Effect of Social Support on Psychological Distress and Disease Activity in Inflammatory Bowel Disease Patients.
Psychological distress increases morbidity in ulcerative colitis (UC) and Crohn's disease (CD). We examined whether social support is associated with distress and disease activity. There were 110 UC and 147 CD patients who completed sociodemography, economic status, disease activity (UC: Patient Simple Clinical Colitis Activity Index (P-SCCAI), CD: Patient Harvey-Bradshaw Index . (P-HBI), Multidimensional Scale of Perceived Social Support (MSPSS), Brief Symptom Inventory with Global Severity Index (GSI) of psychological distress, and 2 health-related quality-of-life scales (SF-36 Physical Health and Mental Health, and Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Analysis included multiple linear regressions and structural equation modeling. Disease activity was mild: UC: P-SCCAI 2.9 ± 3.5, CD: P-HBI 4.7 ± 4.7. Physical Health was better in UC 46.6 ± 11.4 versus CD 43.7 ± 10.9 (P < .02). GSI was lower in UC 0.6 ± 0.7 than CD 0.8 ± 0.7 (P = .002). MSPSS total score was equal in UC (5.9 ± 1.2) and CD (5.9 ± 1.1). MSPSS total correlated with P-SCCAI (correlation coefficient ‒0.240), GSI in UC (‒0.470), and GSI in CD (‒0.333). Economic status correlated with GSI in UC (‒0.408) and CD (‒0.356). MSPSS predicted GSI, Mental Health, and SIBDQ in UC and CD, and predicted P-SCCAI but not P-HBI; economic status predicted all the foregoing. Path analysis depicted GSI as mediating the effects of MSPSS and economic status on disease activity in both UC and CD. MSPSS (UC: β ‒0.34, CD: β ‒0.37) and economic status (UC: β ‒0.38, CD: β ‒0.22) reduced GSI, which then increased the disease activity (UC: β 0.56, CD: β 0.42). Social support and economic status are linked to UC and CD patients' well-being. Interventions addressing these issues should be part of management.


Coronary artery plaques and myocardial ischaemia.
To prospectively examine coronary artery plaques as predictors of myocardial ischaemia using cardiac magnetic resonance (CMR). Fifty-two patients (46 men; age 64 ± 10) with suspected coronary artery disease (CAD) referred for catheter coronary angiography (CA) underwent CMR and computed tomography coronary angiography (CTCA). All coronary segments were evaluated for morphological stenosis based on CA. Any plaque according to its composition was assessed based on CTCA. Numbers of total and calcified coronary artery plaques represented the best predictors of myocardial ischaemia (AUC = 0.87; [95%CI: 0.77-0.97] and AUC = 0.87; [95%CI: 0.77-0.96], respectively, p = 0.56) with the total plaque number significantly higher in patients with corresponding ischaemia than those without (p < 0.01, p < 0.05 adjusted for pre-test probability and stenosis). Compared with the AUC of coronary stenosis assessment by CA (AUC = 0.90; [95%CI: 0.80-1.00]), AUCs were equivalent using either the total number or the number of calcified plaques alone (p = 0.73 and p = 0.69). Multivariate logistic regression analyses demonstrated the total plaque number as an independent predictor of ischaemia (odds +20%; [95%CI: 1.096-1.368]), improving a model including clinical probability estimates of CAD (c-statistics, 0.66 to 0.89). Coronary artery plaque number according to CTCA is a significant, independent predictor of myocardial ischaemia with similar accuracy to stenosis assessment.


