Nutritional aspects in allogeneic hematopoietic stem cell transplantation in children and adolescents in a tertiary hospital.
Introduction: during hematopoietic stem cell transplantation (HSCT) some factors may impact on the patient's nutritional status (NS). Conditioning regimen, as well as signs and symptoms of the gastrointestinal tract, can negatively infl uence on oral food intake. Patients may require the use of complementary nutritional therapies aiming at an adequate caloric intake with the objective of avoiding decreasing in NS. Objective: the study aims to describe the nutritional aspects relevant to the maintenance of NS during hospitalization of children and adolescents undergoing HSCT at a tertiary hospital. Method: a retrospective study with a review of medical records of patients undergoing HSCT, aged between 0 and 19 years of age (incomplete) between January 2009 and December 2014. Data were collected regarding food intake, nutritional therapies used, and clinical signs and symptoms in six times: hospitalization, D0 (day of cell infusion), D+7, D+14, D+21 and D+28. Results: sixty-three patients were evaluated, being 56% males, with a median age of ten years. At the time of hospitalization, 100% of patients had their energy needs met by mouth, decreasing from D0 (about 30%), with more prevalent use of parental nutritional and enteral nutrition from D+7. Loss of appetite, mucositis and nausea were the most frequent signs and symptoms. From D+21 it was possible to observe an increase in caloric intake by mouth. Conclusion: patients showed decreased food intake throughout hospitalization. However, it has been shown that the prescription of complementary nutritional therapies has reduced the impact of weight loss.


A charge-dipole interaction model for the frequency-dependent polarizability of silver clusters.
We present a charge-dipole interaction model for the calculation of the frequency-dependent polarizability of silver clusters. The model relies on the representation of silver atoms by both a net electric charge and a dipole. Time variations of the atomic charges are related to the currents that flow through the bonds of the structures considered and the atomic charges and dipoles are eventually determined from the application of a least-action principle. After a generalization that enables the bonds of the bulk and surface atoms to have specific resistances, the model is parameterized on data obtained by the time-dependent density functional theory for tetrahedral Ag(20), Ag(84) and Ag(120) clusters. We then study the polarization properties of dimers of silver clusters. We compare in particular the polarizability of the dimers with that of the isolated clusters, for a range of gap distances and frequencies. We also consider the field enhancements one can achieve with these systems. The results are in good agreement with reference data and enable an extension of these data to a wider range of situations. They show that significant field enhancements are achieved at frequencies associated with resonant polarization along the axis of the dimer.


Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients.
Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.


Fe protein-independent substrate reduction by nitrogenase MoFe protein variants.
The reduction of substrates catalyzed by nitrogenase normally requires nucleotide-dependent Fe protein delivery of electrons to the MoFe protein, which contains the active site FeMo cofactor. Here, it is reported that independent substitution of three amino acids (β-98(Tyr→His), α-64(Tyr→His), and β-99(Phe→His)) located between the P cluster and FeMo cofactor within the MoFe protein endows it with the ability to reduce protons to H2, azide to ammonia, and hydrazine to ammonia without the need for Fe protein or ATP. Instead, electrons can be provided by the low-potential reductant polyaminocarboxylate-ligated Eu(II) (Em values of -1.1 to -0.84 V vs the normal hydrogen electrode). The crystal structure of the β-98(Tyr→His) variant MoFe protein was determined, revealing only small changes near the amino acid substitution that affect the solvent structure and the immediate vicinity between the P cluster and the FeMo cofactor, with no global conformational changes observed. Computational normal-mode analysis of the nitrogenase complex reveals coupling in the motions of the Fe protein and the region of the MoFe protein with these three amino acids, which suggests a possible mechanism for how Fe protein might communicate subtle changes deep within the MoFe protein that profoundly affect intramolecular electron transfer and substrate reduction.


Health of children born to medical radiographers.
To develop a reliable method for collecting information on reproductive outcome in an occupational setting; and to investigate the health of children born to medical radiographers. The study population comprised 6730 members of the College of Radiographers who were, at the time of survey; aged between 30 and 64 years, on the current membership file of the College, and were resident in Britain. The postal method developed proved to be reliable, with around 87% of questionnaires being returned. The observed frequencies of reproductive events were broadly in line with findings from other studies: of the 9208 pregnancies reported, 83% were livebirths, 12% were miscarriages (gestational age < 20 weeks), 1% were stillbirths (gestational age > or = 20 weeks), and 1% were other rarer spontaneous adverse events (ectopic pregnancy, blighted ovum, and hydatidiform mole). There was little difference between men and women in the frequency of adverse reproductive events reported, with the exception that male radiographers reported fewer medical terminations, the proportions being 3.1% and 1.4% for women and men respectively. Among children, the overall risks of major congenital malformation (RR 1.0, 95%CI 0.9-1.2), chromosomal anomaly (RR 1.4, 95%CI 0.8-2.3), and cancer (RR 1.2 95%CI 0.7-2.0) were as expected based on general population rates. Borderline excesses of chromosomal anomalies other than Down's syndrome in the children of female radiographers (RR 3.9, 95%CI 1.3-9.0, based on five observations), and cancer in the children of male radiographers (RR 2.7, 95%CI 0.9-6.5, based on five observations) were noted. The numbers on which these risks are based are small and the findings should be interpreted cautiously. The postal methods developed for obtaining information about reproductive events and child health proved to be reliable in men, as well as in women. Overall, the findings for medical radiographers are reassuring. Dose-response relations could not, however, be examined as long term dose records of radiographers are not routinely kept in an accessible form.


Protein-based organelles in bacteria: carboxysomes and related microcompartments.
Many bacteria contain intracellular microcompartments with outer shells that are composed of thousands of protein subunits and interiors that are filled with functionally related enzymes. These microcompartments serve as organelles by sequestering specific metabolic pathways in bacterial cells. The carboxysome, a prototypical bacterial microcompartment that is found in cyanobacteria and some chemoautotrophs, encapsulates ribulose-l,5-bisphosphate carboxylase/oxygenase (RuBisCO) and carbonic anhydrase, and thereby enhances carbon fixation by elevating the levels of CO2 in the vicinity of RuBisCO. Evolutionarily related, but functionally distinct, microcompartments are present in diverse bacteria. Although bacterial microcompartments were first observed more than 40 years ago, a detailed understanding of how they function is only now beginning to emerge.


Effects of winter birth season and prenatal cockroach and mouse allergen exposure on indoor allergen-specific cord blood mononuclear cell proliferation and cytokine production.
Season of birth has been associated with the development of atopy and asthma. Relationships among a particular birth season, maternal allergen exposure during the birth season, and childhood development of allergies to allergens in higher concentration during the birth season may be important. To investigate the effects of winter birth (January 1 to March 31) and prenatal cockroach and mouse allergens in settled dust on indoor allergen-specific cord blood mononuclear cell (CBMC) proliferation, TH2 production, and cord blood IgE concentration. As part of an ongoing prospective study, 350 cord blood samples were collected. The CBMCs were cultured with cockroach, dust mite, and mouse protein extracts, and proliferation was measured. Interleukin 5, interferon-delta, and total IgE levels were measured. Home dust samples were analyzed for cockroach and mouse allergens. An isolated association was observed between winter birth and a greater mean (SD) cockroach interleukin 5 ratio (winter vs nonwinter birth: 26,043 [11,403] vs 11,344 [3,701]; P = .02). Other associations between winter birth and increased CBMC proliferation, T-helper cytokines, or cord blood IgE levels were not detected. Higher mouse allergen levels were associated with decreased mouse-induced proliferation (winter vs nonwinter birth: mean [SD] stimulation index, 1.72 [0.12] vs 2.02 [0.11]; P = .04). Winter birth and increased cockroach or mouse allergen levels during pregnancy were not consistently associated with greater CBMC proliferation, T-helper cytokine production, or cord blood IgE levels. Greater indoor allergen exposure during pregnancy does not seem to affect the development of cockroach or mouse immune responses in utero.


Protective effects of Brassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP: role of AMPK/PPARα/UCP2 axis.
Renal damage precedes occurrence of stroke in high-sodium/low-potassium-fed stroke-prone spontaneously hypertensive rat (SHRSP). We previously reported a marked suppression of uncoupling protein-2 (UCP2) upon high-salt Japanese-style diet in SHRSP kidneys. Vegetable compounds are known to exert protective effects in cardiovascular diseases. We aimed at evaluating the impact of Brassica oleracea sprouts juice toward renal damage in Japanese diet-fed SHRSP and exploring the role of 5'-adenosine monophosphate-activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)/peroxisome proliferator-activated receptor-α (PPARα)/UCP2 axis. SHRSP received Japanese diet for 4 weeks. A group of SHRSP received Japanese diet and B. oleracea. A third group received Japanese diet, B. oleracea, and PPARα inhibitor (GW6471). A group of SHRSP fed with regular diet served as control. Japanese diet induced marked increases of oxidative stress, inflammation, and proteinuria, along with glomerular and tubular damage, as compared with regular diet. A significant suppression of AMPK/UCP2 pathway was observed. Despite Japanese diet feeding, concomitant administration of B. oleracea prevented oxidative stress accumulation, inflammation, renal damage, and proteinuria. All components of the UCP2 regulatory pathway were significantly increased by B. oleracea. Superoxide dismutase 2 and phosphoendothelial nitric oxide synthase were also stimulated. Addition of PPARα inhibitor to B. oleracea and Japanese diet significantly reduced the B. oleracea beneficial effects. SBP levels were comparable among the different groups of rats.In vitro, UCP2 inhibition by genipin offset the antioxidant effect of B. oleracea in renal mesangial and proximal tubular cells. B. oleracea administration prevented renal damage in salt-loaded SHRSP, independently from SBP, with parallel stimulation of AMPK/SIRT1/PGC1α/PPARα/UCP2 axis. Stimulation of the latter mechanism may provide relevant renal protective effect and play a therapeutic role in target organ damage progression in hypertension.


