythmic drugs for diagnostic and therapeutic purposes during acute electrophysiologic testing. This article examines the pioneering studies and the subsequent developments in the field of clinical electrophysiology. The specific topics that are reviewed include the sinus node and atrium, atrioventricular conduction, supraventricular tachycardia and ventricular tachycardia. The therapeutic implications of each topic are also discussed. Clinical electrophysiology in its initial stages was a descriptive technique, but has since become an important diagnostic and therapeutic tool. However, electrophysiologic testing is an intensive process, requiring specialized training and a substantial commitment of human and physical resources.


Universal vs Risk Factor Screening for Methicillin-Resistant Staphylococcus aureus in a Large Multicenter Tertiary Care Facility in Canada.
OBJECTIVE To assess the clinical effectiveness of a universal screening program compared with a risk factor-based program in reducing the rates of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) among admitted patients at the Ottawa Hospital. DESIGN Quasi-experimental study. SETTING Ottawa Hospital, a multicenter tertiary care facility with 3 main campuses, approximately 47,000 admissions per year, and 1,200 beds. METHODS From January 1, 2006 through December 31, 2007 (24 months), admitted patients underwent risk factor-based MRSA screening. From January 1, 2008 through August 31, 2009 (20 months), all patients admitted underwent universal MRSA screening. To measure the effectiveness of this intervention, segmented regression modeling was used to examine monthly nosocomial MRSA incidence rates per 100,000 patient-days before and during the intervention period. To assess secular trends, nosocomial Clostridium difficile infection, mupirocin prescriptions, and regional MRSA rates were investigated as controls. RESULTS The nosocomial MRSA incidence rate was 46.79 cases per 100,000 patient-days, with no significant differences before and after intervention. The MRSA detection rate per 1,000 admissions increased from 9.8 during risk factor-based screening to 26.2 during universal screening. A total of 644 new nosocomial MRSA cases were observed in 1,448,488 patient-days, 323 during risk factor-based screening and 321 during universal screening. Secular trends in C. difficile infection rates and mupirocin prescriptions remained stable after the intervention whereas population-level MRSA rates decreased. CONCLUSION At Ottawa Hospital, the introduction of universal MRSA admission screening did not significantly affect the rates of nosocomial MRSA compared with risk factor-based screening. Infect. Control Hosp. Epidemiol. 2015;37(1):41-48.


A neural reward prediction error revealed by a meta-analysis of ERPs using great grand averages.
Economic approaches to decision making assume that people attach values to prospective goods and act to maximize their obtained value. Neuroeconomics strives to observe these values directly in the brain. A widely used valuation term in formal learning and decision-making models is the reward prediction error: the value of an outcome relative to its expected value. An influential theory (Holroyd & Coles, 2002) claims that an electrophysiological component, feedback related negativity (FRN), codes a reward prediction error in the human brain. Such a component should be sensitive to both the prior likelihood of reward and its magnitude on receipt. A number of studies have found the FRN to be insensitive to reward magnitude, thus questioning the Holroyd and Coles account. However, because of marked inconsistencies in how the FRN is measured, a meaningful synthesis of this evidence is highly problematic. We conducted a meta-analysis of the FRN's response to both reward magnitude and likelihood using a novel method in which published effect sizes were disregarded in favor of direct measurement of the published waveforms themselves, with these waveforms then averaged to produce "great grand averages." Under this standardized measure, the meta-analysis revealed strong effects of magnitude and likelihood on the FRN, consistent with it encoding a reward prediction error. In addition, it revealed strong main effects of reward magnitude and likelihood across much of the waveform, indicating sensitivity to unsigned prediction errors or "salience." The great grand average technique is proposed as a general method for meta-analysis of event-related potential (ERP).


Isolated disease of the proximal left anterior descending artery comparing the effectiveness of percutaneous coronary interventions and coronary artery bypass surgery.
This study sought to systematically compare the effectiveness of percutaneous coronary intervention and coronary artery bypass surgery in patients with single-vessel disease of the proximal left anterior descending (LAD) coronary artery. It is uncertain whether percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG) surgery provides better clinical outcomes among patients with single-vessel disease of the proximal LAD. We searched relevant databases (MEDLINE, EMBASE, and Cochrane from 1966 to 2006) to identify randomized controlled trials that compared outcomes for patients with single-vessel proximal LAD assigned to either PCI or CABG. We identified 9 randomized controlled trials that enrolled a total of 1,210 patients (633 received PCI and 577 received CABG). There were no differences in survival at 30 days, 1 year, or 5 years, nor were there differences in the rates of procedural strokes or myocardial infarctions, whereas the rate of repeat revascularization was significantly less after CABG than after PCI (at 1 year: 7.3% vs. 19.5%; at 5 years: 7.3% vs. 33.5%). Angina relief was significantly greater after CABG than after PCI (at 1 year: 95.5% vs. 84.6%; at 5 years: 84.2% vs. 75.6%). Patients undergoing CABG spent 3.2 more days in the hospital than those receiving PCI (95% confidence interval: 2.3 to 4.1 days, p < 0.0001), required more transfusions, and were more likely to have arrhythmias immediately post-procedure. In patients with single-vessel, proximal LAD disease, survival was similar in CABG-assigned and PCI-assigned patients; CABG was significantly more effective in relieving angina and led to fewer repeat revascularizations.


Double-stranded RNA binding protein, Staufen, is required for the initiation of RNAi in coleopteran insects.
RNA interference (RNAi) is being used to develop methods to control pests and disease vectors. RNAi is robust and systemic in coleopteran insects but is quite variable in other insects. The determinants of efficient RNAi in coleopterans, as well as its potential mechanisms of resistance, are not known. RNAi screen identified a double-stranded RNA binding protein (StaufenC) as a major player in RNAi. StaufenC homologs have been identified in only coleopteran insects. Experiments in two coleopteran insects, Leptinotarsa decemlineata and Tribolium castaneum, showed the requirement of StaufenC for RNAi, especially for processing of double-stranded RNA (dsRNA) to small interfering RNA. RNAi-resistant cells were selected by exposing L. decemlineata, Lepd-SL1 cells to the inhibitor of apoptosis 1 dsRNA for multiple generations. The resistant cells showed lower levels of StaufenC expression compared with its expression in susceptible cells. These studies showed that coleopteran-specific StaufenC is required for RNAi and is a potential target for RNAi resistance. The data included in this article will help improve RNAi in noncoleopteran insects and manage RNAi resistance in coleopteran insects.


Decisional attributes of patients with diabetes: the aspirin choice.
The aim of this study was to determine personal characteristics and preferences that affect decision making (decisional attributes) in patients with diabetes. In particular, we were interested in relating these attributes to the choice of using aspirin to reduce cardiovascular risk. We conducted a cross-sectional survey (70% response rate) of 206 diabetic patients (median age, 63 years; 42% women; 91% completed high school; median HbA(1c), 8%) attending a tertiary care diabetes clinic. Patients answered a 42-question survey exploring decisional attributes. Medical records provided the source of clinical information. We evaluated sociodemographic, clinical, and decisional predictors of aspirin use. We also conducted a multivariable analysis with aspirin use as a dependent variable. Sixty-seven percent of patients surveyed used aspirin. Patients using aspirin were at higher risk of cardiovascular disease (odds ratio 1.4, 95% CI 1.0-2.1), knew more about the benefits of aspirin (1.9, 1.4-2.6) and less about the risks of aspirin (1.4, 1.2-1.8), and were more certain about using aspirin (0.5, 0.3-0.8) than patients not using aspirin. Patients using aspirin placed a higher value on preventing cardiovascular events than on avoiding the side effects of aspirin. Patients perceived that their diabetes provider and the American Diabetes Association had greater influence on their decision to use aspirin than family members or other patients with diabetes. The decisional attributes of patients with diabetes are associated with aspirin use. Decisional attributes may be the target of research and interventions to reduce underutilization to levels consistent with patient preferences.


Stochastic modeling of a serial killer.
We analyze the time pattern of the activity of a serial killer, who during 12 years had murdered 53 people. The plot of the cumulative number of murders as a function of time is of "Devil's staircase" type. The distribution of the intervals between murders (step length) follows a power law with the exponent of 1.4. We propose a model according to which the serial killer commits murders when neuronal excitation in his brain exceeds certain threshold. We model this neural activity as a branching process, which in turn is approximated by a random walk. As the distribution of the random walk return times is a power law with the exponent 1.5, the distribution of the inter-murder intervals is thus explained. We illustrate analytical results by numerical simulation. Time pattern activity data from two other serial killers further substantiate our analysis.