An examination of antibacterial and antifungal properties of constituents of Shiitake (Lentinula edodes) and oyster (Pleurotus ostreatus) mushrooms.
Antibiotic agents have been in widespread and largely effective therapeutic use since their discovery in the 20th century. However, the emergence of multi-drug resistant pathogens now presents an increasing global challenge to both human and veterinary medicine. It is now widely acknowledged that there is a need to develop novel antimicrobial agents to minimize the threat of further antimicrobial resistance. With this in mind, a study was undertaken to examine the antimicrobial properties of aqueous extracts of 'exotic' Shiitake and Oyster mushrooms on a range of environmental and clinically important microorganisms. Several batches of Shiitake and oyster mushrooms were purchased fresh from a local supermarket and underwent aqueous extraction of potential antimicrobial components. After reconstitution, aqueous extracts were tested qualitatively against a panel of 29 bacterial and 10 fungal pathogens, for the demonstration of microbial inhibition. Our data quantitatively showed that Shiitake mushroom extract had extensive antimicrobial activity against 85% of the organisms it was tested on, including 50% of the yeast and mould species in the trial. This compared favourably with the results from both the Positive control (Ciprofloxacin) and Oyster mushroom, in terms of the number of species inhibited by the activity of the metabolite(s) inherent to the Shiitake mushroom. This small scale study shows the potential antimicrobial effects of Shitake extracts, however further work to isolate and identify the active compound(s) now requires to be undertaken. Once these have been identified, suitable pharmaceutical delivery systems should be explored to allow concentrated extracts to be prepared and delivered optimally, rather than crude ingestion of raw material, which could promote further bacterial resistance.


Retinol-binding protein and retinol analysis in cerebrospinal fluid and serum of patients with and without idiopathic intracranial hypertension.
Several studies have implicated vitamin A-related compounds in the pathogenesis of idiopathic intracranial hypertension (IIH). The goal of this study was to compare cerebrospinal fluid (CSF) and serum concentrations of retinol and retinol-binding protein (RBP) in subjects with and without IIH. CSF and serum samples were collected from 87 subjects. The study population was composed of subjects with IIH (IIH group, n = 28), subjects with non-IIH neurologic conditions (neurology controls, n = 42), and subjects undergoing preoperative lumbar puncture but with no known neurologic conditions (anesthesia controls, n = 17). RBP levels (nM) were determined using radial immunodiffusion, and retinol levels (nM) were determined using high-performance liquid chromatography. The retinol/RBP ratio was greater in CSF than in serum, especially in subjects with IIH. The finding of increased levels of unbound retinol in the CSF of subjects with IIH provides further evidence that vitamin A may be involved in the pathogenesis of IIH. Comparative statistical analyses revealed multivariate relationships that demonstrate the need to further investigate correlations between vitamin A and RBP levels in CSF and serum.


Serum protein profiles as potential biomarkers for infectious disease status in pigs.
In veterinary medicine and animal husbandry, there is a need for tools allowing the early warning of diseases. Preferably, tests should be available that warn farmers and veterinarians during the incubation periods of disease and before the onset of clinical signs. The objective of this study was to explore the potential of serum protein profiles as an early biomarker for infectious disease status. Serum samples were obtained from an experimental pig model for porcine circovirus-associated disease (PCVAD), consisting of Porcine Circovirus type 2 (PCV2) infection in combination with either Porcine Parvovirus (PPV) or Porcine Reproductive and Respiratory Syndrome virus (PRRSV). Sera were collected before and after onset of clinical signs at day 0, 5 and 19 post infection. Serum protein profiles were evaluated against sera from non-infected control animals. Protein profiles were generated by SELDI-TOF mass spectrometry in combination with the Proteominer™ technology to enrich for low-abundance proteins. Based on these protein profiles, the experimentally infected pigs could be classified according to their infectious disease status. Before the onset of clinical signs 88% of the infected animals could be classified correctly, after the onset of clinical sigs 93%. The sensitivity of the classification appeared to be high. The protein profiles could distinguish between separate infection models, although specificity was moderate to low. Classification of PCV2/PRRSV infected animals was superior compared to PCV2/PPV infected animals. Limiting the number of proteins in the profiles (ranging from 568 to 10) had only minor effects on the classification performance. This study shows that serum protein profiles have potential for detection and identification of viral infections in pigs before clinical signs of the disease become visible.


Covalent inhibition of protein tyrosine phosphatases.
Protein tyrosine phosphatases (PTPs) are a large family of 107 signaling enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in a target protein. The phosphorylation status of tyrosine residues on proteins serve as a ubiquitous mechanism for cellular signal transduction. Aberrant function of PTPs can lead to many human diseases, such as diabetes, obesity, cancer, and autoimmune diseases. As the number of disease relevant PTPs increases, there is urgency in developing highly potent inhibitors that are selective towards specific PTPs. Most current efforts have been devoted to the development of active site-directed and reversible inhibitors for PTPs. This review summarizes recent progress made in the field of covalent inhibitors to target PTPs. Here, we discuss the in vivo and in vitro inactivation of various PTPs by small molecule-containing electrophiles, such as Michael acceptors, α-halo ketones, epoxides, and isothiocyanates, etc. as well as oxidizing agents. We also suggest potential strategies to transform these electrophiles into isozyme selective covalent PTP inhibitors.