A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease.
The genetic architecture of Alzheimer's disease (AD) is only partially understood. We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10-10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10-10). Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.


Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells.
Mutations in Notch receptors and their ligands have been identified as the cause of human congenital heart diseases, indicating the importance of the Notch signaling pathway during heart development. In our study, we use Cre-Lox technology to inactivate Notch2 in several cardiac cell lineages to determine the functional requirements for Notch2 during mammalian heart development. Inactivation of Notch2 in cardiac neural crest cells resulted in abnormally narrow aortas and pulmonary arteries due to a decrease in smooth muscle tissue. The reduction in smooth muscle tissue was not due to cell migration defects but instead was found to be caused by less proliferation in smooth muscle cells during mid to late gestation. Our findings demonstrate that Notch2 is required cell autonomously for proper formation of the heart outflow tract and provides insights into the role of Notch2 in vascular smooth muscle development and the cardiovascular defects associated with Alagille syndrome.


Geographical Variation in Outcomes of Primary Hip and Knee Replacement.
Little is known about variation in outcomes of surgery or about the factors associated with such variation. To evaluate variation in patient outcomes and costs for primary hip and knee replacement across health areas in England and to identify whether patient, surgical, or hospital factors are associated with such variation. This cohort study used data from the National Joint Registry, linked to English Hospital Episode Statistics and Patient Reported Outcome Measures data sets, for 383 382 adult patients who underwent primary total hip replacement (THR) or primary total and unicompartmental knee replacement (TKR) surgical procedures from January 2014 to December 2016. Geographical Information Systems were used to display maps describing adjusted estimates of variation in outcomes across health areas. Data analysis took place from January 2018 to August 2019. Patient characteristics (eg, age, sex, body mass index [BMI], and socioeconomic deprivation), surgical factors (eg, surgeon volume and grade), and hospital organizational factors (eg, number of operating theaters, number of specialist consultants, and hospital volume). Length of stay (LOS), bed-day costs, change in Oxford hip or knee scores 6 months after surgery, and complications 6 months after surgery. A total of 173 107 patients (mean [SD] age, 69.3 [10.7] years; mean [SD] BMI, 28.9 [5.2]) underwent primary THR and 210 275 patients (mean [SD] age 69.7 [9.4] years; mean [SD] BMI, 31.1 [5.5]) underwent primary TKR, nested in 207 health areas. A number of factors were associated with longer LOS, higher bed-day costs, smaller changes in Oxford hip or knee scores, and a higher percentage of complications, including a workforce with a higher number of less experienced physicians (eg, LOS for less experienced surgeons, THR: regression coefficient, 0.02; 95% CI, 0.01 to 0.03; P < .001; TKR: regression coefficient, 0.01; 95% CI, 0.01 to 0.02; P < .001), public hospitals (eg, bed-day costs for private hospitals, THR: regression coefficient, -0.15; 95% CI, -0.15 to -0.14; P < .001; TKR: regression coefficient, -0.19; 95% CI, -0.19 to -0.19; P < .001), low volume of surgical procedures per surgeon (eg, change in Oxford hip or knee scores for lead surgeon with ≤10 vs >150 surgical procedures per year, THR: regression coefficient, -1.03; 95% CI, -1.47 to -0.58; P < .001; TKR: regression coefficient, -0.54; 95% CI, -1.01 to -0.06), and low volume of surgical procedures per hospital (eg, percentage of complications for hospitals with ≤200 vs ≥500 surgical procedures per year, THR: regression coefficient, 0.12; 95% CI, 0.04 to 0.21; P < .001; TKR: regression coefficient, 0.09; 95% CI, 0.01 to 0.18; P = .03). Although these factors did not attenuate the magnitude of variation across health areas, they had ecological correlations with the observed geographical variations in outcomes of surgery by health area. For example, the percentage of public and private hospitals was ecologically correlated at the health area level with longer and shorter stays, respectively (public hospital, THR: ρ, 0.41; public hospital, TKR: ρ, 0.44; private hospital, THR: ρ, -0.37; private hospital, THR: ρ, -0.38). Across health areas, estimated mean length of stay ranged from 3 to 7 days, and associated bed-day costs ranged from £4727 ($5827) to £8800 ($10 848) for both total hip and knee replacement. The absolute estimated mean change in Oxford hip score varied from 18.7 to 24.6 points and, for Oxford knee score, from 13.1 to 18.8. Estimated 6-month complications ranged from 2.9% to 5.8% for both THR and TKR. In this study, models indicated that higher surgical volume by surgeon and by hospital as well as private hospitals were associated with better patient outcomes, which could be explained by the changing case mix of public hospitals treating an increasing number of more complex patients. A higher proportion of less experienced physicians was associated with poorer outcomes. This variation was observed geographically.


Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis.
To determine whether elevated levels of the angiogenic cytokine vascular endothelial growth factor (VEGF), detected on presentation to an early arthritis clinic, are associated with the development of chronic and erosive arthritis. Concentrations of VEGF and its soluble receptor, soluble fms-like tyrosine kinase 1 (sFlt-1), were measured by enzyme-linked immunosorbent assay in serum samples from patients with early (<2 years from onset) arthritic symptoms in the peripheral joints, namely early rheumatoid arthritis (RA), self-limiting arthritis (viral, reactive, and idiopathic inflammatory arthritis), or psoriatic arthritis. In addition, measurements were made in random samples from patients with longstanding (>3 years from symptom onset) RA treated with disease-modifying antirheumatic drugs, from patients with osteoarthritis (OA), and from patients with polyarthralgia without arthritis, as well as from nonarthritic controls. Serum VEGF levels at presentation were elevated in patients with inflammatory arthritis (RA, psoriatic, and self-limiting arthritis) as well as in patients with OA, in comparison with nonarthritic controls. Moreover, serum VEGF concentrations were significantly higher in patients with early RA than in patients with self-limiting arthritis. Serum VEGF levels at presentation in patients with early RA correlated significantly with the development of radiographic damage after 1 year. Improvement in the clinical symptoms of RA was associated with a reduction in serum VEGF levels. Serum sFlt-1 levels were raised in patients with early and longstanding RA and in those with self-limiting arthritis, and correlated positively with the serum VEGF concentrations in patients with inflammatory arthritis. These findings implicate the proangiogenic cytokine VEGF in the persistence of inflammatory arthritis, and support the hypothesis that expansion of the synovial vasculature is important for the development of joint destruction in RA.


Mortality risk attributable to wildfire-related PM2·5 pollution: a global time series study in 749 locations.
Many regions of the world are now facing more frequent and unprecedentedly large wildfires. However, the association between wildfire-related PM2·5 and mortality has not been well characterised. We aimed to comprehensively assess the association between short-term exposure to wildfire-related PM2·5 and mortality across various regions of the world. For this time series study, data on daily counts of deaths for all causes, cardiovascular causes, and respiratory causes were collected from 749 cities in 43 countries and regions during 2000-16. Daily concentrations of wildfire-related PM2·5 were estimated using the three-dimensional chemical transport model GEOS-Chem at a 0·25° × 0·25° resolution. The association between wildfire-related PM2·5 exposure and mortality was examined using a quasi-Poisson time series model in each city considering both the current-day and lag effects, and the effect estimates were then pooled using a random-effects meta-analysis. Based on these pooled effect estimates, the population attributable fraction and relative risk (RR) of annual mortality due to acute wildfire-related PM2·5 exposure was calculated. 65·6 million all-cause deaths, 15·1 million cardiovascular deaths, and 6·8 million respiratory deaths were included in our analyses. The pooled RRs of mortality associated with each 10 μg/m3 increase in the 3-day moving average (lag 0-2 days) of wildfire-related PM2·5 exposure were 1·019 (95% CI 1·016-1·022) for all-cause mortality, 1·017 (1·012-1·021) for cardiovascular mortality, and 1·019 (1·013-1·025) for respiratory mortality. Overall, 0·62% (95% CI 0·48-0·75) of all-cause deaths, 0·55% (0·43-0·67) of cardiovascular deaths, and 0·64% (0·50-0·78) of respiratory deaths were annually attributable to the acute impacts of wildfire-related PM2·5 exposure during the study period. Short-term exposure to wildfire-related PM2·5 was associated with increased risk of mortality. Urgent action is needed to reduce health risks from the increasing wildfires. Australian Research Council, Australian National Health & Medical Research Council.


Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia.
The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.


Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response.
TNF-alpha has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-alpha strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-1beta or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF-alpha antagonist etanercept to discover whether hepatic TNF-alpha, produced as part of the acute-phase response to CNS injury, modulates the inflammatory response in the brain. We report a significant reduction in neutrophil numbers recruited to the IL-1beta- or LPS-challenged brain as a result of TNF-alpha inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF-alpha mRNA and of TNF-alpha-induced genes, such as the chemokines CCL-2, CXCL-5, and CXCL-10, although other chemokines elevated by the injury were not significantly changed. The reduction in hepatic chemokine synthesis results in reduced numbers of circulating neutrophils, and also a reduction in the numbers recruited to the liver as a consequence of brain injury. These findings suggest that TNF-alpha inhibitors may reduce CNS inflammatory responses by targeting the hepatic acute-phase response, and thus therapies for brain injury need not cross the blood-brain barrier to be effective.


Dissociation between p93B-myb and p75c-myb expression during the proliferation and differentiation of human myeloid cell lines.
Direct and indirect evidence strongly indicates that the proto-oncogene c-myb plays an important role in the regulation of both the proliferation and differentiation of hematopoietic cells. In addition, recent data suggest that the structurally related B-myb gene is also necessary for the proliferation of these cells. To help understand the relationship between these two related gene products during proliferation and differentiation of myeloid cells, we have studied in parallel the regulated expression of c-myb and B-myb RNAs and proteins in human myeloid cells that were either growth-arrested or induced to differentiate along different pathways. For this purpose, we have produced a polyclonal antibody directed against a fragment of the recombinant B-myb protein. We have thus been able to detect the B-myb protein in human cell lines and have found it to be a 93-kD protein localized in the nucleus. We have chosen two models to study the expression of both c-myb and B-myb mRNAs and proteins during myeloid proliferation and differentiation. One of the models was the HL-60 cell line, which can be induced to differentiate towards the monocytic pathway with either phorbol ester (phorbol myristate acetate) or vitamin D3 and towards the granulocytic pathway with either dimethyl sulfoxide or retinoic acid. In addition, we have studied another recently established human leukemic cell line, called GF-D8, which is strictly dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) for proliferation. The results show that the expression of B-myb RNA and protein closely correlates with proliferation in all experimental setups studied, whereas the c-myb protein levels do not always do so. We observed that the c-myb protein levels decreased well before the decrease of B-myb protein and of proliferation itself during differentiation toward monocytes. Such a difference was not present during granulocytic differentiation, in which c-myb levels decreased, if anything, later than those of B-myb and proliferation. Most striking was the finding that high levels of c-myb RNA and protein, but not of B-myb, were present in the GF-D8 cell line, even after growth arrest by GM-CSF deprivation. These data suggest that B-myb may function solely in the regulation of cellular proliferation, whereas c-myb has additional functions, for example, in the maintenance of an undifferentiated state.


Posttraumatic stress disorder in an urban population of young adults: risk factors for chronicity.
Despite progress in epidemiologic research on posttraumatic stress disorder (PTSD), little is known about factors that distinguish chronic from nonchronic PTSD. In a previous report, the authors identified a set of personal predispositions associated with PTSD following traumatic events in a general population sample of young adults. The purpose of this analysis was to identify characteristics of chronic PTSD and examine whether any of the suspected risk factors for PTSD was associated specifically with chronic PTSD. A random sample of 1,007 21- to 30-year-old members of a large health maintenance organization in the Detroit area was interviewed, using the National Institute of Mental Health Diagnostic Interview Schedule (DIS), revised for DSM-III-R. The analysis was performed on data from 394 respondents who reported traumatic events, of whom 93 met criteria for PTSD. Chronic PTSD was defined as duration of symptoms for 1 year or more. Persons with chronic PTSD (N = 53) had, on the average, a significantly higher total number of PTSD symptoms and higher rates of overreactivity to stimuli that symbolized the stressor and interpersonal numbing than persons with nonchronic PTSD. The rates of one or more additional anxiety or affective disorders and a variety of medical conditions were higher in persons with chronic than nonchronic PTSD. Family history of antisocial behavior and female sex were associated specifically with chronic PTSD. The findings suggest that chronic PTSD may be associated with specific risk factors and clinical features. Longitudinal data on the course of PTSD are needed to determine whether the distinct features and the medical and psychiatric histories of persons with chronic PTSD are complications attendant on a chronic course or coexisting disturbances that inhibit recovery.


Analysis of case-control age-at-onset data using a modified case-cohort method.
Case-control designs are widely used in rare disease studies. In a typical case-control study, data are collected from a sample of all available subjects who have experienced a disease (cases) and a sub-sample of subjects who have not experienced the disease (controls) in a study cohort. Cases are oversampled in case-control studies. Logistic regression is a common tool to estimate the relative risks of the disease with respect to a set of covariates. Very often in such a study, information of ages-at-onset of the disease for all cases and ages at survey of controls are known. Standard logistic regression analysis using age as a covariate is based on a dichotomous outcome and does not efficiently use such age-at-onset (time-to-event) information. We propose to analyze age-at-onset data using a modified case-cohort method by treating the control group as an approximation of a subcohort assuming rare events. We investigate the asymptotic bias of this approximation and show that the asymptotic bias of the proposed estimator is small when the disease rate is low. We evaluate the finite sample performance of the proposed method through a simulation study and illustrate the method using a breast cancer case-control data set.


A conserved Gly436-Trp-Leu-Ala-Gly-Leu-Phe-Tyr motif in hepatitis C virus glycoprotein E2 is a determinant of CD81 binding and viral entry.
The hepatitis C virus (HCV) glycoproteins E1 and E2 form a heterodimer that mediates CD81 receptor binding and viral entry. In this study, we used site-directed mutagenesis to examine the functional role of a conserved G436WLAGLFY motif of E2. The mutants could be placed into two groups based on the ability of mature virion-incorporated E1E2 to bind the large extracellular loop (LEL) of CD81 versus the ability to mediate cellular entry of pseudotyped retroviral particles. Group 1 comprised E2 mutants where LEL binding ability largely correlated with viral entry ability, with conservative and nonconservative substitutions (W437 L/A, L438A, L441V/F, and F442A) inhibiting both functions. These data suggest that Trp-437, Leu-438, Leu-441, and Phe-442 directly interact with the LEL. Group 2 comprised E2 glycoproteins with more conservative substitutions that lacked LEL binding but retained between 20% and 60% of wild-type viral entry competence. The viral entry competence displayed by group 2 mutants was explained by residual binding by the E2 receptor binding domain to cellular full-length CD81. A subset of mutants maintained LEL binding ability in the context of intracellular E1E2 forms, but this function was largely lost in virion-incorporated glycoproteins. These data suggest that the CD81 binding site undergoes a conformational transition during glycoprotein maturation through the secretory pathway. The G436P mutant was an outlier, retaining near-wild-type levels of CD81 binding but lacking significant viral entry ability. These findings indicate that the G436WLAGLFY motif of E2 functions in CD81 binding and in pre- or post-CD81-dependent stages of viral entry.


Nutrient Timing: A Garage Door of Opportunity?
Nutrient timing involves manipulation of nutrient consumption at specific times in and around exercise bouts in an effort to improve performance, recovery, and adaptation. Its historical perspective centered on ingestion during exercise and grew to include pre- and post-training periods. As research continued, translational focus remained primarily on the impact and outcomes related to nutrient consumption during one specific time period to the exclusion of all others. Additionally, there seemed to be increasing emphasis on outcomes related to hypertrophy and strength at the expense of other potentially more impactful performance measures. As consumption of nutrients does not occur at only one time point in the day, the effect and impact of energy and macronutrient availability becomes an important consideration in determining timing of additional nutrients in and around training and competition. This further complicates the confining of the definition of "nutrient timing" to one very specific moment in time at the exclusion of all other time points. As such, this review suggests a new perspective built on evidence of the interconnectedness of nutrient impact and provides a pragmatic approach to help frame nutrient timing more inclusively. Using this approach, it is argued that the concept of nutrient timing is constrained by reliance on interpretation of an "anabolic window" and may be better viewed as a "garage door of opportunity" to positively impact performance, recovery, and athlete availability.