Physical activity in rheumatoid arthritis: relationship to cardiovascular risk factors, subclinical atherosclerosis, and disease activity.
Objective: To investigate associations between physical activity and risk factors for cardiovascular disease (CVD), subclinical atherosclerosis, and disease activity in patients with early and long-standing rheumatoid arthritis (RA).Method: This cross-sectional study included 84 patients with early and 37 with long-standing RA (disease duration, mean ± sd: 1.4 ± 0.4 and 16.3 ± 2.3 years, respectively). Physical activity was measured using a combined accelerometer and heart-rate monitor. Further assessments were disease activity (erythrocyte sedimentation rate, Disease Activity Score in 28 joints), functional ability (Health Assessment Questionnaire), risk factors for CVD (blood lipids, i.e. triglycerides, high-density lipoprotein, low-density lipoprotein; blood glucose, blood pressure, sleeping heart rate, waist circumference, body mass index, and body fat), and subclinical atherosclerosis (pulse-wave velocity, augmentation index, and carotid intima-media thickness).Results: Physical activity variables did not differ between patients with early and long-standing RA. However, 37% of the patients with early and 43% of those with long-standing RA did not reach the World Health Organization's recommended levels of moderate to vigorous physical activity (MVPA). In a final multiple regression model, adjusted for age, gender, disease duration, and activity monitor wear time, higher total physical activity was associated with lower body fat and higher functional ability. With the same adjustments, more time spent in MVPA was associated with lower high-density lipoprotein and lower sleeping heart rate.Conclusions: Physical activity was associated with more favourable risk factors for CVD. However, many patients were physically inactive, stressing the importance of promoting physical activity in RA.


Frequency of food intake and estimated nutrient intake among men and women: the JACC Study.
The aim of this study was to determine the frequency of food intake and estimated nutrient intake in the JACC study cohort. The subjects were 46,465 men and 64,327 women aged 40-79 years who responded to the self-administered food frequency questionnaire. We calculated the dietary intake of major nutrients by multiplying the frequency of consumption of each food with each portion size, estimated from a validation study. Women reported to more likely consume vegetables, seaweed, fruits, sweets, oolong-tea, western-style-breakfast, and less likely to consume rice and miso-soup than men. Women reported less preference of salty foods and fatty foods than men. Compared with men, women had higher mean intakes of carotene and vitamin C, and lower intake of total energy, carbohydrate and sodium. The frequency of consumption of beef, chicken, dairy products, fresh fish, fish products, rice, and miso-soup increased with age in men, and that of vegetables, seaweed, beans, tofu, fruits, sweets, and green-tea increased with age in both sexes. Men aged 40-49 years had the lowest mean intake levels of crude fiber, calcium, iron, retinol, carotene, and vitamins A, C, and E. Women aged 40-49 years had the lowest mean intake levels of crude fiber, iron, and vitamins C. Women aged 70-79 years had the lowest mean intake levels of calcium, retinol, and vitamins A. Women had a more westernized dietary pattern than men. Elderly men had a mixture of unhealthy and healthy dietary patterns while elderly women generally had a healthier dietary pattern compared with younger persons.


Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART).
Familial hypercholesterolemia (FH) patients are at high risk for premature coronary heart disease (CHD). Despite the use of statins, most patients do not achieve an optimal LDL-cholesterol goal. The aims of this study are to describe baseline characteristics and to evaluate Lipid Lowering Therapy (LLT) in FH patients recruited in SAFEHEART. A cross-sectional analysis of cases recruited in the Spanish FH cohort at inclusion was performed. Demographic, lifestyle, medical and therapeutic data were collected by specific surveys. Blood samples for lipid profile and DNA were obtained. Genetic test for FH was performed through DNA-microarray. Data from 1852 subjects (47.5% males) over 19 years old were analyzed: 1262 (68.1%, mean age 45.6 years) had genetic diagnosis of FH and 590 (31.9%, mean age 41.3 years) were non-FH. Cardiovascular disease was present in 14% of FH and in 3.2% of non-FH subjects (P < 0.001), and was significantly higher in patients carrying a null mutation compared with those carrying a defective mutation (14.87% vs. 10.6%, respectively, P < 0.05). Prevalence of current smokers was 28.4% in FH subjects. Most FH cases were receiving LLT (84%). Although 51.5% were receiving treatment expected to reduce LDL-c levels at least 50%, only 13.6% were on maximum statin dose combined with ezetimibe. Mean LDL-c level in treated FH cases was 186.5 mg/dl (SD: 65.6) and only 3.4% of patients reached and LDL-c under 100 mg/dl. The best predictor for LDL-c goal attainment was the use of combined therapy with statin and ezetimibe. Although most of this high risk population is receiving LLT, prevalence of cardiovascular disease and LDL-c levels are still high and far from the optimum LDL-c therapeutic goal. However, LDL-c levels could be reduced by using more intensive LLT such as combined therapy with maximum statin dose and ezetimibe.


Neutrophil agglutinins in idiopathic chronic neutropenia of early childhood.
Twelve patients with chronic neutropenia, ranging in age from 7 to 27 months, were studied for circulating antineutrophil autoantibodies. Absolute neutrophil counts ranged from 0 to 500/cu mm. None of the patients was transfused or had a history of prior drug ingestion. Edetic acid-microagglutination was employed to detect leukocyte antibodies. Sera from six of 12 patients contained antineutrophil antibodies, four reacting with neutrophils from the father and two from the mother. Patient sera also reacted with neutrophils of several unrelated normal volunteers. Four of the six patient sera with antineutrophil antibodies also reacted with autologous neutrophils. The duration of neutropenia was seven months in one patient with antibody whose neutropenia resolved. Patients with neutrophil autoantibody did not clinically differ from those without demonstrable antibody. The coexistent fall in leukoagglutinin titer and rise in neutrophil counts in one patient suggested an etiologic role for this antibody. Detection and proper diagnosis have important therapeutic implications.


Examining the Effects of Afterschool Reading Interventions for Upper Elementary Struggling Readers.
We examined the efficacy of an afterschool multicomponent reading intervention for third- through fifth-grade students with reading difficulties. A total of 419 students were identified for participation based on a 90 standard score or below on a screening measure of the Test of Silent Reading Efficiency and Comprehension. Participating students were randomly assigned to a business as usual comparison condition or one of two reading treatments. All treatment students received 30 min of computer-based instruction plus 30 min of small-group tutoring for four to five times per week. No statistically significant reading comprehension posttest group differences were identified (p > .05). The limitations of this study included high attrition and absenteeism. These findings extend those from a small sample of experimental studies examining afterschool reading interventions and provide initial evidence that more instruction, after school, may not yield the desired outcome of improved comprehension.


Synthesis of γ-labeled nucleoside 5'-triphosphates using click chemistry.
Real-time enzymatic studies are gaining importance as their chemical and technical instrumentation improves. Here we report the efficient synthesis of γ-alkyne modified triphosphate amidates that are converted into a variety of γ-fluorophore labeled triphosphates by Cu(I) catalyzed alkyne/azide click reactions. The synthesized triphosphates are incorporated into DNA by DNA polymerases.


Identifying the mechanisms of intron gain: progress and trends.
Continued improvements in Next-Generation DNA/RNA sequencing coupled with advances in gene annotation have provided researchers access to a plethora of annotated genomes. Subsequent analyses of orthologous gene structures have identified numerous intron gain and loss events that have occurred both recently and in the very distant past. This research has afforded exceptional insight into the temporal and lineage-specific rates of intron gain and loss among various species throughout evolution. Numerous studies have also attempted to identify the molecular mechanisms of intron gain and loss. However, even after considerable effort, very little is known about these processes. In particular, the mechanism(s) of intron gain have proven exceptionally enigmatic and remain topics of considerable debate. Currently, there exists no definitive consensus as to what mechanism(s) may generate introns. Because many introns are known to affect gene expression, it is necessary to understand the molecular process(es) by which introns may be gained. Here we review the seven most commonly purported mechanisms of intron gain and, when possible, summarize molecular evidence for or against the occurrence of each of these mechanisms. Furthermore, we catalogue indirect evidence that supports the occurrence of each mechanism. Finally, because these proposed mechanisms fail to explain the mechanistic origin of many recently gained introns, we also look at trends that may aid researchers in identifying other potential mechanism(s) of intron gain.


Long-term cognitive impairment after critical illness.
Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized. We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders. Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months. Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.).


p53-mediated delayed NF-κB activity enhances etoposide-induced cell death in medulloblastoma.
Medulloblastoma (MB) is an embryonic brain tumour that arises in the cerebellum. Using several MB cell lines, we have demonstrated that the chemotherapeutic drug etoposide induces a p53- and caspase-dependent cell death. We have observed an additional caspase-independent cell death mechanism involving delayed nuclear factor κB (NF-κB) activity. The delayed induction was controlled by a p53-dependent transcription step and the production of death receptors (especially CD95/Fas). We further demonstrated that in both MB and glioblastoma (GM) cell lines, in which the p53 pathway was not functional, no p65 activation could be detected upon etoposide treatment. MB cell lines that have mutations in p53 or NF-κB are either less sensitive (NF-κB mutant) or even completely resistant (p53 mutant) to chemotherapeutic intervention. The optimal cell death was only achieved when both p53 and NF-κB were switched on. Taken together, our results shed light on the mechanism of NF-κB activation by etoposide in brain tumours and show that the genetic background of MB and GM cells determines their sensitivity to chemotherapy and has to be taken into account for efficient therapeutic intervention.