Transforming general practice: the redistribution of medical work in primary care.
The paper focuses on the redistribution of medical work within primary health care teams. It reports the results of the analysis of interviews with general practitioners, practice nurses and managers, undertaken as part of an ethnographic study of primary care organisation and practice during a period of rapid organisational change. By examining the ways in which the respondents account for how work is being redefined and redistributed, we explore how current government policy and professional discourses combine to reconfigure both the identities of those who work in primary care and the nature of patienthood. In particular, we show how general practitioners are being reconfigured as medical specialists or consultants in ways that seem to depart radically from earlier claims that general practice is a distinctive field of social or biographical medicine. Within this new discourse medical work is distributed between doctors, nurses and unqualified staff in ways which make explicit the reduction of general practice work to sets of biomedical problems or tasks. At the same time, the devolution of much general practice work to less qualified and cheaper personnel is justified by drawing on a discourse of person-centred medicine.


Evolutionary cell biology: two origins, one objective.
All aspects of biological diversification ultimately trace to evolutionary modifications at the cellular level. This central role of cells frames the basic questions as to how cells work and how cells come to be the way they are. Although these two lines of inquiry lie respectively within the traditional provenance of cell biology and evolutionary biology, a comprehensive synthesis of evolutionary and cell-biological thinking is lacking. We define evolutionary cell biology as the fusion of these two eponymous fields with the theoretical and quantitative branches of biochemistry, biophysics, and population genetics. The key goals are to develop a mechanistic understanding of general evolutionary processes, while specifically infusing cell biology with an evolutionary perspective. The full development of this interdisciplinary field has the potential to solve numerous problems in diverse areas of biology, including the degree to which selection, effectively neutral processes, historical contingencies, and/or constraints at the chemical and biophysical levels dictate patterns of variation for intracellular features. These problems can now be examined at both the within- and among-species levels, with single-cell methodologies even allowing quantification of variation within genotypes. Some results from this emerging field have already had a substantial impact on cell biology, and future findings will significantly influence applications in agriculture, medicine, environmental science, and synthetic biology.


Arabidopsis ATP A2 peroxidase. Expression and high-resolution structure of a plant peroxidase with implications for lignification.
Lignins are phenolic biopolymers synthesized by terrestrial, vascular plants for mechanical support and in response to pathogen attack. Peroxidases have been proposed to catalyse the dehydrogenative polymerization of monolignols into lignins, although no specific isoenzyme has been shown to be involved in lignin biosynthesis. Recently we isolated an extracellular anionic peroxidase, ATP A2, from rapidly lignifying Arabidopsis cell suspension culture and cloned its cDNA. Here we show that the Atp A2 promoter directs GUS reporter gene expression in lignified tissues of transgenic plants. Moreover, an Arabidopsis mutant with increased lignin levels compared to wild type shows increased levels of ATP A2 mRNA and of a mRNA encoding an enzyme upstream in the lignin biosynthetic pathway. The substrate specificity of ATP A2 was analysed by X-ray crystallography and docking of lignin precursors. The structure of ATP A2 was solved to 1.45 A resolution at 100 K. Docking of p-coumaryl, coniferyl and sinapyl alcohol in the substrate binding site of ATP A2 were analysed on the basis of the crystal structure of a horseradish peroxidase C-CN-ferulic acid complex. The analysis indicates that the precursors p-coumaryl and coniferyl alcohols are preferred by ATP A2, while the oxidation of sinapyl alcohol will be sterically hindered in ATP A2 as well as in all other plant peroxidases due to an overlap with the conserved Pro-139. We suggest ATP A2 is involved in a complex regulation of the covalent cross-linking in the plant cell wall.


