Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression.
An enhanced understanding of the pathophysiology of depression would facilitate the discovery of new efficacious medications. To this end, we examined hippocampal transcriptional changes in rat models of disease and in humans to identify common disease signatures by using a new algorithm for signature-based clustering of expression profiles. The tool identified a transcriptomic signature comprising 70 probesets able to discriminate depression models from controls in both Flinders Sensitive Line and Learned Helplessness animals. To identify disease-relevant pathways, we constructed an expanded protein network based on signature gene products and performed functional annotation analysis. We applied the same workflow to transcriptomic profiles of depressed patients. Remarkably, a 171-probesets transcriptional signature which discriminated depressed from healthy subjects was identified. Rat and human signatures shared the SCARA5 gene, while the respective networks derived from protein-based significant interactions with signature genes contained 25 overlapping genes. The comparison between the most enriched pathways in the rat and human signature networks identified a highly significant overlap (p-value: 3.85 × 10-6) of 67 terms including ErbB, neurotrophin, FGF, IGF, and VEGF signaling, immune responses and insulin and leptin signaling. In conclusion, this study allowed the identification of a hippocampal transcriptional signature of resilient or susceptible responses in rat MDD models which overlapped with gene expression alterations observed in depressed patients. These findings are consistent with a loss of hippocampal neural plasticity mediated by altered levels of growth factors and increased inflammatory responses causing metabolic impairments as crucial factors in the pathophysiology of MDD.


Zika virus infection during the period of maximal brain growth causes microcephaly and corticospinal neuron apoptosis in wild type mice.
Zika virus (ZIKV) infection in pregnant women has been established as a cause of microcephaly in newborns. Here we test the hypothesis that neurodevelopmental stages when the brain is undergoing rapid growth are particularly vulnerable to the effects of ZIKV infection. We injected ZIKV intracranially into wild type C57BL/6 mice at two different time points: early postnatal development, when the brain is growing at its maximal rate, and at weaning, when the brain has largely reached adult size. Both time points showed widespread immunoreactivity for ZIKV and cleaved caspase 3 (CC3, a marker of apoptosis) throughout the brain. However, in early postnatal ZIKV injected mice, some brain areas and cell types display particularly large increases in apoptosis that we did not observe in older animals. Corticospinal pyramidal neurons, a cell type implicated in human microcephaly associated with ZIKV infection, are an example of one such cell type. Proliferating cells in the ventricular zone stem cell compartment are also depleted. These findings are consistent with the hypothesis that periods of rapid brain growth are especially susceptible to neurodevelopmental effects of ZIKV infection, and establish a valuable model to investigate mechanisms underlying neurodevelopmental effects of ZIKV infection and explore candidate therapeutics.


Climate change enhances primary production in the western Antarctic Peninsula.
Intense regional warming was observed in the western Antarctic Peninsula (WAP) over the last 50 years. Here, we investigate the impact of climate change on primary production (PP) in this highly productive region. This study is based on temporal data series of ozone thickness (1972-2010), sea ice concentration (1978-2010), sea-surface temperature (1990-2010), incident irradiance (1988-2010) and satellite-derived chlorophyll a concentration (Chl-a, 1997-2010) for the coastal WAP. In addition, we apply a photosynthesis/photoinhibition spectral model to satellite-derived data (1997-2010) to compute PP and examine the separate impacts of environmental forcings. Since 1978, sea ice retreat has been occurring earlier in the season (in March in 1978 and in late October during the 2000s) while the ozone hole is present in early spring (i.e. August to November) since the early 1990s, increasing the intensity of ultraviolet-B radiation (UVBR, 280-320 nm). The WAP waters have also warmed over 1990-2010. The modelled PP rates are in the lower range of previously reported PP rates in the WAP. The annual open water PP in the study area increased from 1997 to 2010 (from 0.73 to 1.03 Tg C yr(-1) ) concomitantly with the increase in the production season length. The coincidence between the earlier sea ice retreat and the presence of the ozone hole increased the exposure to incoming radiation (UVBR, UVAR and PAR) and, thus, increased photoinhibition during austral spring (September to November) in the study area (from 0.014 to 0.025 Tg C yr(-1) ). This increase in photoinhibition was minor compared to the overall increase in PP, however. Climate change hence had an overall positive impact on PP in the WAP waters.


Androgen induction of a human prostate-specific kallikrein, hKLK2: characterization of an androgen response element in the 5' promoter region of the gene.
The human prostate-specific kallikreins, human glandular kallikrein-1 (hKLK2) and prostate-specific antigen (hKLK3), have been shown to be regulated by androgens. To determine whether the androgen induction of these genes is transcriptionally regulated via an androgen response element, an hKLK2 promoter DNA fragment was linked to a promoterless chloramphenicol acetyltransferase (CAT) reporter gene and cotransfected with an androgen receptor expression vector in an androgen receptor-less human prostate cell line, PC-3. Dose response and steroid specificity experiments showed that the hKLK2 promoter confers androgen receptor-mediated gene induction in a ligand-specific manner. Moreover, 5' deletion constructs of the hKLK2 promoter DNA and internal deletion constructs devoid of the 5' half-site of the putative androgen responsive element (ARE) were used to show that the putative ARE is indeed acting as a functional ARE in prostate cells. In addition, multiple AREs from both hKLK2 and hKLK3 were able to reconstitute androgenic induction, further strengthening the argument that the AREs are functional. Although previous studies have shown that hKLK3 mRNA is expressed at a higher level than that of hKLK2, our results suggest that the hKLK2 ARE may have higher androgenic inducibility than the hKLK3 ARE. These results suggest that other cis-acting elements may be involved in coordinating in vivo androgenic induction of hKLK2 and hKLK3 genes.


Measuring improvement in depression in cancer patients: a 50% drop on the self-rated SCL-20 compared with a diagnostic interview.
To determine the validity of a 50% drop in the 20-item Symptom Checklist Depression Scale (SCL-20) score against the "gold standard" of no longer meeting criteria for major depression as assessed using a diagnostic interview in an outpatient cancer population and also to examine the validity of other potential cut-offs (i.e., percentage drops). Secondary analysis of data from a randomized trial which compared collaborative care with usual care for cancer patients with major depression. A total of 194 trial participants who had both SCL-20 scores and depression diagnoses on the Structured Clinical Interview for DSM-IV at both baseline and at 12-week outcome formed the analyzed sample. A 50% reduction in the SCL-20 score from baseline to 12 weeks correctly identified the patients who no longer met criteria for major depression in 153 (78.9%) of 194 (95% CI 73.1% to 84.6%) cases. Most of those misclassified had not achieved a 50% reduction in SCL-20 score despite no longer meeting criteria for major depression. Examination of the performance of percentage drops other than 50% on the SCL-20 using a receiver operating characteristics (ROC) curve and histogram of misclassification suggested that the 50% drop was best if both a low overall misclassification rate and the minimizing of false positives of improvement were required. A 50% reduction in the SCL-20 score performs well as a conservative measure of change in depression status in cancer patients.


A comparison of mortality, myocardial infarction, and repeated revascularization for sirolimus-eluting and paclitaxel-eluting coronary stents.
Drug-eluting stents are now used in most percutaneous coronary interventions. There are only 2 approved devices: sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). Only a few population-based studies have compared their patient outcomes. All New York State patients undergoing SES or PES in nonfederal hospitals in the state between April 1 and December 31, 2004, except those with a previous revascularization, left main coronary artery disease, or a recent myocardial infarction (MI) or shock (4867 patients with PES and 6914 with SES) were followed up through the end of 2005. We compared SES and PES with respect to inhospital and 18-month mortality, 18-month mortality/MI, and subsequent target vessel and target lesion revascularization (TVR and TLR) after adjusting for differences in patient risk factors. By 18 months after receiving a PES, 4.0% of the patients died compared with 4.1% for SES patients, 5.9% of PES patients experienced mortality/MI compared with 6.3% of SES patients, 6.8% of the PES patients had a subsequent TVR within 18 months compared with 7.8% for SES patients, and 4.5% of the PES patients had a subsequent TLR within 18 months compared with 5.3% for SES patients. The respective adjusted hazards ratios (PES/SES) for these adverse outcomes were 1.02 (95% CI 0.82-1.26, P = .86), 0.94 (95% CI 0.78-1.13, P = .52), 0.89 (95% CI 0.75-1.06, P = .20), and 0.86 (95% CI 0.70-1.05, P = .14). Patients receiving PES and SES do not have significantly different 18-month mortality, mortality/MI, subsequent TVR, or subsequent TLR rates.


Subliminal presentation of emotionally negative vs positive primes increases the perceived beauty of target stimuli.
Emotions have a profound influence on aesthetic experiences. Studies using affective priming procedures demonstrate, for example, that inducing a conscious negative emotional state biases the perception of abstract stimuli towards the sublime (Eskine et al. Emotion 12:1071-1074, 2012. doi: 10.1037/a0027200). Moreover, subliminal happy facial expressions have a positive impact on the aesthetic evaluation of abstract art (Flexas et al. PLoS ONE 8:e80154, 2013). Little is known about how emotion influences aesthetic perception of non-abstract, representational stimuli, especially those that are particularly relevant for social behaviour, like human bodies. Here, we explore whether the subliminal presentation of emotionally charged visual primes modulates the explicit subjective aesthetic judgment of body images. Using a forward/backward masking procedure, we presented subliminally positive and negative, arousal-matched, emotional or neutral primes and measured their effect on the explicit evaluation of perceived beauty (high vs low) and emotion (positive vs negative) evoked by abstract and body images. We found that negative primes increased subjective aesthetic evaluations of target bodies or abstract images in comparison with positive primes. No influence of primes on the emotional dimension of the targets was found, thus ruling out an unspecific arousal effect and strengthening the link between emotional valence and aesthetic appreciation. More specifically, that subliminal negative primes increase beauty ratings compared to subliminal positive primes indicates a clear link between negative emotions and positive aesthetic evaluations and vice versa, suggesting a possible link between negative emotion and the experience of sublime in art. The study expands previous research by showing the effect of subliminal negative emotions on the subjective aesthetic evaluation not only of abstract but also of body images.