Obesity-independent hyperinsulinemia in nondiabetic first-degree relatives of individuals with type 2 diabetes.
A close association between obesity and hyperinsulinemia is well recognized, but it is not known whether this relationship is affected by the genetic susceptibility to type 2 diabetes. Insulin response to a 75-g oral glucose load was evaluated in healthy nondiabetic Caucasians with first-degree family history of diabetes (relatives, n = 55) and those without family history (nonrelatives, n = 33). A significant correlation between the BMI and insulin response (area under the curve [AUC] during the 2-h period) was seen in nonrelatives (r = 0.68, P < 0.0001) but not in the relatives (r = 0.12, P = 0.37). Multivariate analysis revealed that obesity (BMI) was the primary determinant of insulin response in nonrelatives (P < 0.001), whereas among the relatives, BMI had no significant impact (P = 0.28). Thus, these distinctions between the relatives and nonrelatives remained after adjusting for glucose level, age, and gender. Among first-degree relatives, the commonly observed association between BMI and insulin response is lost, and hyperinsulinemia is present even in the absence of obesity. First-degree family history of diabetes may confer insulin resistance that is independent of obesity. Alternatively, this could suggest a pathological regulation of an obesity-insulin feedback loop, e.g., a defective recognition of adiposity.


fNIRS study of walking and walking while talking in young and old individuals.
Evidence suggests that gait is influenced by higher order cognitive and cortical control mechanisms. However, less is known about the functional correlates of cortical control of gait. Using functional near-infrared spectroscopy, the current study was designed to evaluate whether increased activations in the prefrontal cortex (PFC) were detected in walking while talking (WWT) compared with normal pace walking (NW) in 11 young and 11 old participants. Specifically, the following two hypotheses were evaluated: (a) Activation in the PFC would be increased in WWT compared with NW. (b) The increase in activation in the PFC during WWT as compared with NW would be greater in young than in old participants. Separate linear mixed effects models with age as the two-level between-subject factor, walking condition (NW vs WWT) as the two-level repeated within-subject factor, and HbO2 levels in each of the 16 functional near-infrared spectroscopy channels as the dependent measure revealed significant task effects in 14 channels, indicating a robust bilateral increased activation in the PFC in WWT compared with NW. Furthermore, the group-by-task interaction was significant in 11 channels with young participants showing greater WWT-related increase in HbO2 levels compared with the old participants. This study provided the first evidence that oxygenation levels are increased in the PFC during WWT compared with NW in young and old individuals. This effect was modified by age suggesting that older adults may under-utilize the PFC in attention-demanding locomotion tasks.


Deep Synthesis of Realistic Medical Images: A Novel Tool in Clinical Research and Training.
Making clinical decisions based on medical images is fundamentally an exercise in statistical decision-making. This is because in this case, the decision-maker must distinguish between image features that are clinically diagnostic (i.e., signal) from a large amount of non-diagnostic features. (i.e., noise). To perform this task, the decision-maker must have learned the underlying statistical distributions of the signal and noise to begin with. The same is true for machine learning algorithms that perform a given diagnostic task. In order to train and test human experts or expert machine systems in any diagnostic or analytical task, it is advisable to use large sets of images, so as to capture the underlying statistical distributions adequately. Large numbers of images are also useful in clinical and scientific research about the underlying diagnostic process, which remains poorly understood. Unfortunately, it is often difficult to obtain medical images of given specific descriptions in sufficiently large numbers. This represents a significant barrier to progress in the arenas of clinical care, education, and research. Here we describe a novel methodology that helps overcome this barrier. This method leverages the burgeoning technologies of deep learning (DL) and deep synthesis (DS) to synthesize medical images de novo. We provide a proof-of-principle of this approach using mammograms as an illustrative case. During the initial, prerequisite DL phase of the study, we trained a publicly available deep learning neural network (DNN), using open-sourced, radiologically vetted mammograms as labeled examples. During the subsequent DS phase of the study, the fully trained DNN was made to synthesize, de novo, images that capture the image statistics of a given input image. The resulting images indicated that our DNN was able to faithfully capture the image statistics of visually diverse sets of mammograms. We also briefly outline rigorous psychophysical testing methods to measure the extent to which synthesized mammography were sufficiently alike their original counterparts to human experts. These tests reveal that mammography experts fail to distinguish synthesized mammograms from their original counterparts at a statistically significant level, suggesting that the synthesized images were sufficiently realistic. Taken together, these results demonstrate that deep synthesis has the potential to be impactful in all fields in which medical images play a key role, most notably in radiology and pathology.


Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders.
Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.


Anti-plasmodial activity of some Kenyan medicinal plant extracts singly and in combination with chloroquine.
Sixty organic and aqueous extracts of eleven plants used for the control of malaria by local communities in Kisii District, Kenya were screened for in vitro anti-plasmodial activity. The plants selection was based on existing ethnobotanical information and interviews with local communities. The extracts were tested against chloroquine sensitive and resistant laboratory adapted strains of Plasmodium falciparum. The study revealed that 63.6% of the plants were active (IC50 < or = 100 microg/mL). Extracts of four plants, Ekebergia capensis, Stephania abyssinica, Ajuga remota and Clerodendrum myricoides gave IC50 values below 30 microg/mL against both chloroquine sensitive and resistant P. falciparum strains. Combination of extracts of E. capensis and C. myricoides with chloroquine against the multi-drug resistant P. falciparum isolate (V1/S) revealed synergistic effect. The plants which showed activity may be useful as sources for novel anti-plasmodial compounds.


Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor.
Thrombocytopenia is a common side effect of chemotherapy, responsible for increased risk of bleeding and delay of treatment schedules in cancer patients. It is currently unknown how chemotherapeutic agents affect platelet production and whether the platelet precursors megakaryocytes represent a direct target of cytotoxic drugs. We investigated the effects of chemotherapeutic agents on primary megakaryocytes by using a culture system that recapitulates in vitro human megakaryopoiesis and found that cytotoxic drugs predominantly destroyed megakaryocytic progenitors at early stages of differentiation. Immature megakaryocytes could be protected from chemotherapeutic agents by the cytokine stem cell factor (SCF), which binds the c-kit receptor expressed on hematopoietic stem and progenitor cells. In chemotherapy-treated megakaryocytes, SCF activated Akt, neutralized the mitochondrial apoptotic machinery, and inhibited caspase activity. Interfering with Akt activation abrogated the antiapoptotic effects of SCF, whereas exogenous expression of constitutively active Akt inhibited drug-induced apoptosis of primary megakaryocytes, indicating the Akt pathway as primarily responsible for SCF-mediated protection of megakaryocyte progenitors. These results indicate apoptosis of megakaryocyte progenitors as a major cause of chemotherapy-induced thrombocytopenia and suggest that SCF may be used to prevent platelet loss in cancer patients with c-kit-negative tumors.


Route optimisation and solving Zermelo's navigation problem during long distance migration in cross flows.
The optimum path to follow when subjected to cross flows was first considered over 80 years ago by the German mathematician Ernst Zermelo, in the context of a boat being displaced by ocean currents, and has become known as the 'Zermelo navigation problem'. However, the ability of migrating animals to solve this problem has received limited consideration, even though wind and ocean currents cause the lateral displacement of flyers and swimmers, respectively, particularly during long-distance journeys of 1000s of kilometres. Here, we examine this problem by combining long-distance, open-ocean marine turtle movements (obtained via long-term GPS tracking of sea turtles moving 1000s of km), with a high resolution basin-wide physical ocean model to estimate ocean currents. We provide a robust mathematical framework to demonstrate that, while turtles eventually arrive at their target site, they do not follow the optimum (Zermelo's) route. Even though adult marine turtles regularly complete incredible long-distance migrations, these vertebrates primarily rely on course corrections when entering neritic waters during the final stages of migration. Our work introduces a new perspective in the analysis of wildlife tracking datasets, with different animal groups potentially exhibiting different levels of complexity in goal attainment during migration.


Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants.
A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.


