Feeding cues alter clock gene oscillations and photic responses in the suprachiasmatic nuclei of mice exposed to a light/dark cycle.
The suprachiasmatic nuclei (SCN) of the hypothalamus contain the master mammalian circadian clock, which is mainly reset by light. Temporal restricted feeding, a potent synchronizer of peripheral oscillators, has only weak influence on light-entrained rhythms via the SCN, unless restricted feeding is coupled with calorie restriction, thereby altering phase angle of photic synchronization. Effects of daytime restricted feeding were investigated on the mouse circadian system. Normocaloric feeding at midday led to a predominantly diurnal (60%) food intake and decreased blood glucose in the afternoon, but it did not affect the phase of locomotor activity rhythm or vasopressin expression in the SCN. In contrast, hypocaloric feeding at midday led to 2-4 h phase advances of three circadian outputs, locomotor activity rhythm, pineal melatonin, and vasopressin mRNA cycle in the SCN, and it decreased daily levels of blood glucose. Furthermore, Per1 and Cry2 oscillations in the SCN were phase advanced by 1 and 3 h, respectively, in hypocalorie- but not in normocalorie-fed mice. The phase of Per2 and Bmal1 expression remained unchanged regardless of feeding condition. Moreover, the shape of behavioral phase-response curve to light and light-induced expression of Per1 in the SCN were markedly modified in hypocalorie-fed mice compared with animals fed ad libitum. The present study shows that diurnal hypocaloric feeding affects not only the temporal organization of the SCN clockwork and circadian outputs in mice under light/dark cycle but also photic responses of the circadian system, thus indicating that energy metabolism modulates circadian rhythmicity and gating of photic inputs in mammals.


Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States.
A clinical trial of vitamin E and beta-carotene supplementation for lung cancer prevention among male smokers in Finland recently reported an unexpected, strong protective effect of vitamin E against prostate cancer incidence and mortality. Our objective was to prospectively examine supplemental vitamin E intake and prostate cancer risk in a distinct U.S. population. In 1986, we identified 47,780 U.S. male health professionals, free from diagnosed cancer, who completed a dietary and lifestyle questionnaire; supplemental vitamin E and prostate cancer incidence were updated biennially through 1996. We estimated relative risks (RRs) from multivariate pooled logistic regression models. There were 1896 total (non-stage A1), 522 extraprostatic, and 232 metastatic or fatal incident prostate cancer cases diagnosed between 1986-1996. Men consuming at least 100 IU of supplemental vitamin E daily had multivariate RRs of 1.07 (95% confidence interval [CI], 0.95-1.20) for total and 1.14 (95% CI, 0.82-1.59) for metastatic or fatal prostate cancer compared with those consuming none. Current use, dosage, and total duration of use of specific vitamin E supplements or multivitamins were not associated with risk. However, among current smokers and recent quitters, those who consumed at least 100 IU of supplemental vitamin E per day had a RR of 0.44 (95% CI, 0.18-1.07) for metastatic or fatal prostate cancer compared with nonusers. Thus, supplemental vitamin E was not associated with prostate cancer risk generally, but a suggestive inverse association between supplemental vitamin E and risk of metastatic or fatal prostate cancer among current smokers and recent quitters was consistent with the Finnish trial among smokers and warrants further investigation.


Recent advances in the research and development of RAF kinase inhibitors.
The RAS-RAF-MEK-ERK signaling pathway (ERK pathway) plays a key role in tumorigenesis and cancer progression. Mutations of RAS or B-RAF lead to a constitutive activation of the ERK pathway, which ultimately results in increased cell division, and cell survival. This review article focuses on the recent literature related to ERK pathway inhibitors, with a particular emphasis on RAF kinase inhibitors. Preclinical and clinical data for the RAF kinase inhibitor sorafenib (BAY 43-9006 tosylate), that was recently approved in the US for the treatment of advanced renal cell carcinoma, are also outlined.


Powering Research through Innovative Methods for Mixtures in Epidemiology (PRIME) Program: Novel and Expanded Statistical Methods.
Humans are exposed to a diverse mixture of chemical and non-chemical exposures across their lifetimes. Well-designed epidemiology studies as well as sophisticated exposure science and related technologies enable the investigation of the health impacts of mixtures. While existing statistical methods can address the most basic questions related to the association between environmental mixtures and health endpoints, there were gaps in our ability to learn from mixtures data in several common epidemiologic scenarios, including high correlation among health and exposure measures in space and/or time, the presence of missing observations, the violation of important modeling assumptions, and the presence of computational challenges incurred by current implementations. To address these and other challenges, NIEHS initiated the Powering Research through Innovative methods for Mixtures in Epidemiology (PRIME) program, to support work on the development and expansion of statistical methods for mixtures. Six independent projects supported by PRIME have been highly productive but their methods have not yet been described collectively in a way that would inform application. We review 37 new methods from PRIME projects and summarize the work across previously published research questions, to inform methods selection and increase awareness of these new methods. We highlight important statistical advancements considering data science strategies, exposure-response estimation, timing of exposures, epidemiological methods, the incorporation of toxicity/chemical information, spatiotemporal data, risk assessment, and model performance, efficiency, and interpretation. Importantly, we link to software to encourage application and testing on other datasets. This review can enable more informed analyses of environmental mixtures. We stress training for early career scientists as well as innovation in statistical methodology as an ongoing need. Ultimately, we direct efforts to the common goal of reducing harmful exposures to improve public health.


Association between socioeconomic status and obesity in children.
The perception of obesity among people has not changed significantly regardless numerous public educational programs. Reasons for obesity pandemics are numerous and complex, but can be mostly resumed to life-style changes. The aim of this research was to determine connection between socioeconomic factors and obesity with children of our region. Study included pupils aged 7-8 from 19 first grades in 8 primary schools in Osijek-Baranya County. Body height and weight were measured and socioeconomic data status were collected. Socioeconomic status included data on marital status, educational level, employment, number of children in the family, kindergarten attendance and urban/rural location and also smoking habits of parents. BMI was calculated as a parameter for obesity assessment according to Croatian reference values. Total of 372 children were measured. There were 6.5% of overweight children (BMI between 90th and 97th percentile) and 2.4% of obese children (BMI above 97th percentile). The prevalence of obese children in our research was 8.9%. Obesity is not influenced by rural/urban residence, marital status of parents, number of children in the family, mother's education, or by parents' smoking habits. Positive correlation between obesity and father's education and parents' unemployment was found. Available literature data, same as our study, did not show consistent association between socioeconomic factors and obesity with children. Contradictory results of different studies can be a result of a small sample, difference in study design and different criteria for defining categories within investigated socioeconomic factor.


Oligo Tröger's bases--new molecular scaffolds.
Oligo Tröger's bases are compounds containing two or more Tröger's base subunits (1,5-methanodiareno[b,f][1,5]diazocines) sharing one or more arene parts. Due to their interesting molecular shapes, these compounds are studied as chiral molecular tweezers, clips, cavitands, clefts, calixes, etc. This review includes all available data on oligo Tröger's bases, and introduces their preparation and properties to a wide audience.


Cancer-Related Ischemic Stroke Has a Distinct Blood mRNA Expression Profile.
Background and Purpose- Comorbid cancer is common in patients with acute ischemic stroke (AIS). As blood mRNA profiles can distinguish AIS mechanisms, we hypothesized that cancer-related AIS would have a distinctive gene expression profile. Methods- We evaluated 4 groups of 10 subjects prospectively enrolled at 3 centers from 2009 to 2018. This included the group of interest with active solid tumor cancer and AIS and 3 control groups with active cancer only, AIS only, or vascular risk factors only. Subjects in the AIS-only and cancer-only groups were matched to subjects in the cancer-stroke group by age, sex, and cancer type (if applicable). Subjects in the vascular risk factor group were matched to subjects in the cancer-stroke and stroke-only groups by age, sex, and vascular risk factors. Blood was drawn 72 to 120 hours after stroke. Total RNA was processed using 3' mRNA sequencing. ANOVA and Fisher least significant difference contrast methods were used to estimate differential gene expression between groups. Results- In the cancer-stroke group, 50% of strokes were cryptogenic. All groups had differentially expressed genes that could distinguish among them. Comparing the cancer-stroke group to the stroke-only group and after accounting for cancer-only genes, 438 genes were differentially expressed, including upregulation of multiple genes/pathways implicated in autophagy signaling, immunity/inflammation, and gene regulation, including IL (interleukin)-1, interferon, relaxin, mammalian target of rapamycin signaling, SQSTMI1 (sequestosome-1), and CREB1 (cAMP response element binding protein-1). Conclusions- This study provides evidence for a distinctive molecular signature in blood mRNA expression profiles of patients with cancer-related AIS. Future studies should evaluate whether blood mRNA can predict detection of occult cancer in patients with AIS. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT02604667.


[Is therapy with local infiltrations feasible in primary care consultations?].
To study the feasibility of local infiltration in primary care consultations. Before-and-after intervention study. Two clinics at an urban health centre. Patients diagnosed with pathology of tender areas and treated with corticosteroid infiltration between May 1997 and May 1998. Corticoid infiltration plus local anaesthetic. Weekly check-up. Analysis of the variables: sex, age, diagnosis, time elapsed between indication and start of treatment, subjective assessment of pain before and after treatment (VRS scale), number of infiltrations per patient, side-effects. Evaluation of overall and individual effectiveness. 41 patients were infiltrated. Average age was 58. Most common pathologies were: rotary joint tendinitis (48.7%), anserine bursitis (24.4%), plantar fasciitis (7.3%). Average number of infiltrations per pathology: 1.3. Mean waiting time: 3.5 days. Comparison of pain by means of VRS (range 0-5) before and after treatment used the Wilcoxon test, with a statistically significant difference and p < 0.001 (z = -5.5109). For 35 patients (85.4%), pain was solved very well (values 0 and 1 on the VRS). For 3 patients (7.3%), improvement was moderate; and for 3 (7.3%) there was no improvement. 1. Treatment with local infiltration of corticosteroids is effective in dealing with pain, and is an alternative to treatment with NSAIDs. 2. It is feasible in primary care, and there are many advantages if the general practitioner employs this therapeutic technique.