Arterial oxygenation and oxygen transport during exercise in patients with chronic obstructive pulmonary disease.
Twenty patients with chronic obstructive pulmonary disease (COPD) walked on the treadmill until symptoms limited further exercise. Ventilation, pulmonary gas exchange, arterial and mixed venous blood gas and haemodynamic variables were measured during steady state. It was not possible to predict from any resting cardiopulmonary variables (including static lung function tests) which patients would develop a decline in arterial PO2. In spite of variable PvO2 values at symptom-limited exercise, a good correlation was obtained between arterial haemoglobin saturation with oxygen and the venous admixture fraction. The directional change in PaO2, however, did not always follow that of the total oxygen transport to the tissues as gauged by either the PvO2 or the efficiency of oxygen delivery (oxygen flux/oxygen consumption) when expressed as a percentage of the value predicted for the level of exertion. This was due to the variable and unpredictable response of the cardiac output on exercise. It is concluded that there is a need to assess each patient individually both at rest and on exercise when evaluating arterial oxygenation and oxygen transport. The pattern of exercise-induced change in these oxygen indices is not predictable from resting data and they may even follow opposite directional trends.


Dietary intake of macronutrients and fiber in Mediterranean patients on chronic hemodialysis.
We aimed to measure the dietary intake of calories, proteins, carbohydrates, lipids and fiber in patients on chronic hemodialysis (HD) at 3 centers in 1 metropolitan and 2 urban areas of Italy, and to evaluate whether it met the dietary guidelines for cardiovascular risk reduction. Daily dietary intake was assessed through a 3-day diet diary in 128 HD patients at the hemodialysis units of the Catholic University of Rome, Hospital A. Murri of Jesi and Hospital Principe di Piemonte of Senigallia, Italy. Mean dietary calorie and protein intakes were 22.9 ± 9.1 kcal/kg per day and 0.95 ± 0.76 g protein/kg per day, respectively. Daily carbohydrate and lipid intakes as a percentage of total calorie intake were 51.8% ± 8.9% and 32.1% ± 7.1%. Mean daily dietary cholesterol intake was 206.6 ± 173.6 mg. Mean daily dietary intakes of omega-3 and omega-6 fatty acids were 0.49 ± 0.28 g and 5.1 ± 2.5 g, respectively, while the mean ratio of omega-6 to omega-3 intake was 11.5 ± 4.8. Forty-eighty percent of patients had an omega-6 to omega-3 ratio =10. Mean daily dietary intakes of saturated fatty acids (SFAs), monounsaturated fatty acids and polyunsaturated fatty acids were 5.5 ± 3.3 g, 28.9 ± 9.1 g and 3.1 ± 1.7 g, respectively. Ninety-six percent of HD patients had an SFA intake <10% of total calories. Most unsaturated fatty acids intakes were under the value of =30%. Mean daily dietary fiber intake was 11.8 ± 6.1 g. In HD patients from a Mediterranean country (Italy), daily intakes of calories, proteins and fiber were lower than the recommended values, whereas the intake of lipids was closer to being adequate.


Use of telehealth technology to extend child protection team services.
In response to increased referrals to Florida's Child Protection Teams and concern regarding statewide availability of medical expertise in the area of child abuse and neglect, Children's Medical Services of the Florida Department of Health established a telemedicine project to facilitate immediate expert medical evaluations of alleged child abuse or neglect. This article describes a baseline examination of the project, including the technique of concept mapping, to examine how larger systematic factors influence the adaptation of telemedicine technology in child abuse examination settings. This study included interviews of key staff plus the incorporation of concept mapping, which takes qualitative data (individual statements and opinions) and quantifies them (sorts and ranks them by order of group importance). Findings from interviews revealed that the frequency of use of telehealth services varies across the state as a result of several factors, including space limitations and staff training. Patients, however, seem to be comfortable with the use of the new technology. The concept mapping exercise displayed a progression of issues that are perceived to have an impact on the use of this technology. Technology use is affected by unforeseen variables, such as physical space limitations and examination room availability. Family concerns about patient privacy issues were rare and were resolved quickly by the health care practitioner. Although using this equipment is not difficult, the search for user-friendliness should be continued. Staff engagement early in the process likely will result in a greater likelihood of use of the technology.telehealth, telemedicine, child protection, child abuse and neglect, concept mapping.


Heterotopic bone formation following anterior cruciate ligament reconstruction with BPTB autograft.
In this study, we present a 36-year-old male patient who developed heterotopic ossification after anterior cruciate ligament (ACL) reconstruction performed using bone-patellar tendon-bone autograft harvested from the 1/3 middle part of the patellar tendon. This ossified part, which restricted range of motion of the affected knee, was excised surgically 1 year after diagnosis. Physical examination, conducted 36 months later, revealed the achievement of full range of motion without any complaints or recurrences. Heterotopic ossification following ACL reconstruction is a very rare complication, which should be removed with open surgery.


Factors associated with staff support and resident lifestyle in services for people with multiple disabilities: a path analytic approach.
The quality and costs of residential services for 40 adults with severe learning disabilities and sensory impairments across four different service models were evaluated. A path analytic approach was used to calculate factors associated with four indicators of service quality: (1) assistance received by residents from staff; (2) positive contact received by residents from staff; (3) resident engagement in constructive activity; and (4) the level of physical integration of residents. The path analyses accounted for between 50 and 77% of the variance in the indicators. Factors found to be commonly associated with all four indicators included a community location, a specialized service orientation, the cognitive abilities of residents and a high level of scheduled activity. Service resources in the form of costs or staff ratios were not associated with any indicator of service quality. The findings strongly suggest an inverse system of care in that residents with greater skills receive more staff support. The implications of these and other findings for further research and service practice are discussed.


Booms, Busts, and Divorce.
For almost a century, anecdotes have suggested that divorce rates decline during recessions. However, until very recently there has been surprisingly little formal empirical evidence on whether such a link exists, let alone its magnitude if it does. Moreover, the anticipated direction of the effect is ambiguous theoretically. Although previous studies have concluded that individual job loss destabilizes marriages, macroeconomic conditions may affect divorce probabilities even for those not directly experiencing a job shock. We add to the few existing contemporaneous studies of the effects of macroeconomic shocks on divorce by conducting an empirical analysis of the relationship between state-level unemployment rates and state-level divorce rates using vital statistics data on divorces in the United States from 1976-2009. We find a significant and robust negative relationship between the unemployment and divorce rates, whereby a one percentage point rise in the unemployment rate is associated with a decrease of 0.043 divorces per one thousand people, or about a one percent fall in the divorce rate. The result that divorce is pro-cyclical is robust to a host of alternative empirical specifications, to disaggregating by state characteristics and time period, to expanding the unemployment series back to 1970, and to using alternative measures of local economic conditions.


Utilisation of evidence-based practices by ASD early intervention service providers.
A number of autism intervention practices have been demonstrated to be effective. However, the use of unsupported practices persists in community early intervention settings. Recent research has suggested that personal, professional and workplace factors may influence intervention choices. The aim of this research was to investigate knowledge and use of strategies, organisational culture, individual attitudes, sources of information and considerations informing intervention choices by early intervention providers. An online survey was completed by 72 early intervention providers from four organisations across Australia. Providers reported high levels of trust and access of information from internal professional development, therapists and external professional development. A range of considerations including child factors, family values and research were rated as important in informing intervention choices. Participants reported greater knowledge and use of evidence-based and emerging practices than unsupported. Levels of use were linked to levels of knowledge, as well as some organisational and attitudinal factors. Areas for future research and implications are discussed.


Modelling biological Cr(VI) reduction in aquifer microcosm column systems.
Several chrome processing facilities in South Africa release hexavalent chromium (Cr(VI)) into groundwater resources. Pump-and-treat remediation processes have been implemented at some of the sites but have not been successful in reducing contamination levels. The current study is aimed at developing an environmentally friendly, cost-effective and self-sustained biological method to curb the spread of chromium at the contaminated sites. An indigenous Cr(VI)-reducing mixed culture of bacteria was demonstrated to reduce high levels of Cr(VI) in laboratory samples. The effect of Cr(VI) on the removal rate was evaluated at concentrations up to 400 mg/L. Following the detailed evaluation of fundamental processes for biological Cr(VI) reduction, a predictive model for Cr(VI) breakthrough through aquifer microcosm reactors was developed. The reaction rate in batch followed non-competitive rate kinetics with a Cr(VI) inhibition threshold concentration of approximately 99 mg/L. This study evaluates the application of the kinetic parameters determined in the batch reactors to the continuous flow process. The model developed from advection-reaction rate kinetics in a porous media fitted best the effluent Cr(VI) concentration. The model was also used to elucidate the logistic nature of biomass growth in the reactor systems.


Management of Patients with Gastroschisis Requiring Extracorporeal Membrane Oxygenation for Concurrent Respiratory Failure.
Treatment of gastroschisis often requires multiple surgical procedures to re-establish abdominal domain, reduce abdominal contents, and eventually close the abdominal wall. In patients who have concomitant respiratory failure requiring extracorporeal membrane oxygenation (ECMO), this process becomes further complicated. This situation is rare and only five such cases have been reported in the ECMO registry database. Management of three of the five patients along with results and implications for future care of similar patients is discussed here. Two patients had respiratory failure due to meconium aspiration syndrome and one patient had persistent acidosis as well as worsening pulmonary hypertension leading to the decision of ECMO. The abdominal contents were placed in a spring-loaded silastic silo while on ECMO and primary closure was performed three to six days after the decannulation. All three patients survived and are developmentally appropriate. We recommend avoiding aggressively reducing the abdominal contents and using a silo to conservatively reducing the gastroschisis while the patient is on ECMO therapy. Keeping the intra-abdominal pressure below 20 mm Hg can possibly reduce ECMO days and ventilator time and has been shown to decrease morbidity and mortality. Patients with gastroschisis and respiratory failure requiring ECMO can have good outcomes despite the complexity of required care.