Screening and identification of a gene, PSE-1, that affects protein secretion in Saccharomyces cerevisiae.
Utilizing a screening method designed for the identification of genes involved with enhanced protein secretion in Saccharomyces cerevisiae we identified a gene, which we named PSE-1 (Protein Secretion Enhancer). Overexpression of PSE-1 in a multi-copy plasmid, as shown by Northern hybridization, gave a fourfold enhancement in total protein secretion. The repertoire of proteins that are found to be secreted in greater quantities include three known biologically active proteins: k1 killer toxin, alpha-factor, and acid phosphatase. The PSE-1 gene is located on chromosome XII of the yeast genome and codes for a hydrophobic protein containing 1089 amino acids. Haploid yeast cells that contained a LEU2 insertion mutation in PSE-1 grow very poorly, a phenotype similar to other conditional SEC mutants at restrictive temperature.


Characterisation of OSL and OSLN droplets for dosimetry.
In spite of considerable progress in neutron dosimetry, there is no dosemeter that is capable of measuring neutron doses independently of the neutron spectrum with good accuracy. Carbon-doped aluminium oxide (Al2O3:C) is a sensitive material for ionising radiation (beta-ray, X ray and electron) and has been used for applications in personal and medical dosimetry as an optically stimulated luminescence (OSL) dosemeter. Al2O3:C has a low sensitivity to neutron radiation; this prevents its application to neutron fields, representing a disadvantage of Al2O3:C-OSL when compared with LiF, which is used as a thermoluminescent detector. Recently an improvement for neutron dosimetry (Passmore and Kirr. Neutron response characterisation of an OSL neutron dosemeter. Radiat. Prot. Dosim. 2011; 144: 155-60) uses Al2O3:C coated with (6)Li2CO3 (OSLN),which gives the high-sensitive response as known for Al2O3:C with the advantage of being also sensitive to thermal neutrons. In this article, the authors compare small-size detectors (droplets) of Al2O3:C (OSL) and of Al2O3:C+(6)Li2CO3 (OSLN) and discuss the advantages and drawbacks of both materials, regarding size vs. response.


P21-activated protein kinase 1 is overexpressed in gastric cancer and induces cancer metastasis.
P21-activated protein kinase (Pak1), a main downstream effector of small Rho GTPases, plays an important role in the regulation of cell morphogenesis, motility, mitosis and angiogenesis. However, the role of Pak1 in gastric cancer metastasis remains unclear. Here, we showed that Pak1 is overexpressed in gastric cancer tissues from 74 patients by immunohistochemistry. Overexpression of Pak1 was associated with metastasis and prognosis of gastric cancer. In addition, overexpression of Pak1 increased gastric cancer cell motility and invasion, whereas downregulation of Pak1 expression reduced gastric cancer cell migration and invasion. In further study, data showed that activated Pak1 inhibited stress fiber and focal adhesion complex formation in gastric cancer cells and led to the formation of motile phenotypes. Importantly, activated Pak1 elicited phosphorylation of the ERK and JNK-dependent pathway in gastric cancer cell lines. In conclusion, our results suggest that Pak1 is overexpressed in gastric cancer and plays an important role in the metastasis of gastric cancer. The mechanism by which Pak1 induces cancer metastasis may involve activation of ERK and JNK.


BMPs: from bone to body morphogenetic proteins.
The family of bone morphogenetic proteins (BMPs) comprises approximately 30 secreted cytokines that signal through transmembrane serine/threonine kinase receptors. The BMP signaling pathways are fine-tuned on multiple levels: Extracellular antagonists modify ligand activity; several co-receptors enhance or inhibit downstream signaling events through multiple mechanisms; and intracellular molecules further regulate the signaling outcome and mediate crosstalk with other pathways. BMPs affect structures and processes throughout the entire body, ranging from embryonic patterning and development through stem cells and their niches, to tissue homeostasis and regeneration. This comprehensive involvement in various tissues had not been expected by Marshall Urist, who initially discovered the ability of an unknown factor in bone to induce bone growth in muscle and subsequently suggested the name "bone morphogenetic protein." Today, recombinant BMPs are used in clinical practice for the treatment of bone and kidney disorders, and new genetically modified BMPs are emerging as promising tools in regenerative medicine and tissue engineering. Clearly, the functions of BMPs within the body are more versatile than initially suspected. To discuss modern trends in BMP signaling, leaders in the field met for the First International BMP Workshop in Berlin in September 2009. Here, we summarize new insights on the roles of BMPs in various tissues and highlight recent findings in cell, structural, and developmental biology as well as the therapeutic potential of BMPs. Finally, we conclude that BMPs today deserve to be called body morphogenetic proteins.


Assessing the Registered Nursing Care Contribution for older people in care homes: issues of reliability and validity.
The present paper reports on a study designed to investigate the validity and reliability of the Registered Nursing Care Contribution (RNCC) tool for assessing the level of nursing care required by care home residents. Care plan data from 186 residents in participating care homes were assessed by multiple assessors using the RNCC tool (i.e. care home registered nurses, a nurse researcher, an external care home expert and a nurses consultant). The Minimum Data Set (MDS) rating was used as a validated comparison. The findings from the study indicated that there were disparities between the RNCC and MDS bandings, and between different raters, with the external care home expert achieving the closest agreement with the MDS. This suggests that the use of the RNCC tool varies considerably according to the assessor, which also suggests that training of users is needed to ensure consistency and reliability. However, the difference between the outcomes of using the RNCC tool and the MDS suggests that assessment of nursing need may need to be re-examined to ensure validity.


Proteomic analysis of the autoantibody response following immunization with a single autoantigen.
In most autoimmune diseases, the autoantibody response is directed against several antigens of the target organ whose identification is crucial for understanding the physiopathological process. Thus, technologies allowing a characterization of the whole autoantibody pattern of both human and experimental autoimmune diseases are required. Here we have used immunoproteomic analysis of human epidermal extracts to characterize the diversity of the anti-desmosome antibody response induced in normal mice immunized with desmoglein 1, the major autoantigen of pemphigus foliaceus, an autoimmune blistering skin disease. In particular, this analysis enables us to characterize the binding properties of anti-desmosome mAbs derived from these mice and to show that the autoantibody response induced upon immunization with a single autoantigen targets different epidermal autoantigens with a pattern similar to that observed in certain variety of human pemphigus.


Paternal population history of East Asia: sources, patterns, and microevolutionary processes.
Asia has served as a focal point for human migration during much of the Late Pleistocene and Holocene. Clarification of East Asia's role as a source and/or transit point for human dispersals requires that this region's own settlement history be understood. To this end, we examined variation at 52 polymorphic sites on the nonrecombining portion of the Y chromosome (NRY) in 1,383 unrelated males, representing 25 populations from southern East Asia (SEAS), northern East Asia (NEAS), and central Asia (CAS). The polymorphisms defined 45 global haplogroups, 28 of which were present in these three regions. Although heterozygosity levels were similar in all three regions, the average pairwise difference among haplogroups was noticeably smaller in SEAS. Multidimensional scaling analysis indicated a general separation of SEAS versus NEAS and CAS populations, and analysis of molecular variance produced very different values of Phi(ST) in NEAS and SEAS populations. In spatial autocorrelation analyses, the overall correlogram exhibited a clinal pattern; however, the NEAS populations showed evidence of both isolation by distance and ancient clines, whereas there was no evidence of structure in SEAS populations. Nested cladistic analysis demonstrated that population history events and ongoing demographic processes both contributed to the contrasting patterns of NRY variation in NEAS and SEAS. We conclude that the peopling of East Asia was more complex than earlier models had proposed-that is, a multilayered, multidirectional, and multidisciplinary framework is necessary. For instance, in addition to the previously recognized genetic and dental dispersal signals from SEAS to NEAS populations, CAS has made a significant contribution to the contemporary gene pool of NEAS, and the Sino-Tibetan expansion has left traces of a genetic trail from northern to southern China.