Technical consideration of the MOVARPE technique in intricate pectus excavatum deformity.
For the correction of pectus excavatum (PE) deformities in adolescents, adults, and generally in asymmetric cases, a semi-open approach called the MOVARPE (minor open videoendoscopically assisted repair of pectus excavatum) technique is used, consisting of standard pectus bar implantation hybridized with auxiliary sternum osteotomy and multiple chondrotomies. In this study, we report our experiences, discuss pros and cons, and provide technical refinements. Between September 2005 and March 2015, 61 patients were selected to undergo the MOVARPE instead of the standard MIRPE (minimally invasive repair of pectus excavatum) procedure because of age or specific morphologic characteristics of PE. Patient age ranged from 14 to 45 years (mean 23.4 years). Auxiliary incisions for skeletal relaxation enabled symmetric remodeling and, in most cases, circumvented the need for a second pectus bar. The bars were left in position for a mean of 19.3 months (range: 12 to 35 months). There were no major complications. Minor complications such as pleural effusion, temporary pneumothorax, and mild recurrence of the deformity after bar removal were seen at rates similar to those for standard techniques. In the current study reporting outcomes of the previously described MOVARPE procedure, the authors saw no evidence of a possible disadvantage in the overall concept or execution of the procedure for the suggested indication. From this experience, we can state that, as an alternative to the MIRPE technique, MOVARPE is a method that offers high efficacy, particularly for rigid and complex pectus excavatum deformities at or beyond puberty.


Children's perceptions of rainforest biodiversity: which animals have the lion's share of environmental awareness?
Globally, natural ecosystems are being lost to agricultural land at an unprecedented rate. This land-use often results in significant reductions in abundance and diversity of the flora and fauna as well as alterations in their composition. Despite this, there is little public perception of which taxa are most important in terms of their total biomass, biodiversity or the ecosystem services they perform. Such awareness is important for conservation, as without appreciation of their value and conservation status, species are unlikely to receive adequate conservation protection. We investigated children's perceptions of rainforest biodiversity by asking primary-age children, visiting the University Museum of Zoology, Cambridge to draw their ideal rainforest. By recording the frequency at which children drew different climatic, structural, vegetative and faunal components of the rainforest, we were able to quantify children's understanding of a rainforest environment. We investigated children's perceptions of rainforest biodiversity by comparing the relative numbers of the taxa drawn with the actual contributions made by these taxa to total rainforest biomass and global biodiversity. We found that children have a sophisticated view of the rainforest, incorporating many habitat features and a diverse range of animals. However, some taxa were over-represented (particularly mammals, birds and reptiles) and others under-represented (particularly insects and annelids) relative to their contribution to total biomass and species richness. Scientists and naturalists must continue to emphasise the diversity and functional importance of lesser-known taxa through public communication and outdoor events to aid invertebrate conservation and to ensure that future generations are inspired to become naturalists themselves.


Pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis: New insights on an old topic.
Pancreatic function testing and imaging are used to inform the diagnosis of chronic pancreatitis, but most of these methods are time- and cost-consuming or lack diagnostic accuracy. We investigated the utility of pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis. This was a prospective study of 121 consecutive patients with chronic pancreatitis and a reference population of 94 healthy controls. Pancreas-specific plasma amylase level was determined and analysed for its association with exocrine pancreatic insufficiency, diabetes and other clinical variables. Receiver operating characteristic curve analyses were performed to determine the diagnostic utility of plasma amylase for diagnosing chronic pancreatitis and to study associations with disease severity. The findings were validated in a further cohort of 57 patients with chronic pancreatitis. Significant and independent associations between plasma amylase level and duration of chronic pancreatitis as well as the presence of exocrine pancreatic insufficiency and diabetes were observed (all p < 0.001). An amylase level below 17.3 U/l had a high specificity (94%) and moderate sensitivity (59%) for the diagnosis of chronic pancreatitis. Diagnostic performance was influenced by disease stage with the best performance observed for advanced disease. The findings were replicated in the validation cohort. Pancreas-specific plasma amylase may provide a clinically useful mean for assessment and diagnosis of chronic pancreatitis.


A simple technique for improving the cosmesis of excision of a melanoma and skin grafting.
A simple technique is described to reduce the size of the skin defect resulting from excision of a malignant melanoma. An added advantage of this technique is the smoother contour at the native skin to skin graft junction. These effects are achieved by apposing the skin edge to the muscle using a simple pursestring suture technique which simultaneously draws the wound edges centrally. The resultant smaller area to be grafted, smaller donor site, better graft survival and superior cosmesis represent an improvement over conventional skin grafting techniques.


Broadening Participation: 21st Century Opportunities for Amateurs in Biology Research.
The modern field of biology has its roots in the curiosity and skill of amateur researchers and has never been purely the domain of professionals. Today, professionals and amateurs contribute to biology research, working both together and independently. Well-targeted and holistic investment in amateur biology research could bring a range of benefits that, in addition to positive societal benefits, may help to address the considerable challenges facing our planet in the 21st century. We highlight how recent advances in amateur biology have been facilitated by innovations in digital infrastructure as well as the development of community biology laboratories, launched over the last decade, and we provide recommendations for how individuals can support the integration of amateurs into biology research. The benefits of investment in amateur biology research could be many-fold, however, without a clear consideration of equity, efforts to promote amateur biology could exacerbate structural inequalities around access to and benefits from STEM. The future of the field of biology relies on integrating a diversity of perspectives and approaches-amateur biology researchers have an important role to play.


Identification of a key catalytic intermediate demonstrates that nitrogenase is activated by the reversible exchange of N₂ for H₂.
Freeze-quenching nitrogenase during turnover with N2 traps an S = ½ intermediate that was shown by ENDOR and EPR spectroscopy to contain N2 or a reduction product bound to the active-site molybdenum-iron cofactor (FeMo-co). To identify this intermediate (termed here EG), we turned to a quench-cryoannealing relaxation protocol. The trapped state is allowed to relax to the resting E0 state in frozen medium at a temperature below the melting temperature; relaxation is monitored by periodically cooling the sample to cryogenic temperature for EPR analysis. During -50 °C cryoannealing of EG prepared under turnover conditions in which the concentrations of N2 and H2 ([H2], [N2]) are systematically and independently varied, the rate of decay of EG is accelerated by increasing [H2] and slowed by increasing [N2] in the frozen reaction mixture; correspondingly, the accumulation of EG is greater with low [H2] and/or high [N2]. The influence of these diatomics identifies EG as the key catalytic intermediate formed by reductive elimination of H2 with concomitant N2 binding, a state in which FeMo-co binds the components of diazene (an N-N moiety, perhaps N2 and two [e(-)/H(+)] or diazene itself). This identification combines with an earlier study to demonstrate that nitrogenase is activated for N2 binding and reduction through the thermodynamically and kinetically reversible reductive-elimination/oxidative-addition exchange of N2 and H2, with an implied limiting stoichiometry of eight electrons/protons for the reduction of N2 to two NH3.


Female soldier beetles display a flexible preference for selectively favored male phenotypes.
In Georgia (USA) the soldier beetle, Chauliognathus pennsylvanicus (Coleoptera; Cantharidae), exhibits clinal variation in the length of the spot on its elytron. This suggests that the viability of phenotypes varies by habitat. Evidence of viability selection comes from within-site changes in the spot length distribution across a breeding season. When males with spots of intermediate length became less frequent, they became disproportionately less likely to mate, consistent with either a loss of vigor among remaining males or female rejection of disfavored phenotypes. Persistent, daily courtship by males provides females with the opportunity to track changes in male phenotype frequency and to exercise choice for phenotypes favored under natural selection. A laboratory experiment in which the frequency of one spot morph (long) or the other (short) was increased from 25% to 75% over a period of 30 days revealed that females possess a flexible preference that leads them to prefer whichever spot type has become more common over time. A haploid genetic model demonstrates that a flexible female preference for the locally favored male phenotype can be selected for when different viability alleles, genetically correlated with the male trait, are favored in different habitats that are linked by gene flow. Thus, migration between different kinds of habitat patches of a metapopulation could maintain the variation in male quality. This variation favors female choice for any trait that is directly or indirectly favored by natural selection. Such choice imparts positive frequency-dependent selection that could rapidly fix traits pleiotropically linked to viability. Rapid fixation would cause differentiation between populations of colonizing species as females exercise choice for mates favored under new ecological conditions.


Pancreatic exocrine and endocrine responses in chronic pancreatitis.
To test the discriminatory potential of certain indices of pancreatic function we performed duodenal perfusion studies and measured trypsin, bicarbonate, and lactoferrin outputs, and plasma concentrations of pancreatic polypeptide and motilin in the basal state and during continuous intravenous stimulation with 100 ng kg-1h-1 Ceruletide and 1 CU kg-1h-1 secretin. The following groups were studied: 12 normal volunteers (NV), seven patients with chronic pancreatitis with steatorrhea (CPS), and seven without steatorrhea (CP). Stimulated trypsin outputs, after 45 min of stimulation, were the best discriminant among the groups (NV versus CPS, p less than 0.0005; NV versus CP, p less than 0.005; CP versus CPS, p less than 0.05). Basal trypsin outputs showed similar patterns but failed to discriminate between NV and CP. Bicarbonate outputs were less discriminatory than trypsin outputs. Lactoferrin outputs failed to discriminate, but transient high peak outputs occurred in the initial stimulation period in all four patients with calcific chronic pancreatitis, suggesting a washout phenomenon. Basal motilin levels were elevated in both groups of pancreatitis (p less than 0.05). Stimulated pancreatic polypeptide levels were lower in CPS (NV versus CPS, p less than 0.05) but higher in CP (NV versus CP, p less than 0.005). These differences were also apparent in the basal state. We conclude that the best discrimination among the three groups was achieved by measurement of trypsin outputs, after 45 min of stimulation. In addition, the pancreatic polypeptide response may be used as a marker of residual pancreatic function in chronic pancreatitis.


Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19.
COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.


The prevalence of social phobia, and its impact on quality of life, academic achievement, and identity formation in university students.
The present study aimed to determine the prevalence of social phobia, and the sociodemographic variables, substance use patterns, and comorbid psychiatric disorders associated with it. The impact of social phobia on quality of life, academic achievement, and identity formation were also examined. The study was conducted between 01 March and 01 June 2008, and included 700 undergraduate students at Adnan Menderes University. A sociodemographic data form, the Liebowitz Social Anxiety Scale (LSAS), World Health Organization Quality of Life-Brief Form, Turkish Version (WHOQoL-BREF-TR), and Instrument for Assessing Identity Confusion (IFAIC) were administered to the participants. In all, 20.9% of the participants had social phobia during the previous year and 21.7% had social phobia for a lifetime. In total, 74.6% of those that had social phobia during the previous year and 76.5% of those that had social phobia for their whole lives also had a specific social phobia. There was a significant difference between the participants with generalized social phobia or a specific social phobia, and those without social phobia, in terms of LSAS and IFAIC scores. Logistic regression analysis showed that the risk of social phobia was 1.7-fold higher among the females than males, 1.5-fold higher among those that lived in cities for the last 15 years than those that lived in towns, 1.9-fold higher among those that lived in cities for the last 15 years than those that lived in villages, and 1.8-fold higher among those that had relatives with a psychiatric illness than those that didn't. Higher socioeconomic status was negatively correlated with the prevalence of social phobia. Cigarette smoking was more prevalent among the students without social phobia and suicidal ideation was more prevalent among the students with social phobia. WHOQOL-BREF-TR scores showed that students without social phobia had significantly higher quality of life quality than those with social phobia. Self-reported academic performance did not significantly differ between the students with social phobia and those without social phobia. Social phobia research may be limited, but was highly prevalent among the university students in the present study and had significant negative effects on identity formation and quality of life.


The effects of psychological interventions on neurocognitive functioning in posttraumatic stress disorder: a systematic review.
Posttraumatic stress disorder (PTSD) is a serious mental disorder, which is associated with emotional and cognitive functioning problems. Psychological interventions, such as trauma-focused cognitive behavioural therapy (tf-CBT) and eye movement desensitization and reprocessing (EMDR) are effective in reducing PTSD symptoms. Despite evidence showing that PTSD is associated with neurocognitive deficits, there is no systematic overview available on neurocognitive outcomes following treatment for PTSD. The current systematic review examined whether psychological treatments for PTSD improve neurocognitive functioning outcomes related to memory, attention, information processing, and executive functioning. A literature search in PubMed, PsycINFO, PTSDpubs, and Cochrane Library was performed up to March 7, 2022, in collaboration with a medical information specialist. Eligible PTSD treatment studies examining neurocognitive outcomes (memory, attention, information processing and executive function) in patients with a DSM-IV or ICD diagnosis of PTSD were included. Of the 3023 titles and abstracts identified, 9 articles met inclusion criteria, of which 5 randomized controlled trials (RCTs) and 4 non-randomized studies. Treatments included were cognitive behavioural therapy (CBT), cognitive processing therapy (CPT), brief eclectic psychotherapy (BEP), eye movement desensitization and reprocessing (EMDR), virtual reality graded exposure therapy (VR-GET), and resilience-oriented treatment (ROT). This systematic review showed that psychological treatments for PTSD do not affect most neurocognitive functions, with exception of the memory outcomes. Future research, high-quality studies are needed to provide evidence of the effect of psychological treatment in improving neurocognitive functioning in PTSD. This systematic review investigated the effects of psychological treatments on neurocognitive functioning in adults with PTSD.This review showed that most studies were very heterogeneous in design, method, and analysis.This review supports the evidence for psychological treatments for PTSD on improving memory outcomes.


Postoperative intensive care unit stay after minimally invasive esophagectomy shows large hospital variation. Results from the Dutch Upper Gastrointestinal Cancer Audit.
The value of routine intensive care unit (ICU) admission after minimally invasive esophagectomy (MIE) has been questioned. This study aimed to investigate Dutch hospital variation regarding length of direct postoperative ICU stay, and the impact of this hospital variation on short-term surgical outcomes. Patients registered in the Dutch Upper Gastrointestinal Cancer Audit (DUCA) undergoing curative MIE were included. Length of direct postoperative ICU stay was dichotomized around the national median into short ICU stay ( ≤ 1 day) and long ICU stay ( > 1 day). A case-mix corrected funnel plot based on multivariable logistic regression analyses investigated hospital variation. The impact of this hospital variation on short-term surgical outcomes was investigated using multilevel multivariable logistic regression analyses. Between 2017 and 2019, 2110 patients from 16 hospitals were included. Median length of postoperative ICU stay was 1 day [hospital variation: 0-4]. The percentage of short ICU stay ranged from 0 to 91% among hospitals. Corrected for case-mix, 7 hospitals had statistically significantly higher short ICU stay rates and 6 hospitals had lower rates. ICU readmission, in-hospital/30-day mortality, failure to rescue, postoperative pneumonia, cardiac complications and anastomotic leakage were not associated with hospital variation in length of ICU stay. Total length of hospital stay was significantly shorter in hospitals with relatively short ICU stay. This study showed significant hospital variation in postoperative length of ICU stay after MIE. Short ICU stay was associated with shorter overall hospital admission and did not negatively impact short-term surgical outcomes. More selected use of ICU resources could result in a national significant cost reduction.


[Smoking and alcohol consumption among university students: prevalence and associated factors].
The study aimed to estimate the prevalence of smoking and alcohol intake among university students from the Federal University of Pelotas, Brazil (UFPel), as well as to investigate factors associated with both habits. The sample included 485 students who were admitted to the university in 2008. Students were sampled randomly across all schools of the UFPel campus, and answered a pre-tested questionnaire, which was administered in the classroom by a member of the research team. Of the individuals interviewed, 53.9% were females and 42.3% were under 20 years. Regarding alcohol intake, 75% used alcohol once a month or less frequently, and the prevalence of risk for abusive alcohol intake was 6.2%. Regarding smoking, 10.2% reported smoking regularly or on weekends. More than 90% of those who smoked or used alcohol started before entering the university. Smoking was directly related to age and inversely related to self-rated health. In terms of alcohol intake, those who lived with friends were more likely to use it. Our data suggest the need for implementing strategies to promote healthy lifestyles among university students. However, the fact that more than 90% of individuals started to smoke or drink before entering the university suggests that interventions should target adolescents as a whole, and not only those who are university students, because onset of smoking and alcohol intake seems to occur at earlier ages.


Effectiveness of Orthotic Treatment on Clinical Outcomes of the Patients with Adolescent Idiopathic Scoliosis Under Different Wearing Compliance Levels: A Systematic Review.
Wearing spinal orthosis for 16 to 23 hours a day during the teenage years could be challenging and stressful for patients with adolescent idiopathic scoliosis (AIS). The investigation of clinical outcomes under various orthosis-wearing compliances can provide helpful insight into orthotic treatment dosage. This systematic review aims to investigate actual orthosis-wearing compliance and evaluate the effectiveness of orthotic treatment in controlling scoliotic curvature and preventing surgery for patients with AIS under various levels of orthosis-wearing compliance. A literature search of 7 electronic databases, namely PubMed, MEDLINE, Cochrane Library, Scopus, CINAHL Complete, Web of Science, and Embase, was conducted on May 19, 2023. Participant characteristics, orthotic treatment protocols, compliance information, outcome measures, and key findings were extracted. The Newcastle-Ottawa Scales were used to evaluate the quality of included cohort and case-control studies. This study systematically reviewed 17 of 1,799 identified studies, including 1,981 subjects. The actual compliance was inconsistent and ranged from 7.0 to 18.8 hours daily. The proportion of compliant subjects in each study varied from 16.0% to 78.6% due to the heterogeneity of calculation period, measurement methods, and orthosis prescription time. Thirteen studies were investigated to determine the effectiveness of orthotic treatment in controlling curve deformity under different compliance groups, and 2 studies compared the compliance under different treatment outcomes. The rate of curve progression, defined as surpassing the measurement error threshold of 5° or 6° after orthotic treatment, varied from 1.8% to 91.7% across the studies. Ten studies defined the treatment failure, surgery, or surgery indication as Cobb angle progressing to a certain degree (e.g., 40°, 45°, or 50°) and reported failure/surgery/surgery indication rates ranging from 0.0% to 91.7% among different compliance level groups. This review found that the actual compliance with orthotic treatment was generally lower than the prescribed wearing time and exhibited wide variation among different studies. The electronic compliance monitors show promise in regular orthotic treatment practice. More importantly, the group with higher and consistent compliance has significantly less curve progression and lower surgery or failure rate than the group with lower and inconsistent compliance. Further studies are proposed to investigate the minimal orthosis-wearing compliance in patients with AIS treated with different types of orthoses. Level III, Systematic Review. See Instructions for Authors for a complete description of levels of evidence.


Circadian oscillation of sensitivity of spider eyes: diurnal and nocturnal spiders.
The circadian oscillation of sensitivity of the anterior median eye of a nocturnal spider Araneus ventricosus and that of a diurnal spider Menemerus confusus were examined by recording electroretinograms. The anterior median eye of Araneus ventricosus showed a marked circadian oscillation of sensitivity, but that of Menemerus confusus showed no circadian oscillation.