Type II Inhibitors Targeting CDK2.
Kinases can switch between active and inactive conformations of the ATP/Mg(2+) binding motif DFG, which has been explored for the development of type I or type II inhibitors. However, factors modulating DFG conformations remain poorly understood. We chose CDK2 as a model system to study the DFG in-out transition on a target that was thought to have an inaccessible DFG-out conformation. We used site-directed mutagenesis of key residues identified in structural comparisons in conjunction with biochemical and biophysical characterization of the generated mutants. As a result, we identified key residues that facilitate the DFG-out movement, facilitating binding of type II inhibitors. However, surprisingly, we also found that wild type CDK2 is able to bind type II inhibitors. Using protein crystallography structural analysis of the CDK2 complex with an aminopyrimidine-phenyl urea inhibitor (K03861) revealed a canonical type II binding mode and the first available type II inhibitor CDK2 cocrystal structure. We found that the identified type II inhibitors compete with binding of activating cyclins. In addition, analysis of the binding kinetics of the identified inhibitors revealed slow off-rates. The study highlights the importance of residues that may be distant to the ATP binding pocket in modulating the energetics of the DFG-out transition and hence inhibitor binding. The presented data also provide the foundation for a new class of slow off-rate cyclin-competitive CDK2 inhibitors targeting the inactive DFG-out state of this important kinase target.


Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies.
The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%-13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups.


Trophic overlap between fish and riparian spiders: potential impacts of an invasive fish on terrestrial consumers.
Studies on resource sharing and partitioning generally consider species that occur in the same habitat. However, subsidies between linked habitats, such as streams and riparian zones, create potential for competition between populations which never directly interact. Evidence suggests that the abundance of riparian consumers declines after fish invasion and a subsequent increase in resource sharing of emerging insects. However, diet overlap has not been investigated. Here, we examine the trophic niche of native fish, invasive fish, and native spiders in South Africa using stable isotope analysis. We compared spider abundance and diet at upstream fishless and downstream fish sites and quantified niche overlap with invasive and native fish. Spider abundance was consistently higher at upstream fishless sites compared with paired downstream fish sites, suggesting that the fish reduced aquatic resource availability to riparian consumers. Spiders incorporated more aquatic than terrestrial insects in their diet, with aquatic insects accounting for 45-90% of spider mass. In three of four invaded trout rivers, we found that the average proportion of aquatic resources in web-building spider diet was higher at fishless sites compared to fish sites. The probability of web-building and ground spiders overlapping into the trophic niche of invasive brown and rainbow trout was as high as 26 and 51%, respectively. In contrast, the probability of spiders overlapping into the trophic niche of native fish was always less than 5%. Our results suggest that spiders share resources with invasive fish. In contrast, spiders had a low probability of trophic overlap with native fish indicating that the traits of invaders may be important in determining their influence on ecosystem subsidies. We have added to the growing body of evidence that invaders can have cross-ecosystem impacts and demonstrated that this can be due to niche overlap.


Quantifying Selection Pressure.
Selection is an essential component of any evolutionary system and analysing this fundamental force in evolution can provide relevant insights into the evolutionary development of a population. The 1990s and early 2000s saw a substantial number of publications that investigated selection pressure through methods such as takeover time and Markov chain analysis. Over the last decade, however, interest in the analysis of selection in evolutionary computing has waned. The established methods for analysis of selection pressure provide little insight when selection is based on more than comparison-of-fitness values. This can, for instance, be the case in coevolutionary systems, when measures unrelated to fitness affect the selection process (e.g., niching) or in systems that lack a crisply defined objective function. This article proposes two metrics that holistically consider the statistics of the evolutionary process to quantify selection pressure in evolutionary systems and so can be applied where traditionally used methods fall short. The metrics are based on a statistical analysis of the relation between reproductive success and a quantifiable trait: one method builds on an estimate of the probability that this relation is random; the other uses a correlation measure. These metrics provide convenient tools to analyse selection pressure and so allow researchers to better understand this crucial component of evolutionary systems. Both metrics are straightforward to implement and can be used in post-hoc analyses as well as during the evolutionary process, for example, to inform parameter control mechanisms. A number of case studies and a critical analysis show that the proposed metrics provide relevant and reliable measures of selection pressure.