Assessment of body image in obesity using a digital morphing technique.
Historically, body image research has relied on generic, whole body outlines, which may not be suited to obese individuals. The development of computer generated, individualized digital images to represent body image may be more effective. Sixty volunteers participated, with three categories of subject: lean, obese and lean regular exercisers. Body image was assessed using a digital morphing technique in comparison to two standard paper questionnaires. Using the novel digital morphing tool, obese subjects displayed poorer body awareness (perception) than their lean counterparts (P = 0.03), significantly over-estimating their actual body size. Both genders overestimated body size to a similar degree. For body satisfaction, females wished to be smaller and males to be larger, identifying gender-specific body regions (P < 0.001). Obese subjects showed greatest dissatisfaction (P < 0.001) with body image. There was significant correlation for body image dissatisfaction (P < 0.05) between the digital technique and the questionnaires, which was highest for the figural stimuli questionnaire (r = 0.80, P < 0.001). This method represents a novel and alternative approach to rating body image perception (IP) and satisfaction in obese subjects, particularly providing data on specific regional areas. Body image dissatisfaction appears to be both due to poor body IP compounded with the desire to be smaller.


metaP-server: a web-based metabolomics data analysis tool.
Metabolomics is an emerging field that is based on the quantitative measurement of as many small organic molecules occurring in a biological sample as possible. Due to recent technical advances, metabolomics can now be used widely as an analytical high-throughput technology in drug testing and epidemiological metabolome and genome wide association studies. Analogous to chip-based gene expression analyses, the enormous amount of data produced by modern kit-based metabolomics experiments poses new challenges regarding their biological interpretation in the context of various sample phenotypes. We developed metaP-server to facilitate data interpretation. metaP-server provides automated and standardized data analysis for quantitative metabolomics data, covering the following steps from data acquisition to biological interpretation: (i) data quality checks, (ii) estimation of reproducibility and batch effects, (iii) hypothesis tests for multiple categorical phenotypes, (iv) correlation tests for metric phenotypes, (v) optionally including all possible pairs of metabolite concentration ratios, (vi) principal component analysis (PCA), and (vii) mapping of metabolites onto colored KEGG pathway maps. Graphical output is clickable and cross-linked to sample and metabolite identifiers. Interactive coloring of PCA and bar plots by phenotype facilitates on-line data exploration. For users of commercial metabolomics kits, cross-references to the HMDB, LipidMaps, KEGG, PubChem, and CAS databases are provided. metaP-server is freely accessible at http://metabolomics.helmholtz-muenchen.de/metap2/.


Spatial patterns and temporal trends in mercury concentrations in common loons (Gavia immer) from 1998 to 2016 in New York's Adirondack Park: has this top predator benefitted from mercury emission controls?
Mercury (Hg), a neurotoxic pollutant, can be transported long distances through the atmosphere and deposited in remote areas, threatening aquatic wildlife through methylation and bioaccumulation. Over the last two decades, air quality management has resulted in decreases in Hg emissions from waste incinerators and coal-fired power plants across North America. The common loon (Gavia immer) is an apex predator of the aquatic food web. Long-term monitoring of Hg in loons can help track biological recovery in response to the declines in atmospheric Hg that have been documented in the northeastern USA. To assess spatial patterns and temporal trends in Hg exposure of the common loon in the Adirondack Park of New York State, we analyzed Hg concentrations in loon blood and egg samples from 116 lakes between 1998 and 2016. We found spatially variable Hg concentrations in adult loon blood and feathers across the Park. Loon Hg concentrations (converted to female loon units) increased 5.7% yr-1 from 1998 to 2010 (p = 0.04), and then stabilized at 1.70 mg kg-1 from 2010 to 2016 (p = 0.91), based on 760 observations. Concentrations of Hg in juvenile loons also increased in the early part of the record, stabilizing 2 years before Hg concentrations stabilized in adults. For 52 individual lakes with samples from at least 4 different years, loon Hg increased in 34 lakes and decreased in 18 lakes. Overall, we found a delayed recovery of Hg concentrations in loons, despite recent declines in atmospheric Hg.


Metabolic activation of pradefovir by CYP3A4 and its potential as an inhibitor or inducer.
Metabolic activation of pradefovir to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was evaluated by using cDNA-expressed CYP isozymes in portal vein-cannulated rats following oral administration and in human liver microsomes. The enzyme induction potential of pradefovir was evaluated in rats following multiple oral dosing and in primary cultures of human hepatocytes. The results indicated that CYP3A4 is the only cDNA-expressed CYP isozyme catalyzing the conversion of pradefovir to PMEA. Pradefovir was converted to PMEA in human liver microsomes with a K(m) of 60 microM, a maximum rate of metabolism of 228 pmol/min/mg protein, and an intrinsic clearance of about 359 ml/min. Addition of ketoconazole and monoclonal antibody 3A4 significantly inhibits the conversion of pradefovir to PMEA in human liver microsomes, suggesting the predominant role of CYP3A4 in the metabolic activation of pradefovir. Pradefovir at 0.2, 2, and 20 microM was neither a direct inhibitor nor a mechanism-based inhibitor of CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 in human liver microsomes. In rats, the liver was the site of metabolic activation of pradefovir, whereas the small intestine did not play a significant role in the metabolic conversion of pradefovir to PMEA. Daily oral dosing (300 mg/kg of body weight) to rats for 8 days showed that pradefovir was not an inducer of P450 enzymes in rats. Furthermore, pradefovir at 10 microg/ml was not an inducer of either CYP1A2 or CYP3A4/5 in primary cultures of human hepatocytes.


Evidence of linkage between the serotonin transporter and autistic disorder.
The serotonin transporter gene (HTT) is a primary candidate in autistic disorder based on efficacy of potent serotonin transporter inhibitors in reducing rituals and routines. We initiated a candidate gene study of HTT in trios consisting of probands with autistic disorder and both parents. Preliminary transmission/disequilibrium test (TDT) analysis with 86 families revealed no evidence for linkage or linkage disequilibrium between autistic disorder and a polymorphism in the second intron of HTT. However, preferential transmission of a short variant of the HTT promoter was found in the same 86 trios (TDT chi 2 = 4.69, 1 d.f., P = 0.030). In further analyses, we considered haplotypes of the HTT promoter variant and second intron locus as alleles in a multiallelic TDT. Results confirmed the significance of the effect of this region (TDT chi 2 = 11.85, 4 d.f., P = 0.018). This provides preliminary evidence of linkage and association between HTT and autistic disorder.


High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site.
The high overall genetic homology between humans and rhesus macaques, coupled with the phenotypic conservation of lymphocyte populations, highlights the potential use of nonhuman primates (NHPs) for the preclinical evaluation of vaccine candidates. For HIV-1, experimental models are needed to identify vaccine regimens capable of eliciting desired immune responses, such as broadly neutralizing antibodies (bNAbs). One important neutralization target on the HIV-1 envelope glycoproteins (Envs) is the conserved primary CD4 receptor binding site (CD4bs). The isolation and characterization of CD4bs-specific neutralizing monoclonal Abs (mAbs) from HIV-1-infected individuals have provided insights into how broadly reactive Abs target this conserved epitope. In contrast, and for reasons that are not understood, current Env immunogens elicit CD4bs-directed Abs with limited neutralization breadth. To facilitate the use of the NHP model to address this and other questions relevant to human humoral immunity, we defined features of the rhesus macaque immunoglobulin (Ig) loci and compared these to the human Ig loci. We then studied Env-immunized rhesus macaques, identified single B cells expressing CD4bs-specific Abs, and sequenced and expressed a panel of functional mAbs. Comparison of vaccine-elicited mAbs with HIV-1 infection-induced mAbs revealed differences in the degree of somatic hypermutation of the Abs as well as in the fine specificities targeted within the CD4bs. These data support the use of the preclinical NHP model to characterize vaccine-induced B cell responses at high resolution.


Incidence of Adverse Events at 3 Months Versus at 12 Months After Dual Antiplatelet Therapy Cessation in Patients Treated With Thin Stents With Unprotected Left Main or Coronary Bifurcations.
Incidence and predictors of adverse events after dual antiplatelet therapy (DAPT) cessation in patients treated with thin stents (<100 microns) in unprotected left main (ULM) or coronary bifurcation remain undefined. All consecutive patients presenting with a critical lesion of an ULM or involving a main coronary bifurcation who were treated with very thin strut stents were included. MACE (a composite end point of cardiovascular death, myocardial infarction [MI], target lesion revascularization [TLR], and stent thrombosis [ST]) was the primary endpoint, whereas target vessel revascularization (TVR) was the secondary endpoint, with particular attention to type and occurrence of ST and occurrence of ST, CV death, and MI during DAPT or after DAPT discontinuation. All analyses were performed according to length of DAPT dividing the patients in 3 groups: Short DAPT (3-months), intermediate DAPT (3 to 12 months), and long DAPT (12-months). A total of 117 patients were discharged with an indication for DAPT ≤3 months (median 1: 1 to 2.5), 200 for DAPT between 3 and 12 months (median 8: 7 to 10), and 1,958 with 12 months DAPT. After 12.8 months (8 to 20), MACE was significantly higher in the 3-month group compared with 3 to 12 and 12-month groups (9.4% vs 4.0% vs 7.2%, p ≤0.001), mainly driven by MI (4.4% vs 1.5% vs 3%, p ≤0.001) and overall ST (4.3% vs 1.5% vs 1.8%, p ≤0.001). Independent predictors of MACE were low GFR and a 2 stent strategy. Independent predictors of ST were DAPT duration <3 months and the use of a 2-stent strategy. In conclusion, even stents with very thin strut when implanted in real-life ULM or coronary bifurcation patients discharged with short DAPT have a relevant risk of ST, which remains high although not significant after DAPT cessation.