Comparative safety and efficiency of five percutaneous kidney biopsy approaches of native kidneys: a multicenter study.
Renal biopsy (RB) is necessary for the diagnosis, prognosis, and therapy guidance of native kidney diseases. Few studies have compared outcomes of RB procedures. We retrospectively compared the safety and efficiency of five biopsy procedures. The number of glomeruli on light microscopy (LM) and on immunofluorescence (IF) and serious adverse events following RB performed in five nephrology units (C1-C5) were collected. C1 performed ultrasound (US) assessment before RB and used a 14-gauge core-cutting needle biopsy gun, C2 US guidance and a 14-gauge needle, C3 tomodensitometry guidance and a 14-gauge needle, C4 US guidance and a 16-gauge needle, and C5 tomodensitometry guidance and a 16-gauge needle. RB was performed in 943 adults between January 2006 and July 2010. Serious adverse events occurred in 1.5% of biopsies. The complication rate was not different between nephrology units. The mean number of glomeruli on biopsy was 14.2 ± 8.6 with LM and 4.4 ± 3.3 on IF. It was different according to the nephrology unit for LM (p = 0.01) and for IF (p < 0.001). The number of failed biopsies was influenced by the nephrology unit and radiological guidance technique, favoring real-time US guidance. Failed biopsies using US or tomodensitometry assessment before RB was certainly due to kidney imprecise localization since it was often non-renal tissue sampling. At least 10 glomeruli were found in 69% of biopsies on LM. This rate varied according to the nephrology unit (p = 0.004) and was higher when 14-gauge needles were used in comparison with 16-gauge needles. RB is safe regardless of the technical procedure, but radiological guidance and needle size influence the efficiency of biopsies.


Quantifying the demographic cost of human-related mortality to a raptor population.
Raptors are exposed to a wide variety of human-related mortality agents, and yet population-level effects are rarely quantified. Doing so requires modeling vital rates in the context of species life-history, behavior, and population dynamics theory. In this paper, we explore the details of such an analysis by focusing on the demography of a resident, tree-nesting population of golden eagles (Aquila chrysaetos) in the vicinity of an extensive (142 km2) windfarm in California. During 1994-2000, we tracked the fates of >250 radio-marked individuals of four life-stages and conducted five annual surveys of territory occupancy and reproduction. Collisions with wind turbines accounted for 41% of 88 uncensored fatalities, most of which were subadults and nonbreeding adults (floaters). A consistent overall male preponderance in the population meant that females were the limiting sex in this territorial, monogamous species. Estimates of potential population growth rate and associated variance indicated a stable breeding population, but one for which any further decrease in vital rates would require immigrant floaters to fill territory vacancies. Occupancy surveys 5 and 13 years later (2005 and 2013) showed that the nesting population remained intact, and no upward trend was apparent in the proportion of subadult eagles as pair members, a condition that would have suggested a deficit of adult replacements. However, the number of golden eagle pairs required to support windfarm mortality was large. We estimated that the entire annual reproductive output of 216-255 breeding pairs would have been necessary to support published estimates of 55-65 turbine blade-strike fatalities per year. Although the vital rates forming the basis for these calculations may have changed since the data were collected, our approach should be useful for gaining a clearer understanding of how anthropogenic mortality affects the health of raptor populations, particularly those species with delayed maturity and naturally low reproductive rates.


Observers exploit stochastic models of sensory change to help judge the passage of time.
Sensory stimulation can systematically bias the perceived passage of time, but why and how this happens is mysterious. In this report, we provide evidence that such biases may ultimately derive from an innate and adaptive use of stochastically evolving dynamic stimuli to help refine estimates derived from internal timekeeping mechanisms. A simplified statistical model based on probabilistic expectations of stimulus change derived from the second-order temporal statistics of the natural environment makes three predictions. First, random noise-like stimuli whose statistics violate natural expectations should induce timing bias. Second, a previously unexplored obverse of this effect is that similar noise stimuli with natural statistics should reduce the variability of timing estimates. Finally, this reduction in variability should scale with the interval being timed, so as to preserve the overall Weber law of interval timing. All three predictions are borne out experimentally. Thus, in the context of our novel theoretical framework, these results suggest that observers routinely rely on sensory input to augment their sense of the passage of time, through a process of Bayesian inference based on expectations of change in the natural environment.


OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency.
Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.


Genomic analysis of multidrug-resistant Escherichia coli ST58 causing urosepsis.
Sequence type 58 (ST58) phylogroup B1 Escherichia coli have been isolated from a wide variety of mammalian and avian hosts but are not noted for their ability to cause serious disease in humans or animals. Here we determined the genome sequences of two multidrug-resistant E. coli ST58 strains from urine and blood of one patient using a combination of Illumina and Single Molecule, Real-Time (SMRT) sequencing. Both ST58 strains were clonal and were characterised as serotype O8:H25, phylogroup B1 and carried a complex resistance locus/loci (CRL) that featured an atypical class 1 integron with a dfrA5 (trimethoprim resistance) gene cassette followed by only 24 bp of the 3'-CS. CRL that carry this particular integron have been described previously in E. coli from cattle, pigs and humans in Australia. The integron abuts a copy of Tn6029, an IS26-flanked composite transposon encoding blaTEM, sul2 and strAB genes that confer resistance to ampicillin, sulfathiazole and streptomycin, respectively. The CRL resides within a novel Tn2610-like hybrid Tn1721/Tn21 transposon on an IncF, ColV plasmid (pSDJ2009-52F) of 138 553 bp that encodes virulence associated genes implicated in life-threatening extraintestinal pathogenic E. coli (ExPEC) infections. Notably, pSDJ2009-52F shares high sequence identity with pSF-088-1, a plasmid reported in an E. coli ST95 strain from a patient with blood sepsis from a hospital in San Francisco. These data suggest that extraintestinal infections caused by E. coli carrying ColV-like plasmids, irrespective of their phylogroup or ST, may pose a potential threat to human health, particularly to the elderly and immunocompromised.


Antibiotic-resistant heterotrophic plate count bacteria and amoeba-resistant bacteria in aquifers of the Mooi River, North West province, South Africa.
Groundwater in the Mooi River catchment is prone to mining, agricultural, municipal and septic tank pollution. In this study physico-chemical and microbiological parameters were determined using appropriate methods. Bacterial isolates were identified by 16S rRNA sequencing (heterotrophic plate count (HPC) bacteria and amoeba-resistant bacteria (ARB)) and multiplex polymerase chain reaction (Escherichia coli). Antibiotic resistance tests were also performed. Physico-chemical parameters were generally within target water quality ranges for drinking water. HPC bacteria ranged between 10(5) and 10(7) colony-forming units (cfu)/ml. E. coli were enumerated from Trimpark, School and Cemetery. The Blaauwbank borehole was negative for faecal streptococci. Pseudomonas spp. were most abundant in the bulk water. Opportunistic pathogens isolated included Pseudomonas aeruginosa, Acinetobacter, Aeromonas, Alcaligenes, Flavobacterium, Bacillus cereus and Mycobacterium spp. Varying patterns of antibiotic resistance were observed. Most HPC bacterial isolates were resistant to cephalothin and/or amoxicillin and a few were resistant to erythromycin and streptomycin. Pseudomonas spp. was also the most abundant ARB. Other ARBs included Alcaligenes faecalis, Ochrobactrum sp. and Achromobacter sp. ARBs were resistant to streptomycin, chloramphenicol, cephalothin, and/or amoxicillin compared to HPCs. The presence of E. coli and ARB in these groundwater sources indicates potential human health risks. These risks should be further investigated and quantified, and groundwater should be treated before use.


Catheter survival during long-term insulin therapy with an implanted programmable pump. The Implantable Insulin Pump Trial Study Group.
To survey catheter complications and to analyze catheter survival during long-term intraperitoneal and intravenous insulin therapy with an implanted programmable pump with a sideport. Catheter occlusions were documented by measuring dynamic catheter resistance. Catheter migrations or breaks were demonstrated by X ray. When flushing the catheter with buffer solution through the sideport failed to clear the occlusion, catheters were replaced or laparoscopy was performed for the excision of fibrous tissue growth. Broken or migrated catheters were replaced. Occlusions were the most common catheter complications, and the majority of them (79% intraperitoneal and 84% intravenous) were cleared by flushing the catheter. Survival at 3 years was significantly higher for intraperitoneal catheters compared with intravenous catheters (60% intraperitoneal and 22% intravenous). Nonsurgical management of catheter occlusions contributed to extend catheter lifetime. Intraperitoneal catheters have a lower morbidity and a higher survival than intravenous catheters.


Reproducibility of AJCC Criteria for Classifying Deeply Invasive Colon Cancers Is Suboptimal for Consistent Cancer Staging.
The eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual attempts to address ambiguity in the pT category assignment for colon cancer from prior editions. Despite modifications, the distinction between the pT3 and pT4a categories continues to be a source of diagnostic confusion. In this study, we assessed interobserver agreement among pathologists from different institutions in the application of AJCC eighth edition criteria for categorizing deeply invasive colonic adenocarcinomas. We identified morphologic patterns that produce diagnostic confusion. We assessed 47 colon cancers that closely approached the serosal surface. Six pathologists with interest in gastrointestinal pathology and 4 focused in other subspecialties classified each case as pT3 or pT4a, based on examination of low-magnification and high-magnification images of the most deeply invasive area. Interobserver agreement was assessed using Fleiss' κ. Cases displayed 3 morphologic patterns at the advancing tumor edge, namely, (1) continuous invasion through an inflammatory focus, (2) pushing border, and (3) infiltrative glands and cell clusters with serosal reaction. Gastrointestinal pathologists achieved slight (κ=0.21) or moderate (κ=0.46) and (κ=0.51) agreement in each category, whereas agreement among nongastrointestinal pathologist was fair (0.31) and (0.39), or moderate (0.57) for each category, respectively. In 10 (21%) cases, the distinction between pT3 and pT4a would have changed the overall clinical stage. We conclude that histologic criteria for serosal penetration is a persistent source of diagnostic ambiguity for gastrointestinal and general pathologists in the pT categorization of colon cancers. Clarification of these criteria will help ensure uniform reporting of pathologic and clinical stage.