Tolerance of transcranial direct current stimulation in psychiatric disorders: An analysis of 2000+ sessions.
Transcranial direct current stimulation (tDCS), a non-invasive, neuromodulatory technique, is being increasingly applied to several psychiatric disorders. In this study, we describe the side-effect profile of repeated tDCS sessions (N = 2005) that were administered to 171 patients (156 adults and 15 adolescents) with different psychiatric disorders [schizophrenia [N = 109], obsessive-compulsive disorder [N = 28], alcohol dependence syndrome [N = 13], mild cognitive impairment [N = 10], depression [N = 6], dementia [N = 2] and other disorders [N = 3]]. tDCS was administered at a constant current strength of 2 mA with additional ramp-up and ramp-down phase of 20 s each at the beginning and end of the session, respectively. Other tDCS protocol parameters were: schizophrenia and obsessive-compulsive disorder: 5-days of twice-daily 20-min sessions with an inter-session interval of 3-h; Mild cognitive impairment/dementia and alcohol dependence syndrome: at least 5-days of once-daily 20-min session; Depression: 10-days of once-daily 30 min session. At the end of each tDCS session, any adverse event observed by the administrator and/or reported by the patient was systematically assessed using a comprehensive questionnaire. The commonly reported adverse events during tDCS included burning sensations (16.2%), skin redness (12.3%), scalp pain (10.1%), itching (6.7%), and tingling (6.3%). Most of the adverse events were noted to be mild, transient and well-tolerated. In summary, our observations suggest that tDCS is a safe mode for therapeutic non-invasive neuromodulation in psychiatric disorders in adults as well as the adolescent population.


Immunohistochemical localization and quantitation of NADPH-cytochrome P-450 reductase in human liver.
An antibody raised in a goat against the human liver NADPH-cytochrome P-450 reductase (EC 22.214.171.124.) enzyme has been used to: 1) immunoquantify the level of this enzyme in human liver microsomes, and 2) study the distribution of the reductase across the human liver acinus. Employing the Western blot procedure, anti-human reductase IgG recognized a single band in human liver microsomes which corresponded in molecular weight to the purified reductase. The content of the NADPH-cytochrome P-450 reductase in six normal human livers varied from 87 to 121 pmol/mg of microsomal protein. NADPH-cytochrome P-450 reductase activity of the same microsomes ranged from 107 to 222 nmol of cytochrome c reduced per min per mg of protein. The correlation between reductase content and activity (r = 0.54) was not statistically significant (p greater than 0.1). The total cytochrome P-450 content (cytochrome P-450 and P-420) of the same microsomes varied from 423 to 1413 pmol/mg of microsomal protein. The average ratio of cytochrome P-450 to NADPH-cytochrome P-450 reductase was 7.1:1 +/- 3.1 (mean +/- SD) in the human liver microsomal preparations studied. The reductase was found to be nonuniformly distributed across the human liver acinus. Although all hepatocytes stained positively for NADPH-cytochrome P-450 reductase, the staining intensity was highest in zone 3 and in some cases also in zone 1 hepatocytes. These results show that human liver contains a gross excess of cytochrome P-450 molecules to NADPH-cytochrome P-450 reductase molecules. Furthermore, the differential distribution of the reductase within the human liver acinus may lead to a better understanding of the mechanism underlining site-specific drug hepatotoxicity.


Protection of the rat retina from ischemic injury by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor.
The protective effects of three survival-promoting agents on ischemia-induced retinal injury in the rat were investigated. The agents included brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and basic fibroblast growth factor (bFGF). Retinal ischemia was induced in Lewis albino rats by increasing intraocular pressure to 160 mm Hg for 90 minutes. The agents or buffer controls were injected intravitreally at different times, either before or after the ischemic insult, and the postischemic survival time was either 7 or 14 days. The degree of retinal damage was assessed from plastic-embedded sections by cytologic analysis, measurement of the thickness of several layers, and neuronal counts of the ganglion cell layer. Retinal ischemia thinned and reduced cell numbers in the inner retinal layers, but not in the photoreceptor nuclear layer. Each agent transiently ameliorated the degenerative changes when it was injected 2 days before ischemia. At 7 days postischemia, the inner retinal layers were far less damaged, and more ganglion cells were present than in buffer-injected or uninjected eyes. The protective effect was no longer evident at 14 days postischemia, except in the inner nuclear layer of the BDNF-treated eyes. If a second injection of BDNF was made 5 days after the ischemic insult, then the inner retinal layers were more preserved than buffer controls at 14 days postischemia, but the survival of ganglion cells was not enhanced. A single injection of BDNF at either 1 or 3 days postischemia reduced the degree of inner retinal damage and increased the number of surviving ganglion cells over that in buffer-injected controls. (CNTF and bFGF were not studied with postischemic injections.) BDNF, CNTF, and bFGF transiently protect the retina from pressure-induced ischemic injury when given 2 days before ischemia, and a second injection of BDNF given postischemically can prolong the protective effect. Moreover, protection afforded by BDNF can be seen even when applied only 1 or 3 days after the ischemic insult, although the protective effect is greater at 1 day than at 3 days postischemia.


Mitochondrial DNA in beta-cells is a sensitive target for damage by nitric oxide.
Increasing evidence indicates that nitric oxide (NO) may play a role in immune-mediated injury to beta-cells. One site for the action of this agent is the mitochondrion. Although the exact targets for damage within this organelle have yet to be fully elucidated, a potential location for injury is mitochondrial DNA (mtDNA). Therefore, experiments were initiated to evaluate damage to mtDNA caused by NO. Both exogenous NO generation (spermine/NO adduct [sper/NO]) and endogenous production of NO (IL-1beta) were studied. To study the effects of exogenously produced NO, neonatal rat islet cells in monolayers were exposed to varying doses of sper/NO for 30 min. Total cellular DNA was isolated and treated with alkali to produce strand breaks at abasic sites resulting from exposure to NO. Damage to mtDNA was evaluated using a quantitative Southern blot technique. The results showed that sper/NO caused dose-dependent damage to mtDNA. Additionally, mtDNA was found to be more sensitive to injury generated by either source than a similarly sized fragment of nuclear DNA. To evaluate the effects of endogenously produced NO, beta-cell cultures were treated with IL-1beta for 18 h. Other cultures were treated with IL-1beta and an inhibitor of the inducible form of nitric oxide synthase, aminoguanidine. DNA was evaluated as described for the sper/NO studies. IL-1beta caused appreciable damage to mtDNA, and this damage was reduced in mtDNA from cultures treated with IL-1beta and aminoguanidine. These studies show that mtDNA is a sensitive target for NO generated both endogenously and exogenously and that this DNA is more vulnerable to NO-induced damage than nuclear DNA.


System-Level Strategies to Improve Home Dialysis: Policy Levers and Quality Initiatives.
Advocacy and policy change are powerful levers to improve quality of care and better support patients on home dialysis. While the kidney community increasingly recognizes the value of home dialysis as an option for patients who prioritize independence and flexibility, only a minority of patients dialyze at home in the United States. Complex system-level factors have restricted further growth in home dialysis modalities, including limited infrastructure, insufficient staff for patient education and training, patient-specific barriers, and suboptimal physician expertise. In this article, we outline trends in home dialysis use, review our evolving understanding of what constitutes high-quality care for the home dialysis population (as well as how this can be measured), and discuss policy and advocacy efforts that continue to shape the care of US patients and compare them with experiences in other countries. We conclude by discussing future directions for quality and advocacy efforts.


Barriers to and facilitators of interventions to counter publication bias: thematic analysis of scholarly articles and stakeholder interviews.
When the nature and direction of research results affect their chances of publication, a distortion of the evidence base - termed publication bias - results. Despite considerable recent efforts to implement measures to reduce the non-publication of trials, publication bias is still a major problem in medical research. The objective of our study was to identify barriers to and facilitators of interventions to prevent or reduce publication bias. We systematically reviewed the scholarly literature and extracted data from articles. Further, we performed semi-structured interviews with stakeholders. We performed an inductive thematic analysis to identify barriers to and facilitators of interventions to counter publication bias. The systematic review identified 39 articles. Thirty-four of 89 invited interview partners agreed to be interviewed. We clustered interventions into four categories: prospective trial registration, incentives for reporting in peer-reviewed journals or research reports, public availability of individual patient-level data, and peer-review/editorial processes. Barriers we identified included economic and personal interests, lack of financial resources for a global comprehensive trial registry, and different legal systems. Facilitators identified included: raising awareness of the effects of publication bias, providing incentives to make data publically available, and implementing laws to enforce prospective registration and reporting of clinical trial results. Publication bias is a complex problem that reflects the complex system in which it occurs. The cooperation amongst stakeholders to increase public awareness of the problem, better tailoring of incentives to publish, and ultimately legislative regulations have the greatest potential for reducing publication bias.