Is antimicrobial susceptibility testing necessary before first-line treatment for Helicobacter pylori infection? Meta-analysis of randomized controlled trials.
With the wide use of antibiotics, antibiotic-resistant Helicobacter pylori strains are becoming increasingly prevalent. It has been hypothesized that culture-guided therapy might help to increase treatment success. But the effects and the costs still remain controversial. To systematically review the efficacy and the cost of culture-guided triple therapy, compared to standard triple regimen for first-line treatment of Helicobacter pylori infection. A search of the Cochrane Library, PubMed, EMBASE, Science Citation Index Expanded and CBM was performed. Randomized controlled trials comparing culture-guided triple therapy to standard triple therapy in the first-line treatment of Helicobacter pylori infection were selected for meta-analysis. Relative risk was used as a measure of the effect of two regimens mentioned above with a fixed-effects model using the methods of DerSimonian and Laird. Five randomized controlled trials totaling 701 patients were included. The meta-analysis showed that culture-guided triple therapy was superior referring to a higher eradication rate from intention-to-treat analyses (RR, 0.84; 95% CI,0.77, 0.90; p<0.00001) and a lower overall cost. Culture-guided triple therapy was more effective than standard triple therapy for first-line treatment of Helicobacter pylori infection. Based on the only paper focused on the overall cost, the culture-guided triple therapy was also more cost saving. Antimicrobial susceptibility testing is necessary before first-line treatment for Helicobacter pylori infection.


Control of differentiation in human colorectal carcinoma cell lines: epithelial-mesenchymal interactions.
Mesenchymal elements have been investigated for their effects on the growth and differentiation of seven human colorectal carcinoma-derived cell lines. Epithelial cells were cultured as monolayers on plastic; they were also grown on fibroblast lawns and in collagen matrices, with and without fibroblasts. In each case, differentiation was assessed morphologically with monoclonal antibodies directed against components of normal goblet and columnar cells. The results were compared with those obtained when the cell lines were grown in vivo as xenografts in athymic mice. The xenografts allowed the greatest potential for differentiation, although two cell lines showed little or no response to mesenchyme either in vivo or in vitro. The presence of fibroblasts induced branched structures in all the remaining lines when these were cultured in collagen matrices. The collage matrix alone induced the formation of well-defined glandular structures in SW1222 cells, reminiscent of those seen in SW1222 xenografts and normal colonic crypts. Epithelial response to mesenchymal factors may require specific receptors, the expression of which dictates phenotype. Isolation and analysis of such receptors and factors could lead to clarification of the mechanisms underlying normal tissue morphogenesis and the growth and spread of neoplastic cells.


Factors impacting HIV testing: a review--perspectives from Australia, Canada, and the UK.
With the current global focus on strengthening HIV prevention through greater testing and treatment uptake, it is increasingly salient to identify and address barriers to testing. A review of the published, peer-reviewed literature and national reports from Australia, Canada, and the UK (2003-2013) on barriers to HIV testing was conducted to provide new information relevant to Australia and to complement earlier reviews from Canada and the UK. A systematic database search using keywords and a set of inclusion criteria yielded 36 studies (Australia = 13; Canada = 6; and the UK = 17). In addition 17 unpublished reports were included in the review. Our study uses a novel, comprehensive framework to describe barriers to HIV testing, and thus contributes to moving beyond the traditional patient-provider-system categorization. Within that framework, barriers are categorized as either intrapersonal (reported in 15 studies), interpersonal (21), or extrapersonal (16) and conceptualized within wider sociocultural and structural contexts. People's abilities and motivations to test (intrapersonal factors) are influenced by a host of interconnected factors spanning relationship (interpersonal) and broader socioeconomic, political and cultural (extrapersonal) factors. We suggest that the relative effects of interventions targeting barriers to HIV testing at the intrapersonal and interpersonal levels are limited by the extent to which the social determinants of health are addressed. The framework may also lend itself to thinking about the enabling factors for HIV testing, and future research may investigate the application of that framework for strategizing the most effective response. Future studies should also capture the lived experiences of barriers to HIV testing experienced by patients, especially in populations which are hard to reach based on social and geographic distance. Context-specific studies to evaluate the feasibility and effectiveness of various interventions proposed in the literature to address barriers to HIV testing are needed.


Survival of coliforms and bacterial pathogens within protozoa during chlorination.
The susceptibility of coliform bacteria and bacterial pathogens to free chlorine residuals was determined before and after incubation with amoebae and ciliate protozoa. Viability of bacteria was quantified to determine their resistance to free chlorine residuals when ingested by laboratory strains of Acanthamoeba castellanii and Tetrahymena pyriformis. Cocultures of bacteria and protozoa were incubated to facilitate ingestion of the bacteria and then were chlorinated, neutralized, and sonicated to release intracellular bacteria. Qualitative susceptibility of protozoan strains to free chlorine was also assessed. Protozoa were shown to survive and grow after exposure to levels of free chlorine residuals that killed free-living bacteria. Ingested coliforms Escherichia coli, Citrobacter freundii, Enterobacter agglomerans, Enterobacter cloacae, Klebsiella pneumoniae, and Klebsiella oxytoca and bacterial pathogens Salmonella typhimurium, Yersinia enterocolitica, Shigella sonnei, Legionella gormanii, and Campylobacter jejuni had increased resistance to free chlorine residuals. Bacteria could be cultured from within treated protozoans well after the time required for 99% inactivation of free-living cells. All bacterial pathogens were greater than 50-fold more resistant to free chlorine when ingested by T. pyriformis. Escherichia coli ingested by a Cyclidium sp., a ciliate isolated from a drinking water reservoir, were also shown to be more resistant to free chlorine. The mechanism that increased resistance appeared to be survival within protozoan cells. This study indicates that bacteria can survive ingestion by protozoa. This bacterium-protozoan association provides bacteria with increased resistance to free chlorine residuals which can lead to persistence of bacteria in chlorine-treated water. We propose that resistance to digestion by predatory protozoa was an evolutionary precursor of pathogenicity in bacteria and that today it is a mechanism for survival of fastidious bacteria in dilute and inhospitable aquatic environments.


A multidimensional segmentation evaluation for medical image data.
Evaluation of segmentation methods is a crucial aspect in image processing, especially in the medical imaging field, where small differences between segmented regions in the anatomy can be of paramount importance. Usually, segmentation evaluation is based on a measure that depends on the number of segmented voxels inside and outside of some reference regions that are called gold standards. Although some other measures have been also used, in this work we propose a set of new similarity measures, based on different features, such as the location and intensity values of the misclassified voxels, and the connectivity and the boundaries of the segmented data. Using the multidimensional information provided by these measures, we propose a new evaluation method whose results are visualized applying a Principal Component Analysis of the data, obtaining a simplified graphical method to compare different segmentation results. We have carried out an intensive study using several classic segmentation methods applied to a set of MRI simulated data of the brain with several noise and RF inhomogeneity levels, and also to real data, showing that the new measures proposed here and the results that we have obtained from the multidimensional evaluation, improve the robustness of the evaluation and provides better understanding about the difference between segmentation methods.


Outcome of untethering for symptomatic spina bifida occulta with lumbosacral spinal cord tethering in 31 patients: analysis of preoperative prognostic factors.
The most important goal for treating symptomatic lumbosacral spinal cord tethering is early untethering. To investigate preoperative symptoms that may have affected the outcome. Patients with or without improvement and with or without favorable outcome after untethering were compared retrospectively by chart and image review. Thirty-one patients (age between 2 days to 25 years) with spina bifida occulta and symptomatic cord tethering were analyzed. Presenting symptoms (neurological deficits, urological dysfunction, and lower limb deformities) were assessed before and after untethering. Favorable outcome was defined as complete relief of symptoms or mild symptoms whereby patients are able to look after their own personal care without assistance. Unfavorable outcome was defined as moderate or severe disability whereby patients are unable to attend to their own bodily needs without assistance, are bedridden, or require constant nursing attention. Differences in patient characteristics and presenting symptoms were compared between those with and without clinical improvement and favorable outcome. Multivariate logistic regression was used to identify prognostic factors affecting the outcome. The average age at surgery was 7.2 years, with a male-to-female ratio of 1.2. The average follow-up time was 4 years. At least one of the following symptoms was present in all patients: neurological deficits (83.9%), urological dysfunction (77.4%), or limb deformities (38.7%). After untethering, all patients had either symptoms stabilized (14 patients, 45.2%) or improved (17 patients, 54.8%), and 14 patients (45.2%) achieved total resolving of symptoms. Logistic regression confirmed that younger age (< or =2 years, odds ratio [OR] 22.0, p=.026), lipomas of filum terminale (OR 25.6, p=.042), and a poor anal tone (OR 10.4, p=.061) were positive prognostic factors for the improvement in symptoms. The functional outcome was determined by the age at surgery (OR 0.9 per year since 1 year old, p=.04) and the presence of limb deformities (OR 0.06, p=.017). In conclusion, our study suggests that untethering should be performed immediately once the patient shows evidence of symptomatic lumbosacral cord tethering, irrespective of age. Untethering can interrupt progression of symptoms, but sphincter dysfunction and muscle weakness are more likely to improve or resolve. Benefits can be seen in all patients, but young children (before 2 years old) have a higher chance to gain favorable outcome. Retethering is a main concern during follow-up, particularly for the more complicated lipomyelomeningoceles. Investigations using electrophysiologic and urodynamic studies are helpful for early detection of subtle symptomatic cord tethering or retethering.