Emissions and atmospheric processes influence the chemical composition and toxicological properties of urban air particulate matter in Nanjing, China.
Ambient inhalable particulate matter (PM) is a serious health concern worldwide, but especially so in China where high PM concentrations affect huge populations. Atmospheric processes and emission sources cause spatial and temporal variations in PM concentration and chemical composition, but their influence on the toxicological characteristics of PM are still inadequately understood. In this study, we report an extensive chemical and toxicological characterization of size-segregated urban air inhalable PM collected in August and October 2013 from Nanjing, and assess the effects of atmospheric processes and likely emission sources. A549 human alveolar epithelial cells were exposed to day- and nighttime PM samples (25, 75, 150, 200, 300 μg/ml) followed by analyses of cytotoxicity, genotoxicity, cell cycle, and inflammatory response. PM10-2.5 and PM0.2 caused the greatest toxicological responses for different endpoints, illustrating that particles with differing size and chemical composition activate distinct toxicological pathways in A549 cells. PM10-2.5 displayed the greatest oxidative stress and genotoxic responses; both were higher for the August samples compared with October. In contrast, PM0.2 and PM2.5-1.0 samples displayed high cytotoxicity and substantially disrupted cell cycle; August samples were more cytotoxic whereas October samples displayed higher cell cycle disruption. Several components associated with combustion, traffic, and industrial emissions displayed strong correlations with these toxicological responses. The lower responses for PM1.0-0.2 compared to PM0.2 and PM2.5-1.0 indicate diminished toxicological effects likely due to aerosol aging and lower proportion of fresh emission particles rich in highly reactive chemical components in the PM1.0-0.2 fraction. Different emission sources and atmospheric processes caused variations in the chemical composition and toxicological responses between PM fractions, sampling campaigns, and day and night. The results indicate different toxicological pathways for coarse-mode particles compared to the smaller particle fractions with typically higher content of combustion-derived components. The variable responses inside PM fractions demonstrate that differences in chemical composition influence the induced toxicological responses.


Color flow Doppler sonography in thyrotoxicosis factitia.
Color flow doppler sonography (CFDS) is a powerful technique which displays tissue blood flow and vascularity. Hyperthyroidism due to Graves' disease is characterized by variable degrees of increased blood flow at CFDS. The purpose of this study was to evaluate CFDS patterns in five women with thyrotoxicosis factitia, a condition due to surreptitious ingestion of excess thyroid hormone. Diagnosis was supported by the finding of elevated free thyroxine (FT4), ranging 24.2-67.6 pmol/L (normal values: 8.3-20.5), elevated free triiodothyronine (FT3), ranging 9.9-26.7 pmol/L (normal values: 3.8-8.4), undetectable thyrotropin (TSH), absent anti-thyroid antibodies, undetectable serum thyroglobulin (Tg) concentrations, very low/suppressed thyroidal radioiodine uptake and normal/low urinary iodine excretion. Moreover, all patients admitted thyroid hormone pills intake. All patients had normal thyroid volume and echogenicity at conventional sonography (mean estimated volume, 9.4 ml, range, 6-11 ml), and absent hypervascularity or minimal intrathyroidal vascular spots at CFDS. The peak systolic velocity (PSV) was at the lower limit of normal values (mean, 4 cm/sec, range 3-5 cm/sec). Twenty-six women with untreated Graves' disease had an increase in the mean PSV, (mean 12.9 cm/sec, range 8-20, p < 0.001) and diffuse hypervascularity. CFDS pattern in 24 normal women residing in the same area did not differ from that found in patients with thyrotoxicosis factitia. Thus, due to the nonthyroidal origin of excess thyroid hormone, CFDS showed absent hypervascularity and normal PSV in spite of a thyrotoxic status. These findings well correlate with the etiology of thyrotoxicosis factitia and may represent an additional, useful tool to confirm the diagnosis. For its easiness, rapidity (10 min) and noninvasive features, CFDS can be considered a first line test during office examination when thyrotoxicosis factitia is suspected.


[Diffuse familial interstitial pulmonary fibrosis. Study of a family].
A study of the genealogy of a 53 year old lady (A.M...) suffering from diffuse interstitial pulmonary fibrosis (FID) has revealed several cases of FID in her forbears and relations. Two brothers of A.M... died of histologically proven FID; FID was also discovered in one of their daughters. A sister died young of some unclassified respiratory problem. Two cousins died likewise at a young age of acute FID proven histologically. The level of spontaneous pneumothorax was particularly elevated in this family which represented a clinical peculiarity when compared to sporadic FID. The most probable mode of transmission of familial FID is autosomal dominant with variable penetrance. The HLA group seen in A.M... showed the A2 and B12 alleles. The B12 allele was also present in the niece of A.M...


Heterogeneity characterization of hepatocellular carcinoma based on the sensitivity to 5-fluorouracil and development of a prognostic regression model.
Background: 5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in clinical cancer treatment, including hepatocellular carcinoma (HCC). A correct understanding of the mechanisms leading to a low or lack of sensitivity of HCC to 5-FU-based treatment is a key element in the current personalized medical treatment. Methods: Weighted gene co-expression network analysis (WGCNA) was used to analyze the expression profiles of the cancer cell line from GDSC2 to identify 5-FU-related modules and hub genes. According to hub genes, HCC was classified and the machine learning model was developed by ConsensusClusterPlus and five different machine learning algorithms. Furthermore, we performed quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis on the genes in our model. Results: A total of 19 modules of the cancer cell line were divided by WGCNA, and the most negative correlation with 5-FU was the midnight blue module, from which 45 hub genes were identified. HCC was divided into three subgroups (C1, C2, and C3) with significant overall survival (OS) differences. OS of C1 was the shortest, which was characterized by a high clinical grade and later T stage and stage. OS of C3 was the longest. OS of C2 was between the two subtypes, and its immune infiltration was the lowest. Five out of 45 hub genes, namely, TOMM40L, SNRPA, ILF3, CPSF6, and NUP205, were filtered to develop a risk regression model as an independent prognostic indicator for HCC. The qRT-PCR results showed that TOMM40L, SNRPA, ILF3, CPSF6, and NUP205 were remarkably highly expressed in hepatocellular carcinoma. Conclusion: The HCC classification based on the sensitivity to 5-FU was in line with the prognostic differences observed in HCC and most of the genomic variation, immune infiltration, and heterogeneity of pathological pathways. The regression model related to 5-FU sensitivity may be of significance in individualized prognostic monitoring of HCC.


Adaptive sensing and optimal power allocation for wireless video sensors with sigma-delta imager.
We consider optimal power allocation for wireless video sensors (WVSs), including the image sensor subsystem in the system analysis. By assigning a power-rate-distortion (P-R-D) characteristic for the image sensor, we build a comprehensive P-R-D optimization framework for WVSs. For a WVS node operating under a power budget, we propose power allocation among the image sensor, compression, and transmission modules, in order to minimize the distortion of the video reconstructed at the receiver. To demonstrate the proposed optimization method, we establish a P-R-D model for an image sensor based upon a pixel level sigma-delta (Σ∆) image sensor design that allows investigation of the tradeoff between the bit depth of the captured images and spatio-temporal characteristics of the video sequence under the power constraint. The optimization results obtained in this setting confirm that including the image sensor in the system optimization procedure can improve the overall video quality under power constraint and prolong the lifetime of the WVSs. In particular, when the available power budget for a WVS node falls below a threshold, adaptive sensing becomes necessary to ensure that the node communicates useful information about the video content while meeting its power budget.


Whole-grain intake correlates among adolescents and young adults: findings from Project EAT.
National survey data indicate few adolescents or young adults consume whole grains in the amount recommended to prevent chronic disease and maintain a healthful weight. Interventions are needed to address this gap; however, little is known about what modifiable factors influence whole-grain intake among youth. This study aimed to identify socioenvironmental, personal, and behavioral correlates of whole-grain intake among adolescents and young adults. Data for this cross-sectional analysis were drawn from Project EAT (Eating Among Teens)-II, the second wave of a population-based study in Minnesota. Mailed surveys and food frequency questionnaires were completed by male (44.8%) and female (55.2%) participants in 2003-2004, including 792 adolescents (mean age=17.2 years) and 1,686 young adults (mean age=20.5 years). Linear regression models adjusted for demographic characteristics were used to identify factors associated with energy-adjusted daily intake of whole grains. Mean daily intake of whole grains was lower than recommended among adolescents (males: 0.59+/-0.04 servings, females: 0.61+/-0.04 servings) and young adults (males: 0.68+/-0.03 servings, females: 0.58+/-0.03 servings). Home availability of whole-grain bread, self-efficacy to consume > or =3 daily servings of whole grains, and preference for the taste of whole-grain bread were positively associated with whole-grain intake during adolescence and young adulthood across sex. Conversely, fast-food intake was associated with lower intake of whole grains among adolescents and young adults of both sexes. The factors examined in this study explained 28% to 34% of variance in whole-grain intake across sex and the two age groups. The findings suggest nutrition interventions should address the availability of whole-grain foods in homes and restaurants. In addition, young people should be provided with opportunities to taste a variety of whole-grain foods to enhance taste preferences and self-efficacy to consume whole-grain products.