Factor solutions of the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) in a Swedish population.
Culturally validated rating scales for social anxiety disorder (SAD) are of significant importance when screening for the disorder, as well as for evaluating treatment efficacy. This study examined construct validity and additional psychometric properties of two commonly used scales, the Social Phobia Scale and the Social Interaction Anxiety Scale, in a clinical SAD population (n = 180) and in a normal population (n = 614) in Sweden. Confirmatory factor analyses of previously reported factor solutions were tested but did not reveal acceptable fit. Exploratory factor analyses (EFA) of the joint structure of the scales in the total population yielded a two-factor model (performance anxiety and social interaction anxiety), whereas EFA in the clinical sample revealed a three-factor solution, a social interaction anxiety factor and two performance anxiety factors. The SPS and SIAS showed good to excellent internal consistency, and discriminated well between patients with SAD and a normal population sample. Both scales showed good convergent validity with an established measure of SAD, whereas the discriminant validity of symptoms of social anxiety and depression could not be confirmed. The optimal cut-off score for SPS and SIAS were 18 and 22 points, respectively. It is concluded that the factor structure and the additional psychometric properties of SPS and SIAS support the use of the scales for assessment in a Swedish population.


PLIO: a generic tool for real-time operational predictive optimal control of water networks.
This paper presents a generic tool, named PLIO, that allows to implement the real-time operational control of water networks. Control strategies are generated using predictive optimal control techniques. This tool allows the flow management in a large water supply and distribution system including reservoirs, open-flow channels for water transport, water treatment plants, pressurized water pipe networks, tanks, flow/pressure control elements and a telemetry/telecontrol system. Predictive optimal control is used to generate flow control strategies from the sources to the consumer areas to meet future demands with appropriate pressure levels, optimizing operational goals such as network safety volumes and flow control stability. PLIO allows to build the network model graphically and then to automatically generate the model equations used by the predictive optimal controller. Additionally, PLIO can work off-line (in simulation) and on-line (in real-time mode). The case study of Santiago-Chile is presented to exemplify the control results obtained using PLIO off-line (in simulation).


Incidence of Acute Kidney Injury Among Critically Ill Patients With Brief Empiric Use of Antipseudomonal β-Lactams With Vancomycin.
Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations. The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups. The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09). Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.


On-statin cholesteryl ester transfer protein mass and risk of recurrent coronary events (from the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 [PROVE IT-TIMI 22] study).
Although cholesteryl ester transfer protein (CETP) plays an important role in human lipoprotein metabolism, its relation to coronary artery disease remains controversial. The present study evaluated the relation between on-statin CETP mass and recurrent coronary events. The plasma CETP mass, measured after 4 months of statin therapy, was quantified in 3,218 patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study. Of the 3,218 patients, 150 experienced the combined end point of recurrent myocardial infarction or death from coronary causes during a mean follow-up of 1.8 years. An increasing on-statin CETP mass was inversely related to the risk of coronary events in both unadjusted (hazard ratio [HR] per SD increase 0.77, 95% confidence interval 0.65 to 0.92, p = 0.005) and fully adjusted (HR per SD increase 0.81, 95% confidence interval 0.67 to 0.98, p = 0.027) analyses that included traditional cardiovascular risk factors. A similar trend was observed across increasing CETP mass quartiles (p trend = 0.07). A significant interaction between the CETP mass and on-treatment low-density lipoprotein (LDL) cholesterol was noted (p interaction = 0.007). A CETP mass greater than the median was associated with a decreased risk in patients with LDL cholesterol less than the median of 80 mg/dl (HR 0.52, 95% confidence interval 0.31 to 0.89, p = 0.02), but not in patients with LDL cholesterol greater than the median. In conclusion, an increasing on-statin CETP mass was inversely related to the coronary outcomes in this large clinical trial-based cohort, particularly among those with low LDL cholesterol levels. This finding is consistent with CETP facilitating reverse cholesterol transport in the setting of robust LDL clearance and might have important implications for efforts to optimally target patients with pharmacologic CETP inhibition.


Pharmacognostical and physicochemical evaluation of Agasti leaf.
Sesbania grandiflora (L.) Pers., commonly known as Agasti, is widely used in Ayurveda for the treatment of diseases and for processing of various formulations in Rasashastra. It is used for its astringent, antihistaminic, anxiolytic, anticonvulsive and febrifugal activities. Moreover, because of its edible nature, the leaves and pods are used as flavoring items in the cuisine of South India. A detailed investigation of fresh and powder of leaves of Agasti was carried out. The diagnostic characters of this plant include stomatal characters, presence of resins, oil globules, appressed epidermal hair and mucilage cells. Physicochemical studies revealed loss on drying (0.6%), total ash (10.75%), acid insoluble ash (0.045%), alcohol-soluble extractive (21.7%), and water-soluble extractive (30.72%). Preliminary analysis for the presence of various functional groups revealed the presence of alkaloids, saponins, phenols and proteins. Thin layer chromatographic study of the alcoholic extract showed the presence of five, six and seven spots in short UV, long UV and after spraying developing reagent, respectively. The information generated by this particular study will provide relevant pharmacognostical and physicochemical data needed for proper identification and authentication of leaves of this particular species.


Temperature-Dependent Effects of Cutaneous Bacteria on a Frog's Tolerance of Fungal Infection.
Defense against pathogens is one of many benefits that bacteria provide to animal hosts. A clearer understanding of how changes in the environment affect the interactions between animals and their microbial benefactors is needed in order to predict the impact and dynamics of emerging animal diseases. Due to its dramatic effects on the physiology of animals and their pathogens, temperature may be a key variable modulating the level of protection that beneficial bacteria provide to their animal hosts. Here we investigate how temperature and the makeup of the skin microbial community affect the susceptibility of amphibian hosts to infection by Batrachochytrium dendrobatidis (Bd), one of two fungal pathogens known to cause the disease chytridiomycosis. To do this, we manipulated the skin bacterial communities of susceptible hosts, northern cricket frogs (Acris crepitans), prior to exposing these animals to Bd under two different ecologically relevant temperatures. Our manipulations included one treatment where antibiotics were used to reduce the skin bacterial community, one where the bacterial community was augmented with the antifungal bacterium, Stenotrophomonas maltophilia, and one in which the frog's skin bacterial community was left intact. We predicted that frogs with reduced skin bacterial communities would be more susceptible (i.e., less resistant to and/or tolerant of Bd infection), and frogs with skin bacterial communities augmented with the known antifungal bacterium would be less susceptible to Bd infection and chytridiomycosis. However, we also predicted that this interaction would be temperature dependent. We found a strong effect of temperature but not of skin microbial treatment on the probability and intensity of infection in Bd-exposed frogs. Whether temperature affected survival; however, it differed among our skin microbial treatment groups, with animals having more S. maltophilia on their skin surviving longer at 14 but not at 26°C. Our results suggest that temperature was the predominant factor influencing Bd's ability to colonize the host (i.e., resistance) but that the composition of the cutaneous bacterial community was important in modulating the host's ability to survive (i.e., tolerate) a heavy Bd infection.


Inhibition of tomato shoot growth by over-irrigation is linked to nitrogen deficiency and ethylene.
Although physiological effects of acute flooding have been well studied, chronic effects of suboptimal soil aeration caused by over-irrigation of containerized plants have not, despite its likely commercial significance. By automatically scheduling irrigation according to soil moisture thresholds, effects of over-irrigation on soil properties (oxygen concentration, temperature and moisture), leaf growth, gas exchange, phytohormone [abscisic acid (ABA) and ethylene] relations and nutrient status of tomato (Solanum lycopersicum Mill. cv. Ailsa Craig) were studied. Over-irrigation slowly increased soil moisture and decreased soil oxygen concentration by 4%. Soil temperature was approximately 1°C lower in the over-irrigated substrate. Over-irrigating tomato plants for 2 weeks significantly reduced shoot height (by 25%) and fresh weight and total leaf area (by 60-70%) compared with well-drained plants. Over-irrigation did not alter stomatal conductance, leaf water potential or foliar ABA concentrations, suggesting that growth inhibition was not hydraulically regulated or dependent on stomatal closure or changes in ABA. However, over-irrigation significantly increased foliar ethylene emission. Ethylene seemed to inhibit growth, as the partially ethylene-insensitive genotype Never ripe (Nr) was much less sensitive to over-irrigation than the wild type. Over-irrigation induced significant foliar nitrogen deficiency and daily supplementation of small volumes of 10 mM Ca(NO3 )2 to over-irrigated soil restored foliar nitrogen concentrations, ethylene emission and shoot fresh weight of over-irrigated plants to control levels. Thus reduced nitrogen uptake plays an important role in inhibiting growth of over-irrigated plants, in part by stimulating foliar ethylene emission.


Horseradish peroxidase embedded in polyacrylamide nanoparticles enables optical detection of reactive oxygen species.
We have synthesized and characterized new nanometer-sized polyacrylamide particles containing horseradish peroxidase and fluorescent dyes. Proteins and dyes are encapsulated by radical polymerization in inverse microemulsion. The activity of the encapsulated enzyme has been examined and it maintains its ability to catalyze the oxidation of guaiacol with hydrogen peroxide as the electron acceptor, although at a slightly lower rate compared to that of the free enzyme in solution. The embedded enzyme is also capable of catalyzing the peroxidase-oxidase reaction. However, the rate is decreased by a factor of 2-3 compared to that of the free enzyme. The reduced rate is probably due to limitation of diffusion of substrates and products into and out of the particles. The catalytic activity of horseradish peroxidase in the polyacrylamide matrix demonstrates that the particles have pores which are large enough for substrates to enter and products to leave the polymer matrix containing the enzyme. The polymer matrix protects the embedded enzyme from proteolytic digestion, which is demonstrated by treating the particles with a mixture of the two proteases trypsin and proteinase K. The particles allow for quantification of hydrogen peroxide and other reactive oxygen species in microenvironments, and we propose that the particles may find use as nanosensors for use in, e.g., living cells.