Cancer incidence and mortality risks in a large US Barrett's oesophagus cohort.
Barrett's oesophagus (BE) increases the risk of oesophageal adenocarcinoma by 10-55 times that of the general population, but no community-based cancer-specific incidence and cause-specific mortality risk estimates exist for large cohorts in the USA. Within Kaiser Permanente Northern California (KPNC), we identified patients with BE diagnosed during 1995-2012. KPNC cancer registry and mortality files were used to estimate standardised incidence ratios (SIR), standardised mortality ratios (SMR) and excess absolute risks. There were 8929 patients with BE providing 50 147 person-years of follow-up. Compared with the greater KPNC population, patients with BE had increased risks of any cancer (SIR=1.40, 95% CI 1.31 to 1.49), which slightly decreased after excluding oesophageal cancer. Oesophageal adenocarcinoma risk was increased 24 times, which translated into an excess absolute risk of 24 cases per 10 000 person-years. Although oesophageal adenocarcinoma risk decreased with time since BE diagnosis, oesophageal cancer mortality did not, indicating that the true risk is stable and persistent with time. Relative risks of cardia and stomach cancers were increased, but excess absolute risks were modest. Risks of colorectal, lung and prostate cancers were unaltered. All-cause mortality was slightly increased after excluding oesophageal cancer (SMR=1.24, 95% CI 1.18 to 1.31), but time-stratified analyses indicated that this was likely attributable to diagnostic bias. Cause-specific SMRs were elevated for ischaemic heart disease (SMR=1.39, 95% CI 1.18 to 1.63), respiratory system diseases (SMR=1.51, 95% CI 1.29 to 1.75) and digestive system diseases (SMR=2.20 95% CI 1.75 to 2.75). Patients with BE had a persistent excess risk of oesophageal adenocarcinoma over time, although their absolute excess risks for this cancer, any cancer and overall mortality were modest.


Association of BLM and BRCA1 during Telomere Maintenance in ALT Cells.
Fifteen percent of tumors utilize recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. The mechanisms underlying ALT are unclear but involve several proteins involved in homologous recombination including the BLM helicase, mutated in Bloom's syndrome, and the BRCA1 tumor suppressor. Cells deficient in either BLM or BRCA1 have phenotypes consistent with telomere dysfunction. Although BLM associates with numerous DNA damage repair proteins including BRCA1 during DNA repair, the functional consequences of BLM-BRCA1 association in telomere maintenance are not completely understood. Our earlier work showed the involvement of BRCA1 in different mechanisms of ALT, and telomere shortening upon loss of BLM in ALT cells. In order to delineate their roles in telomere maintenance, we studied their association in telomere metabolism in cells using ALT. This work shows that BLM and BRCA1 co-localize with RAD50 at telomeres during S- and G2-phases of the cell cycle in immortalized human cells using ALT but not in cells using telomerase to maintain telomeres. Co-immunoprecipitation of BRCA1 and BLM is enhanced in ALT cells at G2. Furthermore, BRCA1 and BLM interact with RAD50 predominantly in S- and G2-phases, respectively. Biochemical assays demonstrate that full-length BRCA1 increases the unwinding rate of BLM three-fold in assays using a DNA substrate that models a forked structure composed of telomeric repeats. Our results suggest that BRCA1 participates in ALT through its interactions with RAD50 and BLM.


Effects of a universal classroom behavior management program in first and second grades on young adult behavioral, psychiatric, and social outcomes.
The Good Behavior Game (GBG), a method of classroom behavior management used by teachers, was tested in first- and second-grade classrooms in 19 Baltimore City Public Schools beginning in the 1985-1986 school year. The intervention was directed at the classroom as a whole to socialize children to the student role and reduce aggressive, disruptive behaviors, confirmed antecedents of later substance abuse and dependence disorders, smoking, and antisocial personality disorder. This article reports on impact to ages 19-21. In five poor to lower-middle class, mainly African American urban areas, three or four schools were matched and within each set randomly assigned to one of three conditions: (1) GBG, (2) a curriculum-and-instruction program directed at reading achievement, or (3) the standard program. Balanced assignment of children to classrooms was made, and then, within intervention schools, classrooms and teachers were randomly assigned to intervention or control. By young adulthood significant impact was found among males, particularly those in first grade who were more aggressive, disruptive, in reduced drug and alcohol abuse/dependence disorders, regular smoking, and antisocial personality disorder. These results underline the value of a first-grade universal prevention intervention. REPLICATION: A replication was implemented with the next cohort of first-grade children with the same teachers during the following school year, but with diminished mentoring and monitoring of teachers. The results showed significant GBG impact for males on drug abuse/dependence disorders with some variation. For other outcomes the effects were generally smaller but in the predicted direction.