Hepatoprotective effect of bone marrow-derived mesenchymal stromal cells in CCl4-induced liver cirrhosis.
Bone marrow mesenchymal stromal cells (BM-MSCs) are multipotent stem cells which are ideal candidates for use in regenerative medicine. The objectives of this study were to evaluate the hepatoprotective effect of BM-MSC and its combination treatment with silymarin in carbon tetrachloride (CCl4)-induced liver cirrhosis animal model and to investigate whether tail vein or portal vein infusion was the ideal route for BM-MSC transplantation. 36 female Wistar rats were randomly divided into six groups (n = 6): Group 1 (normal control), Group 2 (received only CCl4, disease model), Group 3 (CCl4 + BM-MSCs through tail vein), Group 4 (CCl4 + BM-MSCs through portal vein), Group 5 (CCl4 + silymarin), Group 6 (CCl4 + BM-MSCs + silymarin). On the 21st day after treatment, blood samples were collected for biochemical estimations. After the experiment, the rats were sacrificed. Liver was dissected out and processed for histopathology and scanning electron microscopy studies. Liver enzyme and marker analysis, histopathological studies indicated that the combination of BM-MSCs and silymarin was effective in treating liver cirrhosis. Transplanted BM-MSCs in combination with silymarin ameliorated the liver tissue damage through their immunoregulatory activities. Among the two routes, the intravenous administration of cells through the tail vein was found to be more effective and safe.


Activated lymphocytes reduce adherence of Aspergillus fumigatus.
Lymphocytes comprise up to 30% of the cells present in human bronchoalveolar lavage fluid and thus could participate in host response to infectious Aspergillus fumigatus conidia. We have examined the possibility that lymphocytes might play a role during early infection by either damaging the fungus or interfering with adherence. When incubated with A. fumigatus conidia for 20 h, highly purified 5-day-old lymphocytes activated with either IL-2 or phytohaemagglutinin, but not untreated lymphocytes, were consistently able to reduce residual fungal biomass as estimated by a metabolic assay. T lymphocytes, but not NK cells, appeared to be responsible for this activity. Lymphocytes bound both A. fumigatus conidia and hyphae, and the antifungal activity of the lymphocytes required direct lymphocyte fungus contact. In a separate set of experiments using release of 51Cr from 51Cr-loaded fungi as an estimate of fungal damage, lymphocyte-induced loss of fungal biomass was found to be due to loss of fungal adherence rather than to direct fungal damage. The detached hyphae were also found to be metabolically intact and to have normal morphology by electron microscopy. These data demonstrate that IL-2- and phytohaemagglutinin-activated lymphocytes exhibit a contact-dependent ability to reduce adherence of germinating conidia of A. fumigatus to a surface.


Ozone triggers different defence mechanisms against powdery mildew (Blumeria graminis DC. Speer f. sp. tritici) in susceptible and resistant wheat genotypes.
Ozone has been proposed as a convenient elicitor against pathogens since it is known to generate different reactive oxygen species (ROS) and induce nonspecific defence by altering gene expression. The mode of action and its interaction with other defence pathways are yet to be elucidated. Besides its negative effects on plants, ozone can be used for triggering defence against environmental stresses, including pathogens, when used at appropriate concentrations. Powdery mildew, caused by the obligate biotrophic fungus Blumera graminis f.sp. tritici (Bgt), is an important plant disease that reduces crop yield and quality. We hypothesised that ozone treatment may elicit defence against Bgt by inducing ROS signalling or other routes such as the salicylic acid (SA) or jasmonic acid (JA) pathways. We conducted experiments with Bgt-susceptible (cv. Pamukova) and resistant (cv. Tahirova) wheat (Triticum aestivum L,) cultivars and treated them with different ozone concentrations before Bgt inoculation. Stress response and defence-related features such as antioxidative enzyme activity; lipid peroxidation; H2O2 and Ca+2 levels; PR1, LOX, PAL and RBOH gene expression; and disease severity were assayed. Clear discrepancies between the responses of susceptible and resistant cultivars were found, suggesting that different defence routes were activated. Here, we showed that ozone treatment was effective for diminishing Bgt invasion in the susceptible cultivar in the short term, which was probably related to defence induced via the SA pathway. Moreover, the resistant cultivar Tahirova exhibited a different mode of action against the pathogen that was triggered by ozone treatment, plausibly related to the JA pathway.


Phage-derived anti-idiotype and anti-YTE antibodies in development of MK-1654 pharmacokinetic and immune response assays.
Background: MK-1654 is a fully human monoclonal antibody with YTE mutations currently in phase III clinical trials for prophylactic use in protecting infants from human respiratory syncytial virus infection. Materials & methods: We generated anti-idiotype (anti-ID) and anti-YTE antibodies against MK-1654 by panning with MorphoSys HuCal phage libraries, and used the antibodies in the development of MK-1654 pharmacokinetic (PK) and immune response (IR) assays. Results: Detection of MK-1654 in nonhuman primate and human nasal wash samples showed combined use of anti-ID and anti-YTE antibodies can deliver desired sensitivity and accuracy in PK studies. IR studies showed anti-ID can serve as suitable positive control in neutralizing antibody assays. Conclusion: Phage-derived anti-IDs and anti-YTEs are suitable for PK and IR assays.


Trends in physical fitness among Canadian children and youth.
Physical fitness during childhood is an important indicator of current and future health. This paper provides an overview of the fitness of Canadian children and youth aged 6 to 19 years. Data are from three cycles of the Canadian Health Measures Survey (CHMS) spanning a 10-year period: 2007 to 2009 (n = 2,081), 2009 to 2011 (n = 2,133) and 2016 to 2017 (n = 2,070). The CHMS is a comprehensive direct health measures survey conducted on a nationally representative sample of Canadians. Descriptive statistics for measures of cardiorespiratory fitness, muscular strength and power, flexibility, and body composition are provided by age group and sex. Physical fitness measures are presented for participants who met and did not meet the physical activity and screen time recommendations. Few changes in the fitness measures occurred over the past decade. Cardiorespiratory fitness decreased between 2007-2009 and 2016-2017 in 8 to 10 (52.1 to. 51.0 mL•kg-1•min-1) and 11 to 14 (50.8 to 49.8 mL•kg-1•min-1) year old boys. Girls generally had lower levels of fitness compared to boys, except for flexibility which was higher in girls. Cardiorespiratory fitness was higher in children and youth who met the current Canadian recommendations for physical activity and screen time. Grip strength was higher in boys who met the current Canadian screen time recommendation. Ongoing and periodic surveillance of fitness through the CHMS is important to monitor trends, assess future interventions designed to improve fitness levels at the population level and to increase our understanding of the relationships between fitness and health.


Dietary salt loading produces baroreflex impairment and mild hypertension in rats.
Mild hypertension with reduced chronotropic baroreflex sensitivity to phenylephrine occurred in Sprague-Dawley rats fed a high-salt diet for 5 wk. Progressive elevation of systolic and mean pressures, detected initially by indirect tail-cuff measurement, was later verified by direct recording of phasic pressures from indwelling aortic catheters in the same rats. Reflex bradycardia during pressor responses to phenylephrine was consistently less pronounced in salt-loaded than in control rats, whether tested while rats were awake or anesthetized. However, attendant decreases in renal nerve activity were not appreciably altered. Neither central nor carotid baroreceptor mechanisms were considered likely but aortic baroreceptors must have somehow been depressed because increases in afferent aortic nerve activity elicited during intravenous infusion of phenylephrine were invariably smaller in salt-loaded than in control rats. Whatever the underlying mechanisms may be, our results show that when hypertension develops during dietary salt loading, baroreflex chronotropic responses are selectively inhibited while attendant decreases in renal nerve activity are preserved.


Systems biology surveillance decrypts pathological transcriptome remodeling.
Pathological cardiac development is precipitated by dysregulation of calreticulin, an endoplasmic reticulum (ER)-resident calcium binding chaperone and critical contributor to cardiogenesis and embryonic viability. However, pleiotropic phenotype derangements induced by calreticulin deficiency challenge the identification of specific downstream transcriptome elements that direct proper cardiac formation. Here, differential transcriptome navigation was used to diagnose high priority calreticulin domain-specific gene expression changes and decrypt complex cardiac-specific molecular responses elicited by discrete functional regions of calreticulin. Wild type (WT), calreticulin-deficient (CALR(-/-)), and calreticulin truncation variant (CALR(-/-)-NP and CALR(-/-)-PC) pluripotent stem cells were used to investigate molecular remodeling underlying a model of cardiopathology. Bioinformatic deconvolution of isolated transcriptomes was performed to identify predominant expression trends, gene ontology prioritizations, and molecular network features characteristic of discrete cell types. Stem cell lines with wild type (WT), calreticulin-deficient (CALR(-/-)) genomes, as well as calreticulin truncation variants exclusively expressing either the chaperoning (CALR(-/-)-NP) or the calcium binding (CALR(-/-)-PC) domain exhibited characteristic molecular signatures determined by unsupervised agglomerative clustering. Kohonen mapping of RNA expression changes identified transcriptome dynamics that segregated into 12 discrete gene expression meta-profiles which were enriched for regulation of Eukaryotic Initiation Factor 2 (EIF2) signaling. Focused examination of domain-specific gene ontology remodeling revealed a general enrichment of Cardiovascular Development in the truncation variants, with unique prioritization of "Cardiovascular Disease" exclusive to the cohort of down regulated genes of the PC truncation variant. Molecular cartography of genes that comprised this cardiopathological category revealed uncharacterized and novel gene relationships, with identification of Pitx2 as a critical hub within the topology of a CALR(-/-) compromised network. Diagnostic surveillance, through an algorithm that integrates pluripotent stem cell transcriptomes with advanced high throughput assays and computational bioinformatics, revealed collective gene expression network changes that underlie differential phenotype development. Stem cell transcriptomes provide a deep collective molecular index that reflects ad hoc robustness of the pluripotent gene network. Remodeling events such as monogenic lesions provide a background by which high priority candidate disease effectors and regulators can be identified, demonstrated here by a molecular profiling algorithm that decrypts pluripotent wild type versus disrupted genomes.