Walking groups for women with breast cancer: Mobilising therapeutic assemblages of walk, talk and place.
Walking is widely accepted as a safe and effective method of promoting rehabilitation and a return to physical activity after a cancer diagnosis. Little research has considered the therapeutic qualities of landscape in relation to understanding women's recovery from breast cancer, and no study has considered the supportive and therapeutic benefits that walking groups might contribute to their wellbeing. Through a study of a volunteer-led walking group intervention for women living with and beyond breast cancer (Best Foot Forward) we address this gap. A mixed-methods design was used including questionnaires with walkers (n = 35) and walk leaders (n = 13); telephone interviews with walkers (n = 4) and walk leaders (n = 9); and walking interviews conducted outdoors and on the move with walkers (n = 15) and walk leaders (n = 4). Questionnaires were analysed descriptively. Interviews were audio-recorded, transcribed verbatim, and analysed thematically. Our study found that the combination of walking and talking enabled conversations to roam freely between topics and individuals, encouraging everyday and cancer-related conversation that created a form of 'shoulder-to-shoulder support' that might not occur in sedentary supportive care settings. Walking interviews pointed to three facets of the outdoor landscape - as un/natural, dis/placed and im/mobile - that walkers felt imbued it with therapeutic qualities. 'Shoulder-to-shoulder support' was therefore found to be contingent on the therapeutic assemblage of place, walk and talk. Thus, beyond the physical benefits that walking brings, it is the complex assemblage of walking and talking in combination with the fluid navigation between multiple spaces that mobilises a therapeutic assemblage that promotes wellbeing in people living with and beyond breast cancer.


Assessing community readiness online: a concurrent validation study.
Community readiness for facilitation and uptake of interventions can impact the success of community-based prevention efforts. As currently practiced, measuring community readiness can be a resource intensive process, compromising its use in evaluating multisite community-based prevention efforts. The purpose of this study was to develop, test and validate a more efficient online version of an existing community readiness tool and identify potential problems in completing assessments. This study was conducted in the context of a complex community-based childhood obesity prevention program in South Australia. Following pre-testing, an online version of the community readiness tool was created, wherein respondents, with detailed knowledge of their community and prevention efforts, rated their communities on five anchored rating scales (Knowledge of Efforts, Leadership, Knowledge of the Issue, Community Climate, and Resources). Respondents completed the standard, over-the-phone community readiness interview ("gold standard") and the new online survey. Paired t-test, St. Laurent's correlation coefficient and intra-class correlation (ICC) were used to determine the validity of the online tool. Contact summary forms were completed after each interview to capture interview quality. Twenty-five respondents completed both assessments. There was a statistically significant difference in the overall community readiness scores between the two methods (paired t-test p = 0.03); online scores were consistently higher than interview scores. St. Laurent's correlation of 0.58 (95% CI 0.42-0.73) was moderate; the ICC of 0.65 (95% CI 0.35-0.83) was good. Only for the leadership and resources dimensions was there no statistically significant difference between the scores from the two methods (p = 0.61, p = 0.08 respectively). St Laurent's correlation (r = 0.83, 95% CI 0.71-0.92) and the ICC (0.78, 95% CI 0.57-0.90) were excellent for leadership. Qualitative results from the standard interview method suggest that some respondents felt reluctant to answer questions on behalf of other community members. This may have impacted their self-selected ratings and/or responses to questions during the interview. Concurrent validity for the online method was supported for the Leadership dimension only. However, the online method holds promise as it reduces time and resource burden, allowing for a quicker return of results to the community to inform program planning, implementation and evaluations to improve community health.


Regional and racial differences in the prevalence of physician-diagnosed essential tremor in the United States.
For reasons that are unclear, prevalence estimates of essential tremor (ET) differ considerably across the United States. Separate communities have never been sampled within the framework of the same study to substantiate these differences. We estimated the prevalence of physician-diagnosed ET in the elderly in four communities in the United States in whom the same screening questions were used, and examined whether this prevalence differed between Caucasians and African Americans. The Cardiovascular Health Study recruited a sample of Medicare beneficiaries >/=65 years of age from four communities in different regions of the United States. In 1998 to 1999, 3,494 participants (mean age, 80.0 years; range, 70-103 years) answered a 12-question screen for ET, including the question, "has a doctor diagnosed you as having familial tremor or benign essential tremor?" Fifty-four participants reported that a doctor had diagnosed them as having ET (1.5%; 95% confidence interval, [CI], 1.1-2.0%). Prevalence was similar across the four communities (1.1-2.0%). A larger proportion of Caucasians than African Americans reported a diagnosis of ET (1.7% vs. 0.4%; odds ratio = 4.9; 95% CI, 1.2-20.2; P = 0.028). In a logistic regression analysis, physician-diagnosed ET was associated with Caucasian ethnicity (P = 0.038) but not with age, gender, education, mental status or depression scores, income, smoking status, or alcohol consumption. When a standardized screening question was used, the proportion of participants with physician-diagnosed ET was similar across four communities, suggesting that the prevalence of this condition may be less variable than is often reported. Caucasians were five times more likely to have physician-diagnosed ET than were African Americans. This study does not provide an explanation for this difference, which deserves further study.


The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is an active transplacental carcinogen in Syrian golden hamsters.
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in adult laboratory rodents. Our previous studies have shown that NNK crosses the placenta in pregnant hamsters and is metabolized into DNA-methylating and clastogenic intermediates by fetal respiratory tract tissues. Based on these findings, we have tested the transplacental carcinogenicity of NNK in this species. Groups of pregnant hamsters were given s.c. injections of single or multiple doses of NNK (cumulative dose range, 50-300 mg/kg) on day 15 (last day of gestation) or on days 13, 14, and 15 of gestation. Within 1 year after treatment, up to 70% of the offspring developed tumors in various organs, including respiratory tract, nasal cavity, adrenal glands, pancreas, and liver. No tumors were found in the control hamsters treated with the vehicle (trioctanoin) alone. The overall tumor incidence was proportional to the cumulative dose. Females had a generally higher tumor incidence than males.


Thrombotic Complications of COVID-19 Infection: A Review.
The novel coronavirus (severe acute respiratory syndrome CoV-2 [SARS-CoV-2]), also known as COVID-19, is a single-stranded enveloped RNA virus that created a Public Health Emergency of International Concern in January 2020, with a global case burden of over 15 million in just 7 months. Infected patients develop a wide range of clinical manifestations-typically presenting with fever, cough, myalgia, and fatigue. Severely ill patients may fall victim to acute respiratory distress syndrome, acute heart injuries, neurological manifestations, or complications due to secondary infections. These critically ill patients are also found to have disrupted coagulation function, predisposing them to consumptive coagulopathies, and both venous and thromboembolic complications. Common laboratory findings include thrombocytopenia, elevated D-dimer, fibrin degradation products, and fibrinogen, all of which have been associated with greater disease severity. Many cases of pulmonary embolism have been noted, along with deep vein thrombosis, ischemic stroke, myocardial infarction, and systemic arterial embolism. The pathogenesis of coronavirus has not been completely elucidated, but the virus is known to cause excessive inflammation, endothelial injury, hypoxia, and disseminated intravascular coagulation, all of which contribute to thrombosis formation. These patients are also faced with prolonged immobilization while staying in the hospital or intensive care unit. It is important to have a high degree of suspicion for thrombotic complications as patients may rapidly deteriorate in severe cases. Evidence suggests that prophylaxis with anticoagulation may lead to a lower risk of mortality, although it does not eliminate the possibility. The risks and benefits of anticoagulation treatment should be considered in each case. Patients should be regularly evaluated for bleeding risks and thrombotic complications.


A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage.
The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.


Hubert Airy, contemporary men of science and the migraine aura.
Although there had been occasional references to the visual aura of migraine even in ancient medicine, little attention was given to the phenomenon until the first half of the nineteenth century when French authors began to describe it. In the medicine of English-speaking countries, apart from a few descriptions, it went largely unnoticed until the British Astronomer Royal, Sir George Airy, described his own experience of the visual aura in 1865. Five years later his son, Hubert Airy, also described his experience of it and that of a number of eminent contemporary men of science. The topic of the migraine aura was almost immediately taken up by two of the younger Airy's contemporaries and fellow Cambridge medical graduates, Peter Wallrock Latham and Edward Liveing, in their monographs. Subsequently, migraine with aura quickly became a well-recognised clinical entity in British medicine.