DNA topoisomerase VIII: a novel subfamily of type IIB topoisomerases encoded by free or integrated plasmids in Archaea and Bacteria.
Type II DNA topoisomerases are divided into two families, IIA and IIB. Types IIA and IIB enzymes share homologous B subunits encompassing the ATP-binding site, but have non-homologous A subunits catalyzing DNA cleavage. Type IIA topoisomerases are ubiquitous in Bacteria and Eukarya, whereas members of the IIB family are mostly present in Archaea and plants. Here, we report the detection of genes encoding type IIB enzymes in which the A and B subunits are fused into a single polypeptide. These proteins are encoded in several bacterial genomes, two bacterial plasmids and one archaeal plasmid. They form a monophyletic group that is very divergent from archaeal and eukaryotic type IIB enzymes (DNA topoisomerase VI). We propose to classify them into a new subfamily, denoted DNA topoisomerase VIII. Bacterial genes encoding a topoisomerase VIII are present within integrated mobile elements, most likely derived from conjugative plasmids. Purified topoisomerase VIII encoded by the plasmid pPPM1a from Paenibacillus polymyxa M1 had ATP-dependent relaxation and decatenation activities. In contrast, the enzyme encoded by mobile elements integrated into the genome of Ammonifex degensii exhibited DNA cleavage activity producing a full-length linear plasmid and that from Microscilla marina exhibited ATP-independent relaxation activity. Topoisomerases VIII, the smallest known type IIB enzymes, could be new promising models for structural and mechanistic studies.


Tuning the properties of mucin via layer-by-layer assembly.
Multilayer films consisting of bovine submaxillary mucin (BSM) and poly(allylamine hydrochloride) (PAH) were prepared on various substrates using layer-by-layer assembly. The effects of both the assembly pH and ionic strength on multilayer characteristics were investigated by assessing film thicknesses (10-80 nm), surface wetting characteristics, and cell repulsion. Also, the dynamic assembly behavior was monitored using quartz crystal microbalance with dissipation monitoring (QCM-D) to further understand the effect of assembly pH on film characteristics. Assembly studies revealed that substantial amounts of BSM adhere to the outermost surface only at low pH conditions. The resulting multilayer films assembled at low pH conditions were found to exhibit hydrophilic and cell repellent behavior. In addition, it was found that batch-to-batch variations of the biopolymer BSM could dramatically alter properties.


Fine-scale habitat heterogeneity and vole runways influence seed dispersal in Plagiobothrys nothofulvus.
Seed dispersal allows plants to colonize new sites and contributes to gene flow among populations. Despite its fundamental importance to ecological and evolutionary processes, our understanding of seed dispersal is limited due to the difficulty of directly observing dispersal events. This is particularly true for the majority of plant species that are considered to have gravity as their primary dispersal mechanism. The potential for long-distance movement of gravity-dispersed seeds by secondary dispersal vectors is rarely evaluated. We employ whole-genome assays of maternally inherited cpDNA in Plagiobothrys nothofulvus to resolve patterns of genetic variation due to effective (realized) seed dispersal within a 16 hectare prairie that is characterized by a mosaic of habitat types. We evaluate the effects of microgeographic landscape features extracted from micro-UAV aerial surveys on patterns of seed dispersal using landscape genetics methods. We found evidence of high resistance to seed-mediated gene flow (effective dispersal) within patches of Plagiobothrys nothofulvus, and strong genetic structure over distances of less than 20 m. Geographic distance was a poor predictor of dispersal distance, while landscape features had stronger influences on patterns of dispersal (distance and direction of seed movement). Patterns of dispersal were best predicted by the combined distribution of flower patches, habitat type, and the network of vole runways, with the latter explaining the largest proportion of variation in the model. Our results suggest that primary dispersal occurs mostly within microhabitats and infrequent secondary dispersal may occur over longer distances due to the activity of small mammals and other vertebrates.


Inference of the oxidative stress network in Anopheles stephensi upon Plasmodium infection.
Ookinete invasion of Anopheles midgut is a critical step for malaria transmission; the parasite numbers drop drastically and practically reach a minimum during the parasite's whole life cycle. At this stage, the parasite as well as the vector undergoes immense oxidative stress. Thereafter, the vector undergoes oxidative stress at different time points as the parasite invades its tissues during the parasite development. The present study was undertaken to reconstruct the network of differentially expressed genes involved in oxidative stress in Anopheles stephensi during Plasmodium development and maturation in the midgut. Using high throughput next generation sequencing methods, we generated the transcriptome of the An. stephensi midgut during Plasmodium vinckei petteri oocyst invasion of the midgut epithelium. Further, we utilized large datasets available on public domain on Anopheles during Plasmodium ookinete invasion and Drosophila datasets and arrived upon clusters of genes that may play a role in oxidative stress. Finally, we used support vector machines for the functional prediction of the un-annotated genes of An. stephensi. Integrating the results from all the different data analyses, we identified a total of 516 genes that were involved in oxidative stress in An. stephensi during Plasmodium development. The significantly regulated genes were further extracted from this gene cluster and used to infer an oxidative stress network of An. stephensi. Using system biology approaches, we have been able to ascertain the role of several putative genes in An. stephensi with respect to oxidative stress. Further experimental validations of these genes are underway.


Activation of LFA-1 through a Ca2(+)-dependent epitope stimulates lymphocyte adhesion.
The leukocyte function-associated molecule-1 (LFA-1) plays a key role in cell adhesion processes between cells of the immune system. We investigated the mechanism that may regulate LFA-1-ligand interactions, which result in cell-cell adhesion. To this end we employed an intriguing anti-LFA-1 alpha mAb (NKI-L16), capable of inducing rather than inhibiting cell adhesion. Aggregation induced by NKI-L16 or Fab fragments thereof is not the result of signals transmitted through LFA-1. The antibody was found to recognize a unique Ca2(+)-dependent activation epitope of LFA-1, which is essentially absent on resting lymphocytes, but becomes induced upon in vitro culture. Expression of this epitope correlates well with the capacity of cells to rapidly aggregate upon stimulation by PMA or through the TCR/CD3 complex, indicating that expression of the NKI-L16 epitope is essential for LFA-1 to mediate adhesion. However, expression of the NKI-L16 epitope in itself is not sufficient for cell binding since cloned T lymphocytes express the NKI-L16 epitope constitutively at high levels, but do not aggregate spontaneously. Based on these observations we propose the existence of three distinct forms of LFA-1: (a) an inactive form, which does not, or only partially exposes the NKI-L16 epitope, found on resting cells; (b) an intermediate, NKI-L16+ form, expressed by mature or previously activated cells; and (c) an active (NKI-L16+) form of LFA-1, capable of high affinity ligand binding, obtained after specific triggering of a lymphocyte through the TCR/CD3 complex, by PMA, or by binding of NKI-L16 antibodies.


Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line.
The biochemical mechanisms mediating the rapid distribution of valproic acid across placenta are not precisely known. We have characterized valproic acid transport by the human trophoblast using the human choriocarcinoma cell line, BeWo. The uptake of [14C]valproic acid by BeWo cells was found to be saturable and blocked by pre-exposure to the metabolic inhibitors, sodium azide and 2,4-dinitrophenol. Valproic acid uptake by the BeWo cells was also inhibited by the protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, but not anion exchange inhibitor. Selected monocarboxylic acids inhibited the uptake of [14C]valproic acid by BeWo cells, whereas dicarboxylic acids did not alter the uptake process. Analysis of Lineweaver-Burk plots of valproic acid uptake in the presence of benzoic acid, a marker for the monocarboxylic acid transporter, revealed a competitive process for uptake. In transcellular transport experiments, the permeation of [14C]valproic acid from the apical-to-basal side of the monolayers was significantly greater than the permeation from basal-to-apical side. Additionally, the permeation of [14C]valproic acid from apical-to-basal side was inhibited by monocarboxylic acids and not dicarboxylic acids. The results provide biochemical evidence of a proton-dependent, saturable, and asymmetric transport system, presumed to be a monocarboxylic acid transporter, for valproic acid in a human trophoblast model.


Using views of Systems Biology Cloud: application for model building.
A large and growing network ("cloud") of interlinked terms and records of items of Systems Biology knowledge is available from the web. These items include pathways, reactions, substances, literature references, organisms, and anatomy, all described in different data sets. Here, we discuss how the knowledge from the cloud can be molded into representations (views) useful for data visualization and modeling. We discuss methods to create and use various views relevant for visualization, modeling, and model annotations, while hiding irrelevant details without unacceptable loss or distortion. We show that views are compatible with understanding substances and processes as sets of microscopic compounds and events respectively, which allows the representation of specializations and generalizations as subsets and supersets respectively. We explain how these methods can be implemented based on the bridging ontology Systems Biological Pathway Exchange (SBPAX) in the Systems Biology Linker (SyBiL) we have developed.


Six (or more) drugs in search of a mechanism: DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes.
The clinical activity of the DNA methyltransferase inhibitors 5-azacitidine and 2'-deoxy-5-azacytidine in myelodysplastic syndromes (MDS) suggests that epigenetic modulation of gene transcription may play an important pathogenetic role in the development and expression of these diseases. Approximately 50% of patients treated with these compounds experience hematologic improvement, making these the most active single agents for unselected patients with MDS. Responses include complete and partial hematologic responses. Two randomized trials have shown that the use of these drugs significantly alters the natural history of MDS compared with supportive care. Histone deacetylase inhibitors, which may also impact the expression of genes through epigenetic mechanisms, seem to have measurable activity in MDS in preliminary studies. Histone deacetylase inhibitors are most likely used in combination with other agents, including DNA methyltransferase inhibitors. Despite the clinical activity of these classes of drugs, there is no conclusive evidence that their clinical activity is attributable to their impact on the epigenome. Such information will be critical in the development of more effective congeners and drug combinations in ongoing attempts to improve the outcome of patients with MDS.