Survival of Escherichia coli O157:H7 in cucumber fermentation brines.
Bacterial pathogens have been reported on fresh cucumbers and other vegetables used for commercial fermentation. The Food and Drug Administration currently has a 5-log reduction standard for E. coli O157:H7 and other vegetative pathogens in acidified pickle products. For fermented vegetables, which are acid foods, there is little data documenting the conditions needed to kill acid resistant pathogens. To address this knowledge gap, we obtained 10 different cucumber fermentation brines at different stages of fermentation from 5 domestic commercial plants. Cucumber brines were used to represent vegetable fermentations because cabbage and other vegetables may have inhibitory compounds that may affect survival. The 5-log reduction times for E. coli O157:H7 strains in the commercial brines were found to be positively correlated with brine pH, and ranged from 3 to 24 d for pH values of 3.2 to 4.6, respectively. In a laboratory cucumber juice medium that had been previously fermented with Lactobacillus plantarum or Leuconostoc mesenteroides (pH 3.9), a 5-log reduction was achieved within 1 to 16 d depending on pH, acid concentration, and temperature. During competitive growth at 30 °C in the presence of L. plantarum or L. mesenteroides in cucumber juice, E. coli O157:H7 cell numbers were reduced to below the level of detection within 2 to 3 d. These data may be used to aid manufacturers of fermented vegetable products determine safe production practices based on fermentation pH and temperature. Disease causing strains of the bacterium E. coli may be present on fresh vegetables. Our investigation determined the time needed to kill E. coli in cucumber fermentation brines and how E. coli strains are killed in competition with naturally present lactic acid bacteria. Our results showed how brine pH and other brine conditions affected the killing of E. coli strains. These data can be used by producers of fermented vegetable products to help assure consumer safety.


Cycloheximide-induced T-cell death is mediated by a Fas-associated death domain-dependent mechanism.
Cycloheximide (CHX) can contribute to apoptotic processes, either in conjunction with another agent (e.g. tumor necrosis factor-alpha) or on its own. However, the basis of this CHX-induced apoptosis has not been clearly established. In this study, the molecular mechanisms of CHX-induced cell death were examined in two different human T-cell lines. In T-cells undergoing CHX-induced apoptosis (Jurkat), but not in T-cells resistant to the effects of CHX (CEM C7), caspase-8 and caspase-3 were activated. However, the Fas ligand was not expressed in Jurkat cells either before or after treatment with CHX, suggesting that the activation of these caspases does not involve the Fas receptor. To determine whether CHX-induced apoptosis was mediated by a Fas-associated death domain (FADD)-dependent mechanism, a FADD-DN protein was expressed in cells prior to CHX treatment. Its expression effectively inhibited CHX-induced cell death, suggesting that CHX-mediated apoptosis primarily involves a FADD-dependent mechanism. Since CHX treatment did not result in the induction of Fas or FasL, and neutralizing anti-Fas and anti-tumor necrosis factor receptor-1 antibodies did not block CHX-mediated apoptosis, these results may also indicate that FADD functions in a receptor-independent manner. Surprisingly, death effector filaments containing FADD and caspase-8 were observed during CHX treatment of Jurkat, Jurkat-FADD-DN, and CEM C7 cells, suggesting that their formation may be necessary, but not sufficient, for cell death.


Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth.
Tobacco smoke is known to be the main cause of lung, head and neck tumors. Recently, evidence for an increasing breast cancer risk associated with tobacco smoke exposure has been emerging. We and other groups have shown that nicotine, as a non-conventional carcinogen, has the potential to facilitate cancer genesis and progression. However, the underlying mechanisms by which the smoke affects the breast, rather than the lung, remain unclear. Here, we examine possible downstream signaling pathways of the nicotinic acetylcholine receptor (nAChR) and their role in breast cancer promotion. Using human benign MCF10A and malignant MDA-MB-231 breast cells and specific inhibitors of possible downstream kinases, we identified nAChR effectors that were activated by treatment with nicotine. We further tested the effects of these effector pathways on the regulation of E2F1 activation, cell cycle progression and on Bcl-2 expression and long-term cell survival. In this study, we demonstrated a novel signaling mechanism by which nicotine exposure activated Src to sensitize epidermal growth factor receptor (EGFR)-mediated pathways for breast cancer cell growth promotion. After the ligation of nAChR with nicotine, EGFR was shown to be activated and then internalized in both MCF10A and MDA-MB-231 breast cancer cells. Subsequently, Src, Akt and ERK1/2 were phosphorylated at different time points following nicotine treatment. We further demonstrated that through Src, the ligation of nicotine with nAChR stimulated the EGFR/ERK1/2 pathway for the activation of E2F1 and further cell progression. Our data also showed that Akt functioned directly downstream of Src and was responsible for the increase of Bcl-2 expression and long-term cell survival. Our study reveals the existence of a potential, regulatory network governed by the interaction of nicotine and nAChR that integrates the conventional, mitogenic Src and EGFR signals for breast cancer development.


Freshwater drowning in a child: A case study demonstrating the role of post-mortem computed tomography.
In recent years, modern imaging techniques have gained ground in forensics. A crucial question is whether virtual autopsy is capable of replacing traditional autopsy. Forensic diagnosis of freshwater drowning (FWD) is based on the evidence of findings from external inspection (e.g. frothy fluid exuding from the mouth and nostrils), internal examination (e.g. pulmonary congestion, enlargement of heart chambers) and biochemical analysis (haemodilution), findings which are non-specific. The detection of diatoms in organs of the systemic circulation may be of some assistance, but this analysis is rarely performed and is of debatable validity. An 18-month-old child was found dead at home in a swimming pool. Considering the family's wishes to avoid autopsy, the district attorney authorised a whole-body post-mortem computed tomography scan (PMCT). The main imaging findings were frothy fluid in the upper airways, fluid in the trachea and main bronchi, many pulmonary nodular ground glass opacities (GGO) in non-dependent regions and haemodilution. CT imaging did not show any other forensically relevant abnormality.A high concordance was found between the CT findings reported in the literature in cases of FWD and the imaging results. Thus, after the exclusion of other causes of death, advised by the forensic pathologist, the district attorney closed the case and the death was attributed to FWD. This case report demonstrates that PMCT imaging in cases of suspected FWD can provide some important findings for the diagnosis of FWD as the cause of death.


Protein complement of rod outer segments of frog retina.
Rod outer segments (ROS) from frog retina have been purified by Percoll density gradient centrifugation, a procedure that preserves their form and intactness. One- and two-dimensional electrophoretic analysis reveals a smaller number of proteins than is observed in many cell organelles and permits quantitation of the 20 most abundant polypeptides. Rhodopsin accounts for 70% of the total protein (3 X 10(9) copies/outer segment), and approximately 70 other polypeptides are present at more than 6 X 10(4) copies/outer segment. Another 17% of the total protein is accounted for by the G-protein (3 X 10(8) copies/outer segment) that links rhodopsin bleaching and the activation of cyclic GMP phosphodiesterase (PDE). The phosphodiesterase accounts for 1.5% of the protein (1.5 X 10(7) copies/outer segment), and a 48,000-dalton component that binds to the membrane in the light accounts for a further 2.6%. The function of approximately 90% of the total protein in the outer segment is known, and two-thirds of the non-rhodopsin protein is accounted for by enzyme activities associated with cyclic GMP metabolism. The relative molar abundance of rhodopsin, G-protein, and PDE is 100:10:1. Apart from these major membrane-associated proteins, most of the other proteins are cytosolic. Thirteen other polypeptides are found at an abundance of one or more copies per 1000 rhodopsins, nine soluble and four membrane-bound, and their abundance relative to rhodopsin has been quantitated. ROS have been separated into subcellular fractions which resolve three classes of soluble, extrinsic membrane, and integral membrane proteins. A listing of the proteins that are phosphorylated and their subcellular localization is given. Approximately 25 phosphopeptides are detected, and most are in the soluble fraction. Fewer phosphorylated proteins are associated with the purified outer segments than with crude ROS. Distinct patterns of phosphorylation are associated with intact rods incubated with [32P]Pi and broken rods incubated with [gamma-32P]ATP.


Surgical treatment of submacular hemorrhage associated with idiopathic polypoidal choroidal vasculopathy.
To report the visual outcome of surgical treatment of submacular hemorrhage associated with idiopathic polypoidal choroidal vasculopathy. Eight eyes of eight consecutive patients with thick submacular hemorrhages associated with idiopathic polypoidal choroidal vasculopathy were treated with pars plana vitrectomy and tissue plasminogen activator-assisted removal of subretinal blood (December 1995 to September 1997) or intravitreal 100% sulfur hexafluoride gas injection without tissue plasminogen activator (October 1997 to March 1998). Postoperatively, laser treatment was performed for active polypoidal lesions outside the foveal avascular zone in four eyes. A retinal pigment epithelial tear was seen outside the foveal avascular zone in three eyes, and one eye developed a retinal detachment. The best-corrected visual acuity improved (by 3 or more lines) or stabilized in seven of the eight eyes. Four eyes had a final best-corrected visual acuity of 20/40 or better, and three eyes had a final best-corrected visual acuity of 20/50 to 20/200. In one eye, the visual acuity decreased from 20/100 to 20/500 because of the development of a subfoveal neovascular membrane. The membrane was excised, and histologic examination showed fibrovascular tissue between the retina and retinal pigment epithelium (type 2 pattern). Surgical intervention may be of benefit in eyes with submacular hemorrhage associated with idiopathic polypoidal choroidal vasculopathy.