Dimethyl sulfoxide decreases interleukin-8-mediated neutrophil recruitment in the airways.
In this study, we investigated the role of dimethyl sulfoxide (DMSO) in inhibiting interleukin-8 (IL-8)-mediated neutrophil recruitment induced by Pseudomonas aeruginosa (PA) bacterial supernatant. First, we tested whether DMSO could inhibit IL-8 production induced by PA in human bronchial epithelial (16-HBE) cells in vitro. In these cells, exposure to PA or H2O2 induced IL-8 production dose dependently, an effect that was inhibited by 1% DMSO at both the protein and RNA level. Second, we tested whether DMSO could block the recruitment of neutrophils induced by PA in a bypassed segment of dog trachea in vivo. PA supernatant was placed in the tracheal segment for 6 h in four dogs, and neutrophil recruitment and IL-8 concentrations were measured in the superfusate. DMSO prevented the recruitment of neutrophils and IL-8 production induced by PA time dependently. The results suggest that DMSO may play an anti-inflammatory role in the airway by inhibiting IL-8 production in epithelial cells.


Building blocks for N-type molecular and polymeric electronics. Perfluoroalkyl- versus alkyl-functionalized oligothiophenes (nTs; n = 2-6). Systematic synthesis, spectroscopy, electrochemistry, and solid-state organization.
The synthesis, comparative physicochemical properties, and solid-state structures of five oligothiophene (nT) series differing in substituent nature and attachment, regiochemistry, and oligothiophene core length (n) are described. These five series include the following 25 compounds: (i) alpha,omega-diperfluorohexyl-nTs 1 (DFH-nTs, n = 2-6), (ii) beta,beta'-diperfluorohexyl-nTs 2 (isoDFH-nTs, n = 2-6), (iii) alpha,omega-dihexyl-nTs 3 (DH-nTs, n = 2-6), (iv) beta,beta'-dihexyl-nTs 4 (isoDH-nTs, n = 2-6), and (v) unsubstituted oligothiophenes 5 (alphanTs, n = 2-6). All new compounds were characterized by elemental analysis, mass spectrometry, and multinuclear NMR spectroscopy. To probe and address quantitatively how the chemistry and regiochemistry of conjugated core substitution affects molecular and solid-state properties, the entire 1-5 series was investigated by differential scanning calorimetry, thermogravimetric analysis, and optical absorption and emission spectroscopies. Single-crystal X-ray diffraction data for several fluorocarbon-substituted oligomers are also presented and compared. The combined analysis of these data indicates that fluorocarbon-substituted nT molecules strongly interact in the condensed state, with unit cell level phase separation between the aromatic core and fluorocarbon chains. Surprisingly, despite these strong intermolecular interactions, high solid-state fluorescence efficiencies are exhibited by the fluorinated derivatives. Insight into the solution molecular geometries and conformational behavior are obtained from analysis of optical and variable-temperature NMR spectra. Finally, cyclic voltammetry data offer a reliable picture of frontier MO energies, which, in combination with DFT computations, provide key information on relationships between oligothiophene substituent effects and electronic response properties.


Ligand-dependent equilibrium fluctuations of single calmodulin molecules.
Single-molecule force spectroscopy allows superb mechanical control of protein conformation. We used a custom-built low-drift atomic force microscope to observe mechanically induced conformational equilibrium fluctuations of single molecules of the eukaryotic calcium-dependent signal transducer calmodulin (CaM). From this data, the ligand dependence of the full energy landscape can be reconstructed. We find that calcium ions affect the folding kinetics of the individual CaM domains, whereas target peptides stabilize the already folded structure. Single-molecule data of full length CaM reveal that a wasp venom peptide binds noncooperatively to CaM with 2:1 stoichiometry, whereas a target enzyme peptide binds cooperatively with 1:1 stoichiometry. If mechanical load is applied directly to the target peptide, real-time binding/unbinding transitions can be observed.


Acute precipitants of congestive heart failure exacerbations.
Few studies have prospectively and systematically explored the factors that acutely precipitate exacerbation of congestive heart failure (CHF) in patients with left ventricular dysfunction. Knowledge of such factors is important in designing measures to prevent deterioration of clinical status. The objective of this study was to prospectively describe the precipitants associated with exacerbation of CHF status in patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study. We conducted a 2-stage, multicenter, randomized trial in 768 patients with CHF who had an ejection fraction of less than 40%. Patients were randomly assigned to receive enalapril maleate, candesartan cilexetil, or both for 17 weeks, followed by randomization to receive metoprolol succinate or placebo for 26 weeks. Investigators systematically documented information on clinical presentation, management, and factors associated with the exacerbation for any episode of acute CHF during follow-up. A total of 323 episodes of worsening of CHF occurred in 180 patients during 43 weeks of follow-up; 143 patients required hospitalization, and 5 died. Factors implicated in worsening of CHF status included noncompliance with salt restriction (22%); other noncardiac causes (20%), notably pulmonary infectious processes; study medications (15%); use of antiarrhythmic agents in the past 48 hours (15%); arrhythmias (13%); calcium channel blockers (13%); and inappropriate reductions in CHF therapy (10%). A variety of factors, many of which are avoidable, are associated with exacerbation of CHF. Attention to these factors and patient education are important in the prevention of CHF deterioration.


Regulation of CRAC channels by Ca2+-dependent inactivation.
CRAC channels are a major route for Ca2+ influx in eukaryotic cells. The channels show prominent Ca2+-dependent inactivation through two spatially and temporally distinct mechanisms: fast inactivation, which develops over milliseconds and is triggered by Ca2+ near the mouth of the channel and slow inactivation, which arises over tens of seconds and requires a rise in global cytosolic Ca2+. Slow inactivation is controlled physiologically by Ca2+ uptake into mitochondria through the MCU. Site-directed mutagenesis studies on STIM1 and Orai1 have led to new molecular insight into how fast inactivation occurs. This review describes properties and molecular mechanisms that contribute to these important Ca2+-dependent inhibitory pathways.


Consensus Recommendations for the Safe Handling of Cytotoxic Agents in Cytotoxic Academic Research Laboratories (CARL).
Cytotoxic agents, also called antineoplastic agents, are used in cancer treatment due to their inherent activity to inhibit cell growth or proliferation, or DNA, RNA and protein synthesis. They are, therefore, hazardous by nature in a non-selective manner leading to disruption of cell growth and function of both diseased and healthy cells of treated patients.While the benefits of receiving cytotoxic agents may outweigh the incurred risks for patients, the same cannot be said for exposed healthcare practitioners involved in the transport, preparation, administration, and resulting waste disposal of these agents.Consequently, many professional bodies around the world have set standards of practice to prevent occupational exposure of healthcare workers to cytotoxic agents, and hospitals have been active in defining strict policies in this concern.However, due to the variability of the practice and infrastructure in academic settings, some activities performed within the cytotoxic academic research laboratory often do not adhere to recommendations published by guidelines.The present recommendations were therefore set forward by members of a working group who are experts on the subject matter representing academic, clinical, and research backgrounds in an attempt to promote safe cytotoxic handling in academic institutions.The document maps out the trajectory of cytotoxic agents being investigated in academic research laboratories while providing recommendations on the delivery, storage, use and disposal of cytotoxic agents in university settings.


Transmission characteristics of primate vocalizations: implications for acoustic analyses.
Acoustic analyses have become a staple method in field studies of animal vocal communication, with nearly all investigations using computer-based approaches to extract specific features from sounds. Various algorithms can be used to extract acoustic variables that may then be related to variables such as individual identity, context or reproductive state. Habitat structure and recording conditions, however, have strong effects on the acoustic structure of sound signals. The purpose of this study was to identify which acoustic parameters reliably describe features of propagated sounds. We conducted broadcast experiments and examined the influence of habitat type, transmission height, and re-recording distance on the validity (deviation from the original sound) and reliability (variation within identical recording conditions) of acoustic features of different primate call types. Validity and reliability varied independently of each other in relation to habitat, transmission height, and re-recording distance, and depended strongly on the call type. The smallest deviations from the original sounds were obtained by a visually-controlled calculation of the fundamental frequency. Start- and end parameters of a sound were most susceptible to degradation in the environment. Because the recording conditions can have appreciable effects on acoustic parameters, it is advisable to validate the extraction method of acoustic variables from recordings over longer distances before using them in acoustic analyses.


Sex and Age Aspects in Patients Suffering From Out-Of-Hospital Cardiac Arrest: A Retrospective Analysis of 760 Consecutive Patients.
Cardiopulmonary resuscitation (CPR) is indicated in patients suffering from out-of-hospital cardiac arrest. Several studies suggest a sex- and age-based bias in the treatment of these patients. This particular bias may have a significant impact on the patient's outcome. However, the reasons for these findings are still unclear and discussed controversially. Therefore, the aim of this study was to retrospectively analyze treatment and out-of-hospital survival rates for potential sex- and age-based differences in patients requiring out-of-hospital CPR provided by an emergency physician in the city of Zurich, Switzerland.A total of 3961 consecutive patients (2003-2009) were included in this retrospective analysis to determine the frequency of out-of-hospital CPR and prehospital survival rate, and to identify potential sex- and age-based differences regarding survival and treatment of the patients.Seven hundred fifty-seven patients required CPR during the study period. Seventeen patients had to be excluded because of incomplete or inconclusive documentation, resulting in 743 patients (511 males, 229 females) undergoing further statistical analysis. Female patients were significantly older, compared with male patients (68 ± 18 [mean ± SD] vs 64 ± 18 years, P = .012). Men were resuscitated slightly more often than women (86.4% vs 82.1%). Overall out-of-hospital mortality rate was found to be 81.2% (492/632 patients) with no differences between sexes (82.1% for males vs 79% for females, odds ratio 1.039, 95% confidence interval 0.961-1.123). No sex differences were detected in out-of-hospital treatment, as assessed by the different medications administered, initial prehospital Glasgow Coma Scale, and prehospital suspected leading diagnosis.The data of our study demonstrate that there was no sex-based bias in treating patients requiring CPR in the prehospital setting in our physician-led emergency ambulance service.