Effects of incomplete pulmonary gas exchange on VO2 max.
Recent evidence suggests that heavy exercise may lower the percentage of O2 bound to hemoglobin (%SaO2) by greater than or equal to 5% below resting values in some highly trained endurance athletes. We tested the hypothesis that pulmonary gas exchange limitations may restrict VO2max in highly trained athletes who exhibit exercise-induced hypoxemia. Twenty healthy male volunteers were divided into two groups according to their physical fitness status and the demonstration of exercise-induced reductions in %SaO2 less than or equal to 92%: 1) trained (T), mean VO2max = 56.5 ml.kg-1.min-1 (n = 13) and 2) highly trained (HT) with maximal exercise %SaO2 less than or equal to 92%, mean VO2max = 70.1 ml.kg-1.min-1 (n = 7). Subjects performed two incremental cycle ergometer exercise tests to determine VO2max at sea level under normoxic (21% O2) and mild hyperoxic conditions (26% O2). Mean %SaO2 during maximal exercise was significantly higher (P less than 0.05) during hyperoxia compared with normoxia in both the T group (94.1 vs. 96.1%) and the HT group (90.6 vs. 95.9%). Mean VO2max was significantly elevated (P less than 0.05) during hyperoxia compared with normoxia in the HT group (74.7 vs. 70.1 ml.kg-1.min-1). In contrast, in the T group, no mean difference (P less than 0.05) existed between treatments in VO2max (56.5 vs. 57.1 ml.kg-1.min-1). These data suggest that pulmonary gas exchange may contribute significantly to the limitation of VO2max in highly trained athletes who exhibit exercise-induced reductions in %SaO2 at sea level.(ABSTRACT TRUNCATED AT 250 WORDS)


Psychometric Validation of the Academic Motivation Scale in a Dental Student Sample.
The Academic Motivation Scale is one of the most frequently used instruments to assess academic motivation. It relies on the self-determination theory of human motivation. However, motivation has been understudied in dental education. Therefore, to address the lack of valid instruments to assess academic motivation in dental education and contribute to future research in the field, the aim of this study was to analyze the psychometric properties of this instrument in a sample of dental students. Participants were 989 Chilean undergraduate dental students (86% response rate) who completed a survey containing a Chilean face-valid version of the Spanish Academic Motivation Scale and three other motivation-related instruments to assess the survey's construct and criterion validity. Later, 76 of the students (out of 100 invited) took the survey again to assess its test-retest stability. The instrument's construct validity was supported by the superior goodness of fit of the seven-subscale Academic Motivation Scale over competing models through confirmatory factor analysis and by the expected correlations among its subscales. The concurrent criterion validity was supported by the confirmation of correlations between its subscales and external criteria. Adequate internal consistency and test-retest correlations were also found. The evidence from this study suggests that the Academic Motivation Scale is a preliminarily valid and reliable instrument to assess motivation in the predoctoral dental context. Future research in this area is needed to confirm or refute these results.


Angiotensin II attenuates renal cortical cyclooxygenase-2 expression.
We have previously shown that in rat renal cortex, cyclooxygenase-2 (COX-2) expression is localized to cTALH cells in the region of the macula densa, and that dietary salt restriction increases COX-2 expression. Administration of the angiotensin converting inhibitor, captopril, further increased COX-2 mRNA and renal cortical COX-2 immunoreactivity, with the most pronounced expression in the macula densa. Administration of an AT1 receptor antagonist, losartan, also significantly increased cortical COX-2 mRNA expression and COX-2 immunoreactivity. Mutant mice homozygous for both Agtr1a and Agtr1b null mutations (Agtr1a-/-,Agtr1b-/-) demonstrated large increases in immunoreactive COX-2 expression inthe cTALH/macula densa. To determine whether increased COX-2expression in response to ACE inhibition mediated increases in renin production, rats were treated with captopril for one week with or without the specific COX-2 inhibitor, SC58236. Plasma renin activity increased significantly in the captropril group, and this increase was significantly inhibited by simultaneous treatment with SC58236. Thus, these studies indicated that angiotensin II inhibitors augment upregulation of renal cortical COX-2 in states of volume depletion, suggesting that negative feedback by the renin-angiotensin system modulates renal cortical COX-2 expression and that COX-2 is a mediator of increased renin production in response to inhibition of angiotension II production.


A Set of Functional Brain Networks for the Comprehensive Evaluation of Human Characteristics.
Many human characteristics must be evaluated to comprehensively understand an individual, and measurements of the corresponding cognition/behavior are required. Brain imaging by functional MRI (fMRI) has been widely used to examine brain function related to human cognition/behavior. However, few aspects of cognition/behavior of individuals or experimental groups can be examined through task-based fMRI. Recently, resting state fMRI (rs-fMRI) signals have been shown to represent functional infrastructure in the brain that is highly involved in processing information related to cognition/behavior. Using rs-fMRI may allow diverse information about the brain through a single MRI scan to be obtained, as rs-fMRI does not require stimulus tasks. In this study, we attempted to identify a set of functional networks representing cognition/behavior that are related to a wide variety of human characteristics and to evaluate these characteristics using rs-fMRI data. If possible, these findings would support the potential of rs-fMRI to provide diverse information about the brain. We used resting-state fMRI and a set of 130 psychometric parameters that cover most human characteristics, including those related to intelligence and emotional quotients and social ability/skill. We identified 163 brain regions by VBM analysis using regression analysis with 130 psychometric parameters. Next, using a 163 × 163 correlation matrix, we identified functional networks related to 111 of the 130 psychometric parameters. Finally, we made an 8-class support vector machine classifiers corresponding to these 111 functional networks. Our results demonstrate that rs-fMRI signals contain intrinsic information about brain function related to cognition/behaviors and that this set of 111 networks/classifiers can be used to comprehensively evaluate human characteristics.


Increased Mast Cell Counts and Degranulation in Microscopic Colitis.
Microscopic colitis (MC) is characterized by chronic diarrhea, normal colonoscopy findings, and mucosal inflammation in colonic biopsies and can be classified as collagenous colitis (CC) or lymphocytic colitis (LC). However, the pathogenesis of MC is largely unknown. In this study, we aimed to study mast cell counts and activation in MC. We investigated 64 biopsy samples from the surgical pathology database of Indiana University Health, which met the diagnostic criteria for CC or LC along with 20 control samples collected from 2014 to 2015. The specimens were used for the quantification of mast cells by examining the presence of intracellular and extracellular tryptase by immunohistochemistry. In the lamina propria, the mast cell count was higher in both CC and LC groups than the control (mean highest count, 39/high-power field (HPF) vs. 30/HPF vs. 23/HPF; P < 0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (P < 0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (P < 0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (. The increased mast cell count and degranulation are identified in MC, suggesting that mast cell activation might be involved in the pathogenesis of MC.


Black cumin seed essential oil, as a potent analgesic and antiinflammatory drug.
The steam-distilled essential oil of Iranian black cumin seed (Nigella sativa L.) was investigated for its composition and analgesic and antiinflammatory properties. After oil analysis by GC/MS, 20 compounds were identified in the oil, obtained in 0.4% (v/w) yield. Among them, para-cymene (37.3%) and thymoquinone (13.7%) were the major components. Acetic acid-induced writhing, formalin and light tail flick tests were used for assessment of analgesic activity. Antiinflammatory activity was evaluated using carrageenan-induced paw oedema in rats and croton oil-induced ear oedema in mice. Black cumin seed essential oil (BCSEO) was found to produce a significant analgesic effect in acetic acid-induced writhing, formalin and light tail flick tests. Naloxone, an opioid antagonist, could not reverse the analgesic effect observed in the formalin test. Although oral administration of BCSEO at doses of 100, 200 and 400 micro L/kg did not exert a significant antiinflammatory effect in the carrageenan test, i.p. injection of the same doses significantly (p < 0.001) inhibited carrageenan-induced paw oedema. BCSEO at doses of 10 and 20 micro L/ear could also reduce croton oil-induced oedema. It seems that mechanism(s) other than opioid receptors is (are) involved in the analgesic effect of BCSEO since naloxone could not reverse this effect. Both systemic and local administration of BCSEO showed antiinflammatory activity. Thymoquinone, as one of the major components of BCSEO, probably has an important role in these pharmacological effects.