Integrating an Interprofessional Education Experience Into a Human Physiology Course.
To obtain physician assistant (PA) student perceptions about an interprofessional education (IPE) training experience embedded in a multidisciplinary science course. An IPE training experience was integrated into a graduate human physiology course offered to PA, physical therapy, and graduate studies students. The focus of the activity related to the Interprofessional Education Collaborative (IPEC) competency domains of (1) roles and responsibilities and (2) teams and teamwork. Effectiveness was assessed in pretraining and posttraining surveys, which included questions addressing student self-perceptions of IPEC competency domains, student assessment of the learning activity, and student reflection. We observed a statistically significant positive change in PA student perceptions of IPEC competency domains. Students also provided a positive evaluation of the IPE activity and communicated personal improvements in IPE perspectives. Incorporating planned IPE experiences into multidisciplinary health science courses represents an appropriate venue for PA students to learn and apply interprofessional competencies, which may benefit future interprofessional practice.


Emergency Transportation Interventions for Reducing Adverse Pregnancy Outcomes in Low- and Middle-Income Countries: A Systematic Review.
To assess the effect of emergency transportation interventions on the outcome of labor and delivery in low- and middle-income countries (LMICs). Eleven databases were searched through December 2019: Medline/PubMed, EMBASE, Web of Science, EBSCO (PsycINFO and CINAHL), SCIELO, LILACS, JSTOR, POPLINE, Google Scholar, the Cochrane Pregnancy and Childbirth Group's Specialized Register, and the Cochrane Central Register of Controlled Trials. Methodological quality of included studies was assessed using the ROBINS-I tool. Nine studies (three in Asia and six in Africa) were included: one cluster randomized controlled trial, three controlled before-and-after (CBA) studies, four uncontrolled before and after studies, and one case-control study. The means of emergency obstetric transportation evaluated by the studies included bicycle (n = 1) or motorcycle ambulances (n = 3), 4-wheel drive vehicles (n = 3), and formal motor-vehicle ambulances (n = 2). Transportation support was offered within multi-component interventions including financial incentives (n = 1), improved communication (n = 7), and community mobilization (n = 2). Two controlled before-and-after studies that implemented interventions including financial support, three-wheeled motorcycles, and use of mobile phones reported reduction of maternal mortality. One cluster-randomized study which involved community mobilization and strengthening of referral, and transportation, and one controlled before-and-after that implemented free-of-charge, 24-hour, 4 × 4 wheel ambulance and a mobile phone showed reductions in stillbirth, perinatal, and neonatal mortality. Six studies reported increases in facility delivery ranging from 12-50%, and one study showed a 19% reduction in home delivery. There was a significant increase of caesarian sections in two studies; use of motorcycle ambulances compared to car ambulance resulted in reduction in referral delay by 2 to 4.5 hours. Only three included studies had low risk of bias on all domains. Integrating emergency obstetric transportation with complimentary maternal health interventions may reduce adverse pregnancy outcomes and increase access to skilled obstetric services for women in LMICs. The strength of evidence is limited by the paucity of high-quality studies.


Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability.
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158. PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6-8 weeks old male Ldlr -/- mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization. High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis.


Antimicrobial agents--Part II. The aminoglycosides: streptomycin, kanamycin, gentamicin, tobramycin, amikacin, neomycin.
Aminoglycoside antibiotics are poorly absorbed from the gastrointestinal tract, do not penetrate well into the cerebrospinal fluid, are minimally bound to plasma proteins, and are rapidly excreted by the normal kidney. Neomycin is limited by its toxicity to irrigating and topical preparations or to oral medication for surgical bowel preparations or hepatic coma. Streptomycin has only a few specific indications, because newer agents are available that have broader spectrums of activity. Kanamycin is indicated in serious gram-negative infections in which Pseudomonas aeruginosa is not a likely causative agent. Gentamicin, tobramycin, and amikacin are effective against a broad spectrum of gram-negative organisms including P. aeruginosa. In general, both gentamicin and tobramycin are more active in vitro than amikacin on a weight basis; however, higher serum levels are achievable with amikacin than with the two others. Amikacin is probably the aminoglycoside of first choice when gentamicin resistance is strongly suspected.


Mesenchymal stem cells from human amniotic membrane differentiate into cardiomyocytes and endothelial-like cells without improving cardiac function after surgical administration in rat model of chronic heart failure.
Introduction: Human amnion-derived mesenchymal stem cells (hAMSCs) have been used in the treatment of acute myocardial infarction. In the current study, we investigated the efficacy of hAMSCs for the treatment of chronic model of myocardial ischemia and heart failure (HF) in rats. Methods: Male Wistar rats weighing between 250 to 350 g were randomized into three groups: sham, HF control and HF+hAMSCs. For HF induction, animals were anesthetized and underwent left anterior descending artery ligation. In HF+hAMSCs group, 2×106 cells were injected into the left ventricular muscle four weeks post ischemia in the border zone of the ischemic area. Cardiac function was studied using echocardiography. Masson's trichrome staining was used for studying tissue fibrosis. Cells were transduced with green fluorescent protein (GFP) coding lentiviral vector. Immunohistochemistry was used for detecting GFP, vascular-endothelial growth factor (VEGF) and troponin T markers in the tissue sections. Results: Assessment of the cardiac function revealed no improvement in the myocardial function compared to the control HF group. Moreover, tissue fibrosis was similar in two groups. Immunohistochemical study revealed the homing of the injected hAMSCs to the myocardium. Cells were stained positive for VEGF and troponin T markers. Conclusion: injection of hAMSCs 4 weeks after ischemia does not improve cardiac function and cardiac muscle fibrosis, although the cells show markers of differentiation into vascular endothelial cells and cardiomyocytes. In sum, it appears that hAMSCs are effective in the early phases of myocardial ischemia and does not offer a significant advantage in patients with chronic HF.


Attitudes on voluntary and mandatory vaccination against COVID-19: Evidence from Germany.
Several vaccines against COVID-19 have now been developed and are already being rolled out around the world. The decision whether or not to get vaccinated has so far been left to the individual citizens. However, there are good reasons, both in theory as well as in practice, to believe that the willingness to get vaccinated might not be sufficiently high to achieve herd immunity. A policy of mandatory vaccination could ensure high levels of vaccination coverage, but its legitimacy is doubtful. We investigate the willingness to get vaccinated and the reasons for an acceptance (or rejection) of a policy of mandatory vaccination against COVID-19 in June and July 2020 in Germany based on a representative real time survey, a random sub-sample (SOEP-CoV) of the German Socio-Economic Panel (SOEP). Our results show that about 70 percent of adults in Germany would voluntarily get vaccinated against the coronavirus if a vaccine without side effects was available. About half of residents of Germany are in favor, and half against, a policy of mandatory vaccination. The approval rate for mandatory vaccination is significantly higher among those who would get vaccinated voluntarily (around 60 percent) than among those who would not get vaccinated voluntarily (27 percent). The individual willingness to get vaccinated and acceptance of a policy of mandatory vaccination correlates systematically with socio-demographic and psychological characteristics of the respondents. We conclude that as far as people's declared intentions are concerned, herd immunity could be reached without a policy of mandatory vaccination, but that such a policy might be found acceptable too, were it to become necessary.


Connecting scanning tunneling spectroscopy to device performance for polymer:fullerene organic solar cells.
Scanning tunneling microscopy and spectroscopy have been used to measure the local photovoltaic performance of prototypical polymer:fullerene (MDMO-PPV:PCBM) bulk heterojunction films with approximately 10 nm resolution. Fullerene-rich clusters are found to act as sinks, extracting electrons from a shell layer of a homogeneously mixed polymer:fullerene matrix, surrounding the fullerene cluster. The experimental results were quantitatively modeled with a drift-diffusion model that in first order accounts for the specific morphology. The same model has subsequently been used to calculate performance indicators of macroscopic solar cells as a function of film composition and characteristic size of the phase separation. As such, a first step has been set toward a quantitative correlation between nanoscopic and macroscopic device photovoltaic performance.


Menopause is a determinant of breast adipose inflammation.
Chronic inflammation is recognized as a risk factor for the development of several malignancies. Local white adipose tissue (WAT) inflammation, defined by the presence of dead or dying adipocytes encircled by macrophages that form crown-like structures (CLS), occurs in the breasts (CLS-B) of most overweight and obese women. Previously, we showed that the presence of CLS-B is associated with elevated tissue levels of proinflammatory mediators and aromatase, the rate-limiting enzyme for estrogen biosynthesis. The associated increased levels of aromatase in the breast provide a plausible mechanistic link between WAT inflammation and estrogen-dependent breast cancers. Thus, breast WAT inflammation could be relevant for explaining the high incidence of estrogen-dependent tumors with aging despite diminished circulating estrogen levels after menopause. To explore this possibility, we determined whether menopause in addition to body mass index (BMI) is associated with breast WAT inflammation among 237 prospectively enrolled women. The presence of CLS-B and its severity (CLS-B/cm(2)) as indicators of WAT inflammation correlated with menopausal status (P = 0.008 and P < 0.001) and BMI (P < 0.001 for both). In multivariable analyses adjusted for BMI, the postmenopausal state was independently associated with the presence (P = 0.03) and severity of breast WAT inflammation (P = 0.01). Mean adipocyte size increased in association with CLS-B (P < 0.001). Our findings demonstrate that breast WAT inflammation, which is associated with elevated aromatase levels, is increased in association with the postmenopausal state independent of BMI. Breast WAT inflammation, a process that can potentially be targeted, may help to explain the high incidence of estrogen-dependent tumors in postmenopausal women.