The Pragmatic Language Skills of Severely Neglected 42-Month-Old Children: Results of the ELLAN Study.
The goals of this study were twofold: (1) to compare the pragmatic language skills (i.e., social communication skills) of 42-month-old neglected children with those of same-aged non-neglected children and (2) to measure the prevalence of pragmatic difficulties among the neglected children. The study sample was composed of 45 neglected and 95 non-neglected 42-month-old French-speaking children. The Language Use Inventory: French (LUI-French) was completed with all parents. This measure, comprised of 159 scored items divided into 10 subscales, was used to assess the children's pragmatic skills. The 10th percentile on the LUI-French (95% confidence interval ) was used to identify children with pragmatic difficulties. The neglected children had lower scores than the non-neglected children on all 10 dimensions of pragmatics evaluated (p < .01), as well as lower LUI-French Total Scores (p < .001). The effect sizes of these differences varied between 0.84 and 2.78. Forty-four percent of the neglected children presented significant pragmatic difficulties compared to 4.2% of their non-neglected peers (p < .001). It can be concluded that exposure to neglect significantly compromises children's pragmatic skills. These results support the need for interventions geared toward neglected children and their families to support the early development of their pragmatic skills.


Osteosclerosis due to endemic fluorosis.
Endemic water borne fluorosis is a public health problem in Isparta, a city located in southern Turkey. In order to investigate the association between osteosclerosis and fluorosis, we retrospectively screened the results of lumbar spine and femur neck bone mineral density (BMD) of 1500 patients who were examined before, for any reason in between 2001-2003. Sixty nine patients (67 females and 2 males, mean age 52.6+/-10.2) with vertebra T-scores>or=+2 were found only except a patient with osteoid osteoma in the femur neck (femur T-score+6.64). Thirty-four of the patients could be reexamined with lateral vertebra BMD and investigated for fluorosis and the other etiologic causes of osteosclerosis. Of 34 patients, 14 had either mottled tooth enamel or urine fluoride level greater than 1.5 mg/l. Other etiologic causes were hypothyroidism (2), hypoparathyroidism (1), history of lumbar fracture (1), use of retinoids (1), vitamin D (7), oral calcium preparations (9), and bisphosphanates (3). Lateral lumbar vertebral T-score was greater than+2 in 12 patients (35.3%). Femur T-score was greater than+2 in 7 patients (20.6%). Fourteen patients (41.2%) had lateral vertebral or femur T-score>or=+2. Five (35.7%) of these patients had signs of fluorosis, as discussed before. Mean body mass index of individuals with fluorosis was 36.4+/-7.9 and this result was significantly higher than other osteosclerotic subjects (31.6+/-4.4). In conclusion we believe that approximately one third of the osteosclerosis in our region was due to endemic skeletal fluorosis and obesity may enhance this osteosclerotic type bone changes in endemic fluorosis.


A biophysically detailed model of neocortical local field potentials predicts the critical role of active membrane currents.
Brain activity generates extracellular voltage fluctuations recorded as local field potentials (LFPs). It is known that the relevant microvariables, the ionic currents across membranes, jointly generate the macrovariables, the extracellular voltage, but neither the detailed biophysical knowledge nor the required computational power have been available to model these processes. We simulated the LFP in a model of the rodent neocortical column composed of >12,000 reconstructed, multicompartmental, and spiking cortical layer 4 and 5 pyramidal neurons and basket cells, including five million dendritic and somatic compartments with voltage- and ion-dependent currents, realistic connectivity, and probabilistic AMPA, NMDA, and GABA synapses. We found that, depending on a number of factors, the LFP reflects local and cross-layer processing. Active currents dominate the generation of LFPs, not synaptic ones. Spike-related currents impact the LFP not only at higher frequencies but below 50 Hz. This work calls for re-evaluating the genesis of LFPs.


Morphology of soft and rough contact via fluid drainage.
The dynamic of contact formation between soft materials immersed in a fluid is accompanied by fluid drainage and elastic deformation. As a result, controlling the coupling between lubrication pressure and elasticity provides strategies to design materials with reversible and dynamic adhesion to wet or flooded surfaces. We characterize the elastic deformation of a soft coating with nanometer-scale roughness as it approaches and contacts a rigid surface in a fluid environment. The lubrication pressure during the approach causes elastic deformation and prevents contact formation. We observe deformation profiles that are drastically different from those observed for elastic half-space when the thickness of the soft coating is comparable to the hydrodynamic radius. In contrast, we show that surface roughness favors fluid drainage without altering the elastic deformation. As a result, the coupling between elasticity and slip (caused by surface roughness) can lead to trapped fluid pockets in the contact region.


The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia formation.
The chicken talpid(3) mutant, with polydactyly and defects in other embryonic regions that depend on hedgehog (Hh) signalling (e.g. the neural tube), has a mutation in KIAA0568. Similar phenotypes are seen in mice and in human syndromes with mutations in genes that encode centrosomal or intraflagella transport proteins. Such mutations lead to defects in primary cilia, sites where Hh signalling occurs. Here, we show that cells of talpid(3) mutant embryos lack primary cilia and that primary cilia can be rescued with constructs encoding Talpid3. talpid(3) mutant embryos also develop polycystic kidneys, consistent with widespread failure of ciliogenesis. Ultrastructural studies of talpid(3) mutant neural tube show that basal bodies mature but fail to dock with the apical cell membrane, are misorientated and almost completely lack ciliary axonemes. We also detected marked changes in actin organisation in talpid(3) mutant cells, which may explain misorientation of basal bodies. KIAA0586 was identified in the human centrosomal proteome and, using an antibody against chicken Talpid3, we detected Talpid3 in the centrosome of wild-type chicken cells but not in mutant cells. Cloning and bioinformatic analysis of the Talpid3 homolog from the sea anemone Nematostella vectensis identified a highly conserved region in the Talpid3 protein, including a predicted coiled-coil domain. We show that this region is required to rescue primary cilia formation and neural tube patterning in talpid(3) mutant embryos, and is sufficient for centrosomal localisation. Thus, Talpid3 is one of a growing number of centrosomal proteins that affect both ciliogenesis and Hh signalling.


Coenzyme Q10 supplementation reduces peripheral oxidative stress and inflammation in interferon-β1a-treated multiple sclerosis.
Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluated the effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress and inflammation, and on MS clinical severity. We included 60 relapsing-remitting patients with MS treated with interferon beta1a 44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (in an open-label crossover design). At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage and inflammation in the peripheral blood, and collected data on disease severity. After 3 months, CoQ10 supplementation was associated with improved scavenging activity (as mediated by uric acid), reduced intracellular reactive oxygen species production, reduced oxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheral blood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R, IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability Status Scale, fatigue severity scale, Beck's depression inventory, and the visual analogue scale for pain. CoQ10 supplementation improved scavenging activity, reduced oxidative damage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral blood of relapsing-remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effect was noted but deserves to be confirmed over longer follow ups.


Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells.
Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978-1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC(50)s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71%, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.


Review article: Sepsis in the emergency department - Part 2: Investigations and monitoring.
Sepsis is characterised by organ dysfunction resulting from infection, with no reliable single objective test and current diagnosis based on clinical features and results of investigations. In the ED, investigations may be conducted to diagnose infection as the cause of the presenting illness, identify the source, distinguish sepsis from uncomplicated infection (i.e. without organ dysfunction) and/ or risk stratification. Appropriate sample collection for microbiological testing remains key for subsequent confirmation of diagnosis and rationalisation of antimicrobials. Routine laboratory investigations such as creatinine, bilirubin, platelet count and lactate are now critical elements in the diagnosis of sepsis and septic shock. With no biomarker sufficiently validated to rule out bacterial infection in the ED, there remains substantial interest in biomarkers representing various pathogenic pathways. New technologies for screening multiple genes and proteins are identifying unique network 'signatures' of clinical interest. Other future directions include rapid detection of bacterial DNA in blood, genes for antibiotic resistance and EMR-based computational biomarkers that collate multiple information sources. Reliable, cost-effective tests, validated in the ED to promptly and accurately identify sepsis, and to guide initial antibiotic choices, are important goals of current research efforts.