Parent and physician beliefs, perceptions and knowledge of plant milks for children.
Background: Parent and physician perceptions of plant milk are unclear. Aim: To explore parent and physician perceptions of plant milk for children and to gain a better understanding of why parents and physicians might choose plant milk for children. Methods: A mixed methods study was conducted using a questionnaire and interviews with parents and physicians participating in the TARGet Kids! cohort study. Questionnaire data were analyzed using descriptive statistics. Interview transcripts were analyzed using thematic analysis. Results: Parents reported a variety of reasons for choosing plant milk for their children including concerns around allergies, the environment, animal welfare, plant-based diet, health benefits, taste and hormones in cow's milk. Parents gave their children various types of plant milks and physicians provided various recommendations to parents of children not consuming cow's milk. Our study identified that 79% of parents and 51% of physicians were unaware that soy milk is the recommended cow's milk substitute for children. Additionally, 26% of parents did not know some plant milks are not fortified and can contain added sugar. Three main themes were identified from interviews about why parents and physicians may choose plant milk for children: (i) healthiness of plant milk; (ii) concerns about hormones; and (iii) environmental impacts. Conclusions: Parents and physicians choose the milk that they believe is healthiest for their child or patient. However, a lack of clarity on the effects of plant milk consumption on children's health resulted in conflicting views on whether plant milk or cow's milk is healthier for children.


Sensitivity of Next-Generation Sequencing Metagenomic Analysis for Detection of RNA and DNA Viruses in Cerebrospinal Fluid: The Confounding Effect of Background Contamination.
Next-generation sequencing (NGS) followed by metagenomic enables the detection and identification of known as well as novel pathogens. It could be potentially useful in the diagnosis of encephalitis, caused by a variety of microorganisms. The aim of the present study was to evaluate the sensitivity of isothermal RNA amplification (Ribo-SPIA) followed by NGS metagenomic analysis in the detection of human immunodeficiency virus (HIV) and herpes simplex virus (HSV) in cerebrospinal fluid (CSF). Moreover, we analyzed the contamination background. We detected 102 HIV copies and 103 HSV copies. The analysis of control samples (two water samples and one CSF sample from an uninfected patient) revealed the presence of human DNA in the CSF sample (91 % of all reads), while the dominating sequences in water were qualified as 'other', related to plants, plant viruses, and synthetic constructs, and constituted 31 % and 60 % of all reads. Bacterial sequences represented 5.9 % and 21.4 % of all reads in water samples and 2.3 % in the control CSF sample. The bacterial sequences corresponded mainly to Psychrobacter, Acinetobacter, and Corynebacterium genera. In conclusion, Ribo-SPIA amplification followed by NGS metagenomic analysis is sensitive for detection of RNA and DNA viruses. Contamination seems common and thus the results should be confirmed by other independent methods such as RT-PCR and PCR. Despite these reservations, NGS seems to be a promising method for the diagnosis of viral infections.


Repair of DNA Dewar photoproduct to (6-4) photoproduct in (6-4) photolyase.
Dewar photoproduct (Dewar PP) is the valence isomer of (6-4) photoproduct ((6-4)PP) in photodamaged DNA. Compared to the extensive studied CPD photoproducts, the underlying repair mechanisms for the (6-4)PP, and especially for the Dewar PP, are not well-established to date. In this paper, the repair mechanism of DNA Dewar photoproduct T(dew)C in (6-4) photolyase was elucidated using hybrid density functional theory. Our results showed that, during the repair process, the T(dew)C has to isomerize to T(6-4)C photolesion first via direct C6'-N3' bond cleavage facilitated by electron injection. This isomerization mechanism is energetically much more efficient than other possible rearrangement pathways. The calculations provide a theoretical interpretation to recent experimental observations.


Polyribosomes and cisternal accumulations in root cells of radish.
The zone of root hair formation of seedling radish roots, Raphanus sativus L., was studied by phase-contrast and electron microscopy. Localized dilations of the endoplasmic reticulum, which contained a moderately dense proteinaceous material, were found to be a common component of the cytoplasm in cells of the epidermis and cortex. The surfaces of these dilations were covered with polyribosomes in discrete coils commonly composed of 15 to 17 ribosomes. The function of these structures and the fate of the material accumulated in them are unknown. Their similarity to structures described in some types of animal cells is discussed.


Assessment of articular cartilage and subchondral bone using EPIC-microCT in Labrador retrievers with incipient medial coronoid disease.
The aetiopathogenesis of medial coronoid disease (MCD) remains obscure, despite its high prevalence. The role of changes to subchondral bone or articular cartilage is much debated. Although there is evidence of micro-damage to subchondral bone, it is not known whether this is a cause or a consequence of MCD, nor is it known whether articular cartilage is modified in the early stages of the disease. The aim of the present study was to use equilibrium partitioning of an ionic contrast agent with micro-computed tomography (microCT) to investigate changes to both the articular cartilage and the subchondral bone of the medial coronoid processes (MCP) of growing Labrador retrievers at an early stage of the disease and at different bodyweights. Of 14 purpose-bred Labrador retrievers (15-27 weeks), six were diagnosed with bilateral MCD and one was diagnosed with unilateral MCD on the basis of microCT studies. The mean X-ray attenuation of articular cartilage was significantly higher in dogs with MCD than in dogs without MCD (P<0.01). In all dogs, the mean X-ray attenuation of articular cartilage was significantly higher at the lateral (P<0.001) than at the proximal aspect of the MCP, indicating decreased glycosaminoglycan content. Changes in parameters of subchondral bone micro-architecture, namely the ratio of bone volume to tissue volume (BV/TV), bone surface density (BS/TV), bone surface to volume ratio (BS/BV), trabecular thickness (Tb.Th; mm), size of marrow cavities described by trabecular spacing (Tb.Sp; mm), and structural model index (SMI), differed significantly by litter (P<0.05) due to the difference in age and weight, but not by the presence/absence of MCD (P>0.05), indicating that subchondral bone density is not affected in early MCD. This study demonstrated that cartilage matrix and not subchondral bone density is affected in the early stages of MCD.


The clinical significance and optimal timing of postoperative computed tomography following cranial surgery.
This study was conducted to evaluate the value of postoperative CT scans in determining the probability of return to the operating room (OR) and the optimal time to obtain such scans to determine the effects of surgery. Between January and December 2006 (12 months), all postoperative head CT scans obtained for 3 individual surgeons were reviewed. Scans were divided into 3 groups, which were determined by the preference of each surgeon: Group A (early scans-scheduled between 0 and 7 hours); Group B (delayed scans-scheduled between 8 and 24 hours); and Group C (urgent scans-ordered because of a new neurological deficit). The initial scans were reviewed and analyzed in 2 different fashions. The first was to analyze the efficacy of the scans in predicting return to the OR. The second was to determine the optimal time for obtaining a scan. The second analysis was a review of serial postoperative scans for expected versus unexpected findings and changes in the acuity of these findings over time. In 251 (74%) of 338 cases, the patients had postoperative head CT scans within 24 hours of surgery. Analysis 1 determined the percent of patients returning to the OR for emergency treatment based on postoperative scans: Group A (early)-133 patients, with 0% returning to the OR; Group B (delayed)-108 patients, with 0% returning to the OR; and Group C (urgent)-10 patients, with 30% returning to the OR (p < 0.05). Analysis 2 determined the optimal timing of postoperative scans and changes in scan acuity: Group A (early scan) had an 11% incidence of change in acuity on subsequent scans. Group B (delayed scan) had a 3% incidence of change in acuity on follow-up scans (p < 0.05). Routine postoperative scans at 0-7 hours or at 8-24 hours are not predictive of return to the OR, whereas patients with a new neurological deficit in the postoperative period have a 30% chance of emergency reoperation based on CT scans. In addition, early postoperative scans (0-7 hours) fail to predict CT changes, which might evolve over time and may influence postoperative medical management.


Therapy and ideology: psychoanalysis and its vicissitudes in pre-state Israel (including some hitherto unpublished letters by Sigmund Freud and Albert Einstein).
Few chapters in the historiography of psychoanalysis are as densely packed with trans-cultural, ideological, institutional, and moral issues as the coming of psychoanalysis to Jewish Palestine--a geopolitical space which bears some of the deepest scars of twentieth-century European, and in particular German, history. From the historical as well as the critical perspective, this article reconstructs the intricate connections between migration, separation and loss, continuity and new beginning which resonate in the formative years of psychoanalysis in pre-state Israel.


Parenting and physical punishment: primary care interventions in Latin America.
Physical punishment is a form of intrafamilial violence associated with short- and long-term adverse mental health outcomes. Despite these possible consequences, it is among the most common forms of violent interpersonal behavior. For many children it begins within the first year of life. The goal of this study was to determine the feasibility of involving public sector primary health care providers to inform parents about alternatives to physical punishment. The study used a qualitative design utilizing focus groups and survey questionnaires with parents and providers at six clinic sites chosen to be representative of public sector practice settings in Costa Rica and in metropolitan Santiago, Chile. The data were collected during 1998 and 1999. In the focus groups and surveys the parents voiced a range of opinions about physical punishment. Most acknowledged its common use but listed it among their least preferred means of discipline. Frequency of its use correlated positively with the parents' belief in its effectiveness and inversely with their satisfaction with their children's behavior. Some parents wanted to learn more about discipline; others wanted help with life stresses they felt led them to use physical punishment. Parents reported they chose other family members more frequently as a source of parenting information than they did health care providers. Some parents saw providers as too rushed and not knowledgeable enough to give good advice. Providers, in turn, felt ill equipped to handle parents' questions, but many of the health professionals expressed interest in more training. Parents and providers agreed that problems of time, space, and resources were barriers to talking about child discipline in the clinics. Many parents and providers would welcome a primary-care-based program on physical punishment. Such a program would need to be customized to accommodate local differences in parent and provider attitudes and in clinic organization. Health care professionals need more training in child discipline and in the skills required to interact with parents on issues relating to child behavior.