Panic attack as a risk factor for severe psychopathology.
The purpose of the study was to examine the relationship between panic attack and the onset of specific mental disorders and severe psychopathology across the diagnostic spectrum among adolescents and young adults. Data were drawn from the Early Developmental Stages of Psychopathology Study (N=3,021), a 5-year prospective longitudinal study of psychopathology among youths ages 14-24 years at baseline in the community. Multiple logistic regression analyses were used to examine the associations between panic attacks at baseline, comorbid mental disorders in adolescence, and the risk of mental disorders across the diagnostic spectrum at follow-up. The large majority of subjects with panic attacks at baseline developed at least one DSM-IV mental disorder at baseline (89.4% versus 52.8% of subjects without panic attacks). Subjects with panic attacks at baseline had significantly higher baseline levels of any anxiety disorder (54.6% versus 25.0%), any mood disorder (42.7% versus 15.5%), and any substance use disorder (60.4% versus 27.5%), compared to subjects without panic attacks at baseline. Preexisting panic attacks significantly increased the risk of onset of any anxiety disorder, social phobia, specific phobia, generalized anxiety disorder, any substance use disorder, and any alcohol use disorder at follow-up in young adulthood, and these associations persisted after adjustment for all comorbid mental disorders assessed at baseline. More than one-third (37.6% versus 9.8%) of the subjects with panic attack at baseline met the criteria for at least three mental disorders at follow-up during young adulthood. Panic attacks are associated with significantly increased odds of mental disorders across the diagnostic spectrum among young persons and appear to be a risk factor for the onset of specific anxiety and substance use disorders. Investigation of key family, environmental, and individual factors associated with the onset of panic attacks, especially in youth, may be an important direction for future research.


Experimental demonstration of multi-Gbps multi sub-bands FBMC transmission in mm-wave radio over a fiber system.
The filter bank multicarrier (FBMC) modulation format is considered as a potential candidate for future wireless 5G due to its feature of high suppression for out-of-band emissions, which allows combining multiple sub-bands with very narrow band-gaps, and hence increases the overall wireless transmission capacity. In this paper, we experimentally demonstrate the generation of multi sub-bands FBMC signals at millimeter-wave (mm-wave) for radio-over-fiber (RoF) systems. The designed multi sub-bands FBMC system consists of 5 sub-bands of 800 MHz with inter sub-band gaps of 781.25 kHz. The composite 5 sub-bands FBMC signal is generated with no band-gap between dc to the first sub-band to preserve the bandwidth of the system. Each FBMC sub-band consists of 1024 sub-carriers and is modulated with uncorrelated data sequences. The aggregate FBMC signal is carried optically by externally modulating a free running laser and is converted to millimeter waves (mm-waves) by photomixing with another free running laser at a frequency offset of 53 GHz. At the receiver, the received electrical mm-wave signal is down-converted to an intermediate frequency (IF) and then post-processed using digital signal processing (DSP) techniques. With the use of the simple recursive least square (RLS) equalizer in the DSP receiver, the achieved aggregate data rate is 8 Gbps and 12 Gbps for 16 quadrature amplitude modulation (QAM), and 64 QAM, respectively with a total bandwidth of 4.2 GHz. The system performance is evaluated by measuring error vector magnitude (EVM) and bit error rate (BER) calculations.


Hamiltonian Monte Carlo methods for efficient parameter estimation in steady state dynamical systems.
Parameter estimation for differential equation models of intracellular processes is a highly relevant bu challenging task. The available experimental data do not usually contain enough information to identify all parameters uniquely, resulting in ill-posed estimation problems with often highly correlated parameters. Sampling-based Bayesian statistical approaches are appropriate for tackling this problem. The samples are typically generated via Markov chain Monte Carlo, however such methods are computationally expensive and their convergence may be slow, especially if there are strong correlations between parameters. Monte Carlo methods based on Euclidean or Riemannian Hamiltonian dynamics have been shown to outperform other samplers by making proposal moves that take the local sensitivities of the system's states into account and accepting these moves with high probability. However, the high computational cost involved with calculating the Hamiltonian trajectories prevents their widespread use for all but the smallest differential equation models. The further development of efficient sampling algorithms is therefore an important step towards improving the statistical analysis of predictive models of intracellular processes. We show how state of the art Hamiltonian Monte Carlo methods may be significantly improved for steady state dynamical models. We present a novel approach for efficiently calculating the required geometric quantities by tracking steady states across the Hamiltonian trajectories using a Newton-Raphson method and employing local sensitivity information. Using our approach, we compare both Euclidean and Riemannian versions of Hamiltonian Monte Carlo on three models for intracellular processes with real data and demonstrate at least an order of magnitude improvement in the effective sampling speed. We further demonstrate the wider applicability of our approach to other gradient based MCMC methods, such as those based on Langevin diffusions. Our approach is strictly benefitial in all test cases. The Matlab sources implementing our MCMC methodology is available from https://github.com/a-kramer/ode_rmhmc.


The role of caspase-8 in inflammatory signalling and pyroptotic cell death.
The programmed cell death machinery exhibits surprising flexibility, capable of crosstalk and non-apoptotic roles. Much of this complexity arises from the diverse functions of caspase-8, a cysteine-aspartic acid protease typically associated with activating caspase-3 and - 7 to induce apoptosis. However, recent research has revealed that caspase-8 also plays a role in regulating the lytic gasdermin cell death machinery, contributing to pyroptosis and immune responses in contexts such as infection, autoinflammation, and T-cell signalling. In mice, loss of caspase-8 results in embryonic lethality from unrestrained necroptotic killing, while in humans caspase-8 deficiency can lead to an autoimmune lymphoproliferative syndrome, immunodeficiency, inflammatory bowel disease or, when it can't cleave its substrate RIPK1, early onset periodic fevers. This review focuses on non-canonical caspase-8 signalling that drives immune responses, including its regulation of inflammatory gene transcription, activation within inflammasome complexes, and roles in pyroptotic cell death. Ultimately, a deeper understanding of caspase-8 function will aid in determining whether, and when, targeting caspase-8 pathways could be therapeutically beneficial in human diseases.


[General surgery in a rural hospital in the State of Quintana Roo, Mexico].
The general surgeon maintains extraordinary validity worldwide, especially in countries like the United States, Canada, India, and continents such as Australia and Africa. In addition to their role as a general surgeon, they assist with surgical pathologies in rural areas where there is generally a lack of technology to carry out complicated procedures. Therefore, we undertook this study to determine the number and type of surgical procedures carried out in a rural hospital with three general surgeons, as well as to determine morbidity and respective mortality. The study was retrospective and longitudinal, using descriptive statistics during a 5.5-year period. During the period of June 1999 to December 2004, a total of 651 (100%) surgical procedures were carried out. There were 351 males (53%) and 300 females (47%) with average age of 28.5 +/- 16.0 years. There were 408 (63%) minor surgical procedures accomplished in the operating room: 150 (45%) for females with average age of 25.8 +/- 13.8 years old and 258 (55%) for males with average age of 27.7 +/- 15.5 years old. There were 243 major surgical procedures (37%): for females there were 150 (60%) with average age of 28.4 +/- 11.8 years old and for males there were 93 (40%) with average age of 29.5 +/- 16.6 years old [morbidity, six cases (0.9%) and mortality, two cases (0.3%)]. The demand for surgery in rural areas is not different from the surgery carried out in large cities, although there are limitations. It is important in this regard to adequately prepare the general surgeon in Mexico.


Ontogeny of 11beta-hydroxysteroid dehydrogenase: activity in the placenta, kidney, colon of fetal rats and rabbits.
Mechanisms to regulate closely fetal GC exposure are of considerable importance, as certain organs (kidney, brain) are adversely affected by excess GCs. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) reduces transplacental passage of maternal GCs to the fetus. We hypothesized that 11beta-HSD2, if active in fetal kidney and colon, might allow local tissue modulation of GC access during the critical last trimester. We determined the presence, ontogeny and functionality of 11beta-HSD in the placenta and fetal, neonatal and adult kidney and colon in rats and rabbits and the cortisol:cortisone ratio in human amniotic fluid, which represents fetal urine. There was clear a 11beta-HSD2 expression in last trimester fetal colon, kidney and placenta in both rats and rabbits. This appeared of functional importance, since the potency of cortisol on fetal rabbit colonic sodium flux in the Ussing chamber was increased by 11beta-HSD inhibition. In human amniotic fluid, we found a decreasing ratio of cortisol:cortisone across the last trimester, suggesting an analogous onset of renal 11beta-HSD2 activity in the human fetal kidney. Local fetal tissue 11beta-HSD2 may modulate exposure to the deleterious effects of GCs upon target tissue maturation during sensitive periods of late gestation when fetal GC levels rise to prepare other organs (lung) for adaptations at birth.


Reduced hippocampal volume is associated with overgeneralization of negative context in individuals with PTSD.
Previous studies demonstrated reduced hippocampal volume in individuals with posttraumatic stress disorder (PTSD). However, the functional role the hippocampus plays in PTSD symptomatology is still unclear. The aim of the present study was to explore generalization learning and its connection to hippocampal volume in individuals with and without PTSD. Animal and human models argue that hippocampal deficit may result in failure to process contextual information. Therefore we predicted associations between reduced hippocampal volume and overgeneralization of context in individuals with PTSD. We conducted MRI scans of bilateral hippocampal and amygdala formations as well as intracranial and total brain volumes. Generalization was measured using a novel-learning paradigm, which separately evaluates generalization of cue and context in conditions of negative and positive outcomes. As expected, MRI scans indicated reduced hippocampal volume in PTSD compared to non-PTSD participants. Behavioral results revealed a selective deficit in context generalization learning in individuals with PTSD, F(1, 43) = 8.27, p < .01, η(p)² = .16. Specifically, as predicted, while generalization of cue was spared in both groups, individuals with PTSD showed overgeneralization of negative context. Hence, they could not learn that a previously negative context is later associated with a positive outcome, F(1, 43) = 7.33, p = .01, η(p)² = .15. Most importantly, overgeneralization of negative context significantly correlated with right and left hippocampal volume (r = .61, p = .000; r = .5, p = .000). Finally, bilateral hippocampal volume provided the strongest prediction of overgeneralization of negative context. Reduced hippocampal volume may account for the difficulty of individuals with PTSD to differentiate negative and novel conditions and hence may facilitate reexperiencing symptoms.