Demographics of patients affected by surgical disease in rural hospitals in two sub-Saharan African countries: a retrospective analysis.
Awareness is growing of both the importance of surgical disease as a major cause of death and disability in low-income and middle-income countries (LMICs) and the cost-effectiveness of fairly simple surgical interventions. We hypothesised that surgical disease predominantly affects young adults and is therefore significant in both the macroeconomic effect of untreated disease and the microeconomic effects on patients and families in low-resource settings. We retrospectively reviewed all admission data from two rural government district hospitals, Bo District Hospital in Sierra Leone and Thyolo District Hospital in Malawi. Both hospitals serve a rural population of roughly 600 000. We analysed data from 3 months in the wet season and 3 months in the dry season for each hospital by careful analysis of all hospital logbook data. For the purposes of this study, a surgical diagnosis was defined as a diagnosis in which the patient should be managed by a surgically trained provider. We analysed all surgical admissions with respect to patient demographics (age and sex), diagnoses, and the procedures undertaken. In Thyolo, 835 (12·9%) of 6481 hospital admissions were surgical admissions. In Bo, 427 (19·8%) of 2152 hospital admissions were surgical admissions. In Thyolo, if all patients who had undergone a procedure in theatre were admitted overnight, the total number of admissions would have been 6931, with 1344 (19·4%) hospital admissions being surgical and 1282 (18·5%) hospital patients requiring a surgical procedure. In Bo, 133 patients underwent a surgical procedure. This corresponded to 6·18% of all hospital admissions; although notably many of the obstetric admissions were referred to a nearby Médecins Sans Frontières (MSF) hospital for treatment. Analysis of the admission data showed that younger than 16-year-olds accounted for 10·5% of surgical admissions in Bo, and 17·9% of surgical admissions in Thyolo. 16-35-year-olds accounted for 57·3% of all surgical admissions in Bo and 53·5% of all surgical admissions in Thyolo. Men accounted for 53·7% of surgical admissions in Bo and 46·0% of surgical admissions in Thyolo. Analysis of the procedure data showed that younger than 16-year-olds accounted for 7·0% of procedures in Bo and 4·5% of procedures in Thyolo, with 16-35-year-olds accounting for 65·6% of all procedures in Bo and 84·4% of all procedures in Thyolo. Men underwent 63% of all surgical procedures in Bo, but only 7·7% of surgical procedures in Thyolo. This discrepancy is explained by the high rate of maternal surgery in Thyolo, which was not present in Bo because this service was provided at the nearby MSF hospital. Most people affected by disease requiring surgery are young adults. It would be expected that failure to provide surgical care could have long-term adverse effects on both individual and national wealth. The Sir Ratanji Dalal Scholarship from the Royal College of Surgeons of England.


Patterns of diversification and ancestral range reconstruction in the southeast Asian-Pacific angiosperm lineage Cyrtandra (Gesneriaceae).
The genus Cyrtandra is the largest in the Gesneriaceae family and is one of the most widely dispersed plant genera in southeast Asia and the Pacific. Species of Cyrtandra are morphologically diverse but characters are often homoplastic causing considerable difficulty in defining monophyletic classification units. In this study, we used molecular phylogenetic analysis of 88 taxa representing approximately 70 species to construct a well-resolved evolutionary hypothesis for Cyrtandra. Diversification rates analysis and ancestral range analysis were also conducted to infer timing of major lineage divergences and geographic origin of these lineages, principally among Pacific species. Using these data, we compared existing classification schemes to better understand the applicability of current taxonomy. Divergence time estimates support a diversification of the Pacific clade at approximately 20 MYBP. Although the origin of the Pacific lineage remains unresolved, ancestral range reconstruction analysis supports Fiji as the most likely "first-step" into the Pacific with subsequent dispersals to Hawai'i, and other archipelagos. A greater Fiji-Samoa region, corresponding with Takhtajan's Fijian Region, is implicated as a major Pacific region interface and possibly a center of origin for expansion of Cyrtandra throughout the Pacific. Among South Pacific taxa sampled, several supported clades in our evolutionary hypothesis are characterized by distinct morphological traits possibly warranting sectional rankings. Relationships among Hawaiian taxa are less resolved and the distributions of species within this clade do not consistently correspond to existing sectional rankings. More detailed, population-level research is needed to clarify these relationships. We argue that future sectional classifications should correspond with monophyletic lineages and that species-level relationships should be more closely studied within these lineages.


Endoscopic ultrasound fine-needle aspiration characteristics of primary adenocarcinoma versus other malignant neoplasms of the pancreas.
Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) is often used to assist in the evaluation of pancreatic lesions and may help to diagnose benign versus malignant neoplasms. However, there is a paucity of literature regarding comparative EUS characteristics of various malignant pancreatic neoplasms (primary and metastatic). To compare and characterize primary pancreatic adenocarcinoma versus other malignant neoplasms, hereafter referred to as nonprimary pancreatic adenocarcinoma (NPPA), diagnosed by EUS-guided FNA. The present study was a retrospective analysis of a prospectively maintained database. The setting was a tertiary care, academic medical centre. Patients referred for suspected pancreatic neoplasms were evaluated. Based on EUS-FNA characteristics, primary pancreatic adenocarcinoma was differentiated from other malignant neoplasms. The subset of other neoplasms was defined as malignant lesions that were 'NPPAs' (ie, predominantly solid or solid⁄cystic based on EUS appearance and primary malignant lesions or metastatic lesions to the pancreas). Pancreatic masses that were benign cystic lesions (pseudocyst, simple cyst, serous cystadenoma) and focal inflammatory lesions (acute, chronic and autoimmune pancreatitis) were excluded. A total of 230 patients were evaluated using EUS-FNA for suspected pancreatic mass lesions. Thirty-eight patients were excluded because they were diagnosed with inflammatory lesions or had purely benign cysts. One hundred ninety-two patients had confirmed malignant pancreatic neoplasms (ie, pancreatic adenocarcinoma [n=144], NPPA [n=48]). When comparing adenocarcinoma with NPPA lesions, there was no significant difference in mean age (P=0.0675), sex (P=0.3595) or average lesion size (P=0.3801). On average, four FNA passes were necessary to establish a cytological diagnosis in both lesion subtypes (P=0.396). Adenocarcinomas were more likely to be located in the pancreatic head (P=0.0198), whereas masses in the tail were more likely to be NPPAs (P=0.0006). Adenocarcinomas were also more likely to exhibit vascular invasion (OR 4.37; P=0.0011), malignant lymphadenopathy (P=0.0006), pancreatic duct dilation (OR 2.4; P=0.022) and common bile duct dilation (OR 2.87; P=0.039). Adenocarcinoma was more likely to be present in the head of the pancreas, have lymph node and vascular involvement, as well as evidence of pancreatic duct and common bile duct obstruction. Of all malignant pancreatic lesions analyzed by EUS-FNA, 25% were NPPA, suggesting that FNA is crucial in establishing a diagnosis and may be helpful in preoperative planning.


Anti-Atherosclerotic Effects of Vitamins D and E in Suppression of Atherogenesis.
Atherosclerosis is a progressive and multifactorial disease which occurs under the influence of various risk factors including endothelial dysfunction (ED), oxidative stress, and low-density lipoprotein (LDL) oxidation. In contract to the initial hypotheses on the usefulness of vitamin E supplementation for cardiovascular disease prevention, large outcome trials showed consumption of vitamin E has no obvious effect on cardiovascular disease and, in some cases, it may even increase the rate of mortality. This seemingly unexpected finding may be due to the opposite effects of vitamin E compounds. Vitamin E is a group of compounds which have different and even opposing effects, yet in most of the studies, the exact consumed component of vitamin E is not determined. It appears that the combined consumption of gamma-tocopherol, vitamin C, D, and tetrahydrobiopterin (BH4) may be extremely effective in both preventing atherogenesis and suppressing plaque development. In this regard, one of main issues is effect of vitamins E and D deficiency on microRNAs network in atherosclerosis. Various studies have indicated that miRNAs have key roles in atherosclerosis pathogenesis. The deficiency of vitamins E and D could provide a deregulation for miRNAs network and these events could lead to progression of atherosclerosis. Here, we highlighted a variety of mechanisms involve in the progression of atherosclerosis and effects of vitamins D and E on these mechanisms. Moreover, we summarized miRNAs involve in atherosclerosis and their regulation by vitamins E and D deficiency. J. Cell. Physiol. 232: 2968-2976, 2017. © 2016 Wiley Periodicals, Inc.