The use of intraoral radiographs for identification of edentulous patients rehabilitated with implants.
The aims of this study were; i) to determine the accuracy by which two intra-oral radiographic examinations performed on patients with edentulous mandibles treated with dental implants can be matched. ii) to determine whether prosthodontic supra-construction is important for matching. iii) to investigate whether there is a difference between oral and maxilla-facial radiologists (OMR) and dental practitioners, not specialized in oral and maxillofacial radiology (NOMR), regarding their ability to match. The specific features of the radiographs used by the operators to acquire a match were also investigated. Intra-oral radiographic examinations from 59 patients were utilized. Radiographic examinations from 47 patients carried out at placement of the supra-construction and at subsequent follow-up examinations were used as "ante-mortem" and "post-mortem" records respectively. Examinations from 12 patients were added to the "post-mortem" records without "ante-mortem" records being available. The study was divided into two parts. In Part One all "ante"- and "post-mortem" records had the supra-construction masked and in Part Two it was visible. Seven dentists (4 OMR, 3 NOMR) were instructed to specify on what basis each matching was made on the confidence of a three-graded scale OMR had 93.2 % and 98.5 % accuracy in Parts One and Two respectively. NOMR had 63.8 % and 87.9 %. Bone anatomy was the most commonly used feature by OMR to obtain a match. For NOMR it was the appearance of the fixtures. OMR reported higher confidence in their ability to match the examinations. This study indicates that OMR could be a valuable resource in cases of identification where dental implants are a feature of the post-mortem dental records.


Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease.
The discovery that platelets express CD40 and the CD40 ligand has transformed these cells, once seen as exclusively involved in coagulation and thrombosis, into active players of immunity and inflammatory injury. Many of the broad and potent biological activities mediated through the CD40/CD40 pathway by immune and nonimmune cells are also exerted by activated platelets. This occurs either through the constitutive expression of CD40 on the platelet surface or the activation-induced expression of the CD40 ligand, which is membrane bound and released from the surface in a soluble form. The most prominent activities mediated by the platelet CD40/CD40 ligand pathway include inflammatory, immunoregulatory, and hemostatic functions, all of which contribute to the newly expanded view of platelets as key biological mediators involved in disease processes such as atherosclerosis, inflammatory bowel disease, and diabetes. Therefore, considering platelet CD40 and CD40 ligand as novel biological targets is justified and supported by animal studies. The clinical profit to be gained from blocking this molecular pair will be determined by results in humans with conditions in which the platelet CD40/CD40 ligand pathway is crucially involved in disease pathogenesis.


Effects of Immediate or Delayed Estradiol on Behavior in Old Menopausal Macaques on Obesogenic Diet.
Macaques have served as effective models of human disease, including pathological processes associated with obesity and the metabolic syndrome. This study approached several questions: (1) does a western-style diet (WSD) contribute to sedentary behavior or is sedentary behavior a consequence of obesity and (2) does estradiol (E) hormone therapy offset WSD or ameliorate sedentary behavior? We further questioned whether the timing of E administration (immediately following hysterectomy, ImE; or after a 2-year delay, DE) would impact behavior. Focal observations were taken on the animals in social housing over a period of 2.5 years before and after initiation of the WSD and hysterectomy. In addition, anxiety was assessed through the Human Intruder and Novel Object Tests. All animals gained weight, but ImE delayed the time to maximum weight achieved at 18 months. Over the course of the study, ImE-treated monkeys spent more time "alone" and less time in "close social" contact than placebo-controls. The DE-treated monkeys were not different from placebo-controls in these 2 outcomes. The placebo-control group exhibited more "self-groom" behavior, an indicator of anxiety, than did the ImE-treated group, and DE-treated animals approached levels observed in the ImE-treated animals. All animals exhibited an increase in "consume" behavior over time with no statistical difference between the groups. By the end of the protocol, the placebo-control group exhibited less activity compared to ImE + DE-treated animals combined. Animals also showed increased anxiety after starting on the WSD in the Human Intruder Test and the Novel Object Test. In summary, the data indicated that WSD per se promoted increased consummatory behavior, sedentary behavior, and anxiety-type behaviors, whereas ImE promoted activity. Thus, WSD may precipitate the behaviors observed in humans who then become obese, sedentary, anxious, and socially isolated. ImE replacement ameliorates some of these behaviors, but not all.


Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke.
One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke.


Dendrons with spermine surface groups as potential building blocks for nonviral vectors in gene therapy.
This paper investigates a series of dendrons based on the Newkome dendritic scaffold that displays a naturally occurring polyamine (spermine) on their surface. These dendrons have previously been shown to interact with DNA in a generation dependent manner with the more highly branched dendrons exhibiting a strong multivalency effect for the spermine surface groups. In this paper, we investigate the ability of these dendrons to transfect DNA into cells (human breast carcinoma cells, MDA-MB-231, and murine myoblast cells, C2C12) as determined by the luciferase assay. Although the dendrons are unable to transfect DNA in their own right, they are capable of delivering DNA in vitro when administered with chloroquine, which assists with escape from endocytic vesicles. The cytotoxicity of the dendrons was determined using the XTT assay, and it was shown that the dendrons were nontoxic either alone or in the presence of DNA. However, when administered with DNA and chloroquine, the most highly branched dendron did exhibit some cytotoxicity. This paper elucidates the relationship between in vitro transfection efficiency and toxicity. While transfection efficiencies are modest, the low toxicity of the dendrons, both in their own right, and in the presence of DNA, provides encouragement that this type of building block, which has a relatively high affinity for DNA, will provide a useful starting point for the further synthetic development of more effective gene transfection agents.


Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes.
Sarcoidosis is a systemic inflammatory disease mainly affecting the lungs. The hallmark of sarcoidosis are granulomas that are surrounded by activated T cells, likely targeting the disease-inducing antigen. IFNγ-producing Th1 and Th17.1 T cells are elevated in sarcoidosis and associate with disease progression. Monocytes and dendritic cells (DCs) are antigen-presenting cells (APCs) and required for T cell activation. Several subsets of monocytes and DCs with different functions were identified in sarcoidosis. However, to what extent different monocyte and DC subsets can support activation and skewing of T cells in sarcoidosis is still unclear. In this study, we performed a transcriptional and functional side-by-side comparison of sorted monocytes and DCs from matched blood and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients. Transcriptomic analysis of all subsets showed upregulation of genes related to T cell activation and antigen presentation in DCs compared with monocytes. Allogeneic T cell proliferation was higher after coculture with monocytes and DCs from blood compared with BAL and DCs induced more T cell proliferation compared with monocytes. After coculture, proliferating T cells showed high expression of the transcription factor Tbet and IFNγ production. We also identified Tbet and RORγt coexpressing T cells that mainly produced IFNγ. Our data show that DCs rather than monocytes from sarcoidosis patients have the ability to activate and polarize T cells towards Th1 and Th17.1 cells. This study provides a useful in vitro tool to better understand the contribution of monocytes and DCs to T cell activation and immunopathology in sarcoidosis.


Trends in incidence, treatment and survival of small bowel adenocarcinomas between 1999 and 2013: a population-based study in The Netherlands.
We conducted a population-based study to establish the incidence, treatment and overall survival over time of patients with small bowel adenocarcinoma. All patients diagnosed with small bowel adenocarcinoma in the Netherlands between 1999 and 2013 were included (n = 1775). Age-standardized incidence rates were calculated per 100 000 person-years using the European standardized population rate. The influence of patient and tumor characteristics on the administration of chemotherapy was analyzed by means of a multivariable logistic regression analysis. The Cochran-Armitage trend test was conducted to evaluate trends in treatment and survival and the Cox proportional hazards model was used to identify prognostic factors of overall survival. The incidence of small bowel adenocarcinomas increased, mainly due to an almost twofold increase of duodenal adenocarcinomas. Patients with locoregional duodenal tumors were less likely to undergo surgery (58%), towards 95% of the locoregional jejunal and ileal tumors (p < 0.0001). The use of chemotherapy doubled for adjuvant (7-15%) and palliative chemotherapy (19-37%). Median overall survival of patients with locoregional disease increased from 19 to 34 months (p = 0.0006), whereas median overall survival of patients with metastatic disease remained 4-5 months. Favorable prognostic factors for prolonged survival in locoregional disease, identified by multivariable survival analysis, included age <60 years, tumor stage I or II, diagnosis in 2009-2013, surgical treatment and chemotherapy. Favorable prognostic factors for prolonged survival in metastatic disease were age <50 years, jejunal tumors, surgical treatment and chemotherapy. Small bowel adenocarcinomas are rare tumors with an increasing incidence. The administration of adjuvant and palliative chemotherapy doubled, but median overall survival only increased for patients with locoregional disease. Given the rarity and dismal prognosis, it is important to develop international studies to determine the optimal treatment for these patients.


Use of cognitive aids in a simulated anesthetic crisis.
We evaluated empirically the extent to which the use of a cognitive aid during a high-fidelity simulation of a malignant hyperthermia (MH) event facilitated the correct and prompt treatment of MH. We reviewed the management of 48 simulated adult MH scenarios; 24 involving CA 1 and 24 involving CA 2 residents. In the CA 1 group, 19 of the 24 teams (79%) used a cognitive aid, but only 8 of the 19 teams used it frequently or extensively. In the CA 2 group, 18 of the 23 teams (78%) used a cognitive aid but only 6 of them used it frequently or extensively. The frequency of cognitive aid use correlated significantly with the MH treatment score for the CA 1 group (Spearman r = 0.59, P < 0.01) and CA 2 group (Spearman r = 0.68, P < 0.001). The teams that performed the best in treating MH used a cognitive aid extensively throughout the simulation. Although the effect was less pronounced in the more experienced CA 2 cohort, there was still a strong correlation between performance and cognitive aid use. We were able to show a strong correlation between the use of a cognitive aid and the correct treatment of MH.