A randomized controlled trial of electromagnetic therapy in the primary care management of venous leg ulceration.
The aim was to establish the potential efficacy, tolerability and side-effect profile of electromagnetic therapy as an adjunct to conventional dressings in the treatment of venous leg ulcers. A prospective, randomized, double blind controlled clinical trial was carried out in a dedicated leg ulcer clinic based in one urban general practice. Nineteen patients with leg ulcers of confirmed venous aetiology were assessed. The main outcome measures were rate and scale of venous leg ulcer healing, changes in patient-reported pain levels, quality of life, degree of mobility, side effect profile and acceptability to patients and staff. Sixty-eight per cent of patients attending this dedicated clinic achieved improvements in the size of their ulcer (4, 21%, healed fully) and in reduced pain levels (P < 0.05) during the trial, despite the chronicity of ulcer histories. Patients treated with electromagnetic therapy at 800 Hz were found at day 50 to have significantly greater healing (P < 0.05) and pain control (P < 0.05) than placebo therapy or treatment with 600 Hz. All patients reported improved mobility at the end of the study. The electromagnetic therapy was well tolerated by patients, with no differences between groups in reporting adverse events, and proved acceptable to staff. Despite the small numbers in this pilot study, electromagnetic therapy provided significant gains in the healing of venous leg ulcers and reduction in pain.


Alcohol brief intervention for hospitalized veterans with hazardous drinking: protocol for a 3-arm randomized controlled efficacy trial.
Various hospital accreditation and quality assurance entities in the United States have approved and endorsed performance measures promoting alcohol brief intervention (BI) for hospitalized individuals who screen positive for unhealthy alcohol use, the spectrum of use ranging from hazardous use to alcohol use disorders. These performance measures have been controversial due to the limited and equivocal evidence for the efficacy of BI among hospitalized individuals. The few BI trials conducted with hospital inpatients vary widely in methodological quality. While the majority of these studies indicate limited to no effects of BI in this population, none have been designed to account for the most pervasive methodological issue in BI studies presumed to drive study findings towards the null: assessment reactivity (AR). This is a three-arm, single-site, randomized controlled trial of BI for hospitalized patients at a large academic medical center affiliated with the U.S. Department of Veterans Affairs who use alcohol at hazardous levels but do not have an alcohol use disorder. Participants are randomized to one of three study conditions. Study Arm 1 receives a three-part alcohol BI. Study Arm 2 receives attention control. To account for potential AR, Study Arm 3 receives AC with limited assessment. Primary outcomes will include the number of standard drinks/week and binge drinking episodes reported in the 30-day period prior to a final measurement visit obtained 6 months after hospital discharge. Additional outcomes will include readiness to change drinking behavior and number of adverse consequences of alcohol use. To assess differences in primary outcomes across the three arms, we will use mixed-effects regression models that account for a patient's repeated measures over the timepoints and clustering within medical units. Intervention implementation will be assessed by: a) review of intervention audio recordings to characterize barriers to intervention fidelity; and b) feasibility of participant recruitment, enrollment, and follow-up. The results of this methodologically rigorous trial will provide greater justification for or against the use of BI performance measures in the inpatient setting and inform organizational responses to BI-related hospital accreditation and performance measures. NCT01602172.


Adenovirus-mediated P311 inhibits TGF-β1-induced epithelial-mesenchymal transition in NRK-52E cells via TGF-β1-Smad-ILK pathway.
P311, a highly conserved 8-kDa intracellular protein, has been indicated as an important factor in myofibroblast transformation and in the progression of fibrosis. In the present study, we constructed a recombinant adenovirus vector of p311 (called Ad-P311) and transferred it into rat renal proximal tubular epithelial cells (NRK-52E) to explore the effect of P311 on epithelial-mesenchymal transition (EMT) of NRK-52E cells induced by TGF-β1 and to elucidate its underlying mechanism against EMT. After successfully construction of Ad-P311 and transfer into NRK-52E cells, the proliferation and growth of P311-expressing cells was detected by MTT assay. TGF-β1 was used to induce NRK-52E cells and Western blot analysis was used to examine the EMT markers (E-cadherin and α-smooth muscle actin (α-SMA)), signal transducers (p-Smad2/3 and Smad7). Integrin Linked Kinase (ILK) as a key intracellular mediator that controls TGF-β1-induced-EMT was also assayed by Western blot analysis. The results showed that P311 transfection could significantly inhibit the proliferation and growth of TGF-β1 induced NRK-52E cells. The results also showed that TGF-β1 could induce EMT in NRK-52E cells through Smad-ILK signaling pathway with an increase in α-SMA, pSmad2/3 and ILK expression, and a decrease in E-cadherin and Smad7 expression. However, P311 efficiently blocked Smad-ILK pathway activation and attenuated all these EMT changes induced by TGF-β1. These findings suggest that P311 might be involved in the pathogenesis of renal fibrosis by inhibiting the EMT process via TGF-β1-Smad-ILK pathway. P311 might be a novel target for the control of renal fibrosis and the progression of CKD.


Large-volume iodinated contrast medium extravasation: low frequency and good outcome after conservative management in a single-centre cohort of more than 67,000 patients.
Our aim was to retrospectively investigate the frequency and outcome of large-volume iodinated contrast medium (CM) extravasation in our institution and to compare our management protocol to current practice. Institutional review board approval was obtained, and informed consent was waived because the study was retrospective. From January 2008 to September 2016, radiological examinations with intravenous non-ionic iodinated CM administration were performed in 67,129 patients. Contrast medium extravasation events on CT scans and intravenous pyelograms but not on angiograms were included. All data were collected prospectively and stratified according to age, injection method (manual vs auto-injection), prevention of extravasation by various means (including intercom alarm), management of extravasation (routine application of silver sulfadiazine ointment, clobetasol propionate cream, and damp gauze at room temperature), etc. RESULTS: The incidence of large-volume CM extravasation was very low (0.04% [27/67,129] overall; 0.03% related to manual injection [age range, 59-92 years; mean, 75.4 years], and 0.045% related to auto-injection [age range, 36-86 years; mean, 65.8 years]). The CM extravasation volume in majority of patients was 20-40 ml in 5 of 9 patients (55.6%) in the manual injection group and 14 of 18 (77.8%) in the auto-injection group. Swelling and pain were the most common symptoms. No patient developed severe signs or needed surgical intervention. Results show a very low incidence of large-volume CM extravasation without severe complications or sequelae. The casual effect between our protocols and good outcome cannot be scrutinised thoroughly because the study lacks a control group and is retrospective. • The incidence of large-volume contrast medium extravasation (≥20 ml) was 0.04%. • No patient needed surgical intervention, and most recovered within 7 days. • Each element of our management protocol contributed to good outcome.


Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial.
To assess clinical outcomes, efficacy, and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a randomized, double-blind, placebo-controlled, multicentre trial that included 11 785 (64.7%) men and 6416 (35.3%) women with atrial fibrillation or flutter randomized to receive either warfarin or apixaban. The primary efficacy endpoint was stroke or systemic embolism; secondary efficacy endpoints were death from any cause and cardiovascular death. The primary safety endpoint was major bleeding; secondary safety endpoints were a composite of major bleeding and non-major clinically relevant bleeding. The risk of stroke or systemic embolism was similar in women vs. men [adjusted hazard ratio (adjHR): 0.91; 95% confidence interval (CI): 0.74-1.12; P = 0.38]. However, among patients with history of stroke or transient ischaemic attack, women had a lower risk of recurrent stroke compared with men (adjHR: 0.70; 95% CI: 0.50-0.97; P = 0.036). Women also had a lower risk of all-cause death (adjHR: 0.63; 95% CI: 0.55-0.73; P < 0.0001) and cardiovascular death (adjHR: 0.62; 95% CI: 0.51-0.75; P < 0.0001), and a trend towards less major bleeding (adjHR: 0.86; 95% CI: 0.74-1.01; P = 0.066) and major or non-major clinically relevant bleeding (adjHR: 0.89; 95% CI: 0.80-1.00; P = 0.049). The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex. In the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinically relevant bleeding than men. The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women. ARISTOTLE ClinicalTrials.gov number, NCT00412984.


Associations between retirement reasons, chronic pain, athletic identity, and depressive symptoms among former professional footballers.
Retirement from professional sport has been recognised as a major psychological stressor, and there is a need to identify factors that increase the risk of mental health problems after career termination. The current study examined associations between career-ending injury, chronic pain, athletic identity, and depressive symptomology in retired professional footballers. A cross-sectional study was performed with 307 retired male footballers who had played within a professional United Kingdom league. Participants completed measures of depressive symptoms (Short Depression-Happiness Scale), chronic pain (Pain Intensity Numerical Rating Scale), and athletic identity (Athletic Identity Measurement Scale), and reported their reasons for retirement. A total of 48 participants (16%) met the cut-off score for possible cases of clinically relevant depression. These participants were more recently retired, and had higher athletic identity than those without depressive symptoms. Former players with depressive symptoms were more likely to cite injury as a retirement reason, and report higher levels of ongoing injury-related pain. Multivariate logistic regression revealed that the presence of depressive symptoms was independently associated with retirement through injury (OR = 3.44; 95% CI = 1.39, 8.51), higher pain levels (OR = 1.38; 95% CI = 1.02, 1.86), and increased athletic identity (OR = 1.28; 95% CI = 1.14, 1.44). Career-ending injury is strongly associated with higher odds of depressive symptomology during retirement, while experiencing chronic pain, and maintaining a high sense of athletic identity, are additional potential contributors.