Concerted action of the MutLβ heterodimer and Mer3 helicase regulates the global extent of meiotic gene conversion.
Gene conversions resulting from meiotic recombination are critical in shaping genome diversification and evolution. How the extent of gene conversions is regulated is unknown. Here we show that the budding yeast mismatch repair related MutLβ complex, Mlh1-Mlh2, specifically interacts with the conserved meiotic Mer3 helicase, which recruits it to recombination hotspots, independently of mismatch recognition. This recruitment is essential to limit gene conversion tract lengths genome-wide, without affecting crossover formation. Contrary to expectations, Mer3 helicase activity, proposed to extend the displacement loop (D-loop) recombination intermediate, does not influence the length of gene conversion events, revealing non-catalytical roles of Mer3. In addition, both purified Mer3 and MutLβ preferentially recognize D-loops, providing a mechanism for limiting gene conversion in vivo. These findings show that MutLβ is an integral part of a new regulatory step of meiotic recombination, which has implications to prevent rapid allele fixation and hotspot erosion in populations.


Structural basis of tubulin recruitment and assembly by microtubule polymerases with tumor overexpressed gene (TOG) domain arrays.
XMAP215/Stu2/Alp14 proteins accelerate microtubule plus-end polymerization by recruiting tubulins via arrays of tumor overexpressed gene (TOG) domains, yet their mechanism remains unknown. Here, we describe the biochemical and structural basis for TOG arrays in recruiting and polymerizing tubulins. Alp14 binds four tubulins via dimeric TOG1-TOG2 subunits, in which each domain exhibits a distinct exchange rate for tubulin. X-ray structures revealed square-shaped assemblies composed of pseudo-dimeric TOG1-TOG2 subunits assembled head-to-tail, positioning four unpolymerized tubulins in a polarized wheel-like configuration. Crosslinking and electron microscopy show Alp14-tubulin forms square assemblies in solution, and inactivating their interfaces destabilize this organization without influencing tubulin binding. An X-ray structure determined using approach to modulate tubulin polymerization revealed an unfurled assembly, in which TOG1-TOG2 uniquely bind to two polymerized tubulins. Our findings suggest a new microtubule polymerase model in which TOG arrays recruit tubulins by forming square assemblies that then unfurl, facilitating their concerted polymerization into protofilaments.


Current Trends on Seaweeds: Looking at Chemical Composition, Phytopharmacology, and Cosmetic Applications.
Seaweeds have received huge interest in recent years given their promising potentialities. Their antioxidant, anti-inflammatory, antitumor, hypolipemic, and anticoagulant effects are among the most renowned and studied bioactivities so far, and these effects have been increasingly associated with their content and richness in both primary and secondary metabolites. Although primary metabolites have a pivotal importance such as their content in polysaccharides (fucoidans, agars, carragenans, ulvans, alginates, and laminarin), recent data have shown that the content in some secondary metabolites largely determines the effective bioactive potential of seaweeds. Among these secondary metabolites, phenolic compounds feature prominently. The present review provides the most remarkable insights into seaweed research, specifically addressing its chemical composition, phytopharmacology, and cosmetic applications.


The relationship between faecal-associated and mucosal-associated microbiota in irritable bowel syndrome patients and healthy subjects.
The faecal-associated microbiota is commonly seen as a surrogate of the mucosal-associated microbiota. However, previous studies indicate that they are different. Furthermore, analyses of the mucosal microbiota are commonly done after standard bowel cleansing, affecting the microbial composition. To compare the mucosal-associated microbiota, obtained from unprepared colon, with faecal-associated microbiota in healthy subjects and irritable bowel syndrome (IBS) patients. Faecal and mucosal biopsies were obtained from 33 IBS patients and 16 healthy controls. Of IBS patients, 49% belonged to the diarrhoea-predominant subgroup and 80% suffered from IBS symptoms during at least 5 years. Biopsies were collected from unprepared sigmoid colon and faecal samples a day before colonoscopy. Microbiota analyses were performed with a phylogenetic microarray and redundancy discriminant analysis. The composition of the mucosal- and the faecal-associated microbiota in unprepared sigmoid colon differs significantly (P = 0.002). Clinical characteristics of IBS did not correlate with this difference. Bacteroidetes dominate the mucosal-associated microbiota. Firmicutes, Actinobacteria and Proteobacteria dominate the faecal-associated microbiota. Healthy subjects had a significantly higher (P < 0.005) abundance (1.9%) of the bacterial group uncultured Clostridiales I in the mucosal-associated microbiota than IBS patients (0.3%). Bacterial diversity was higher in faecal- compared with mucosal-associated microbiota in IBS patients (P < 0.005). No differences were found in healthy subjects. Differences in the mucosal-associated microbiota between healthy individuals and IBS patients are minimal (one bacterial group) compared to differences in the faecal microbiota of both groups (53 bacterial groups). Microbial aberrations characterising IBS are more pronounced in the faeces than in the mucosa.


The effect of strut allograft and its position on Vancouver type B1 periprosthetic femoral fractures: a biomechanical study.
The aim of this study is to assess the biomechanical advantage of adding strut allograft and the effect of its position on the construct in Vancouver type B1 fractures. Fifteen forth-generation synthetic femurs were used and created a fracture model at the tip of prosthesis, and subsequently fixated with a lateral plate only, lateral plate and medial strut, lateral plate and anterior strut. Rotational and axial tests were performed. In all loading tests, the plate with medial strut group was stiffer than the other constructs and had higher failure load values and had less displacement in the fracture site. A combination of a plate with a medial strut allograft provides more mechanical stability on periprosthetic femoral fractures near the tip of a total hip arthroplasty.


The Polls-Trends: Welfare Regimes and Support for Income Redistribution in Europe.
Income redistribution and changes in redistributive policies are highly contested issues that often have a bearing on societal debate and electoral competition. Using European Social Survey data, we trace trends in public attitudes toward income redistribution in 18 European countries from 2002 to 2019, a time period which included the Great Recession, the 2015 migrant crisis, and an increase in income inequality. Although attitudes toward income redistribution were relatively stable, trends presented by countries grouped by welfare regime display considerable variation both among countries and among welfare regimes. We also trace trends in public support for redistribution by income groups and gauge the strength of belief in meritocracy and egalitarianism. The level of redistribution support among middle-income residents is similar to redistribution support of low-income residents, most notably in post-communist and social-democratic regimes. While egalitarianism is most widespread in the Mediterranean regime, meritocracy is most common in liberal and conservative regimes.


SOCIETY FOR ENDOCRINOLOGY CLINICAL GUIDANCE: Inpatient management of cranial diabetes insipidus.
Cranial diabetes insipidus (CDI) is a treatable chronic condition that can potentially develop into a life-threatening medical emergency. CDI is due to the relative or absolute lack of the posterior pituitary hormone vasopressin (AVP), also known as anti-diuretic hormone. AVP deficiency results in uncontrolled diuresis. Complete deficiency can lead to polyuria exceeding 10 L/24 h. Given a functioning thirst mechanism and free access to water, patients with CDI can normally maintain adequate fluid balance through increased drinking. Desmopressin (DDAVP, a synthetic AVP analogue) reduces uncontrolled water excretion in CDI and is commonly used in treatment. Critically, loss of thirst perception (through primary pathology or reduced consciousness) or limited access to water (through non-availability, disability or inter-current illness) in a patient with CDI can lead to life-threatening dehydration. This position can be further exacerbated through the omission of DDAVP. Recent data have highlighted serious adverse events (including deaths) in patients with CDI. These adverse outcomes and deaths have occurred through a combination of lack of knowledge and treatment failures by health professionals. Here, with our guideline, we recommend treatment pathways for patients with known CDI admitted to hospital. Following these guidelines is essential for the safe management of patients with CDI.


Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide.
Generation of reactive oxygen species (ROS) causes cellular oxidative damage and has been implicated in the etiology of Alzheimer's disease (AD). In contrast, multiple lines of evidence indicate that ROS can normally modulate long-term potentiation (LTP), a cellular model for memory formation. We recently showed that decreasing the level of superoxide through the overexpression of mitochondrial superoxide dismutase (SOD-2) prevents memory deficits in the Tg2576 mouse model of AD. In the current study, we explored whether AD-related LTP impairments could be prevented when ROS generation from mitochondria was diminished either pharmacologically or via genetic manipulation. In wild-type hippocampal slices treated with exogenous amyloid β peptide (Aβ1-42) and in slices from APP/PS1 mutant mice that model AD, LTP was impaired. The LTP impairments were prevented by MitoQ, a mitochondria-targeted antioxidant, and EUK134, an SOD and catalase mimetic. In contrast, inhibition of NADPH oxidase either by diphenyliodonium (DPI) or by genetically deleting gp91(phox), the key enzymatic component of NADPH oxidase, had no effect on Aβ-induced LTP blockade. Moreover, live staining with MitoSOX Red, a mitochondrial superoxide indicator, combined with confocal microscopy, revealed that Aβ-induced superoxide production could be blunted by MitoQ, but not DPI, in agreement with our electrophysiological findings. Finally, in transgenic mice overexpressing SOD-2, Aβ-induced LTP impairments and superoxide generation were prevented. Our data suggest a causal relationship between mitochondrial ROS imbalance and Aβ-induced impairments in hippocampal synaptic plasticity.