Genetic diversity of Mycobacterium tuberculosis in Sicily based on spoligotyping and variable number of tandem DNA repeats and comparison with a spoligotyping database for population-based analysis.
In a previous study, we proposed to associate spoligotyping and typing with the variable number of tandem DNA repeats (VNTR) as an alternative strategy to IS6110-restriction fragment length polymorphism (RFLP) for molecular epidemiological studies on tuberculosis. The aim of the present study was to further evaluate this PCR-based typing strategy and to describe the population structure of Mycobacterium tuberculosis in another insular setting, Sicily. A collection of 106 DNA samples from M. tuberculosis patient isolates was characterized by spoligotyping and VNTR typing. All isolates were independently genotyped by the standard IS6110-RFLP method, and clustering results between the three methods were compared. The totals for the clustered isolates were, respectively, 15, 60, and 82% by IS6110-RFLP, spoligotyping, and VNTR typing. The most frequent spoligotype included type 42 that missed spacers 21 to 24 and spacers 33 to 36 and derived types 33, 213, and 273 that, together represented as much as 26% of all isolates, whereas the Haarlem clade of strains (types 47 and 50, VNTR allele 32333) accounted for 9% of the total strains. The combination of spoligotyping and VNTR typing results reduced the number of clusters to 43% but remained superior to the level of IS6110-RFLP clustering (ca. 15%). All but one IS6110-defined cluster were identified by the combination of spoligotyping and VNTR clustering results, whereas 9 of 15 spoligotyping-defined clusters could be further subdivided by IS6110-RFLP. Reinterpretation of previous IS6110-RFLP results in the light of spoligotyping-VNTR typing results allowed us to detect an additional cluster that was previously missed. Although less discriminative than IS6110-RFLP, our results suggest that the use of the combination of spoligotyping and VNTR typing is a good screening strategy for detecting epidemiological links for the study of tuberculosis epidemiology at the molecular level.


Differentiation potential of CD14+ monocytes into myofibroblasts in patients with systemic sclerosis.
Circulating monocytes are a highly plastic and functionally heterogeneic cell type with an activated phenotype in patients with systemic sclerosis (SSc). CD14(+) monocytes have the potential to differentiate into extra-cellular matrix (ECM) producing cells, possibly participating in fibrogenesis. To study the effect of GM-CSF, IL-4 and endothelin -1 (ET-1) alone or in combination on monocyte differentiation into myofibroblasts. CD14(+) cells were isolated from peripheral blood from 14 SSc patients and healthy controls by positive selection and incubated with different combinations of GM-CSF, IL-4 and ET-1 for 14 days. Type-1 collagen and α-SMA were detected by Western blot, qPCR and confocal microscopy. HLA-DR, CD11c and CD14 expression was analysed by flow cytometry. A collagen gel contraction assay was performed for functional myofibroblast assessment. GM-CSF both induced collagen and α-SMA expression after 14 days. ET-1 further increased GM-CSF-induced collagen expression in a dose dependent manner up to 30-fold. IL-4/GM-CSF combination leads to a more DC-like phenotype of monocytes associated with reduced collagen and α-SMA expression compared to GM-CSF alone. Collagen and α-SMA expression was higher in monocytes from SSc patients and monocytes were more prone to obtain a spindle form. In contrast to controls, ET-1 and IL-4 alone were sufficient to induce α-SMA expression in monocytes from SSc patients. Despite the induction of α-SMA expression, monocyte-derived myofibroblasts only had a moderate capability of contraction in functional analyses. SSc monocytes display increased maturation towards myofibroblasts demonstrated by their phenotype and α-SMA expression when compared to monocytes from healthy controls, however only with minor functional contraction properties.


The coordination dynamics of mobile conjugate reinforcement.
What we know about infant learning and memory is founded largely on systematic studies by the late Carolyn Rovee-Collier (1942-2014) and her associates of a phenomenon called mobile conjugate reinforcement. Experiments show that when a ribbon is attached from a 3-month-old infant's foot to a mobile suspended overhead the baby quickly realizes it can make the mobile move. The mobile, which offers interesting sights and sounds, responds conjugately to the baby's vigorous kicks which increase in rate by a factor of 3-4. In this paper, using the concepts, methods and tools of coordination dynamics, we present a theoretical model which reproduces the experimental observations of Rovee-Collier and others and predicts a number of additional features that can be experimentally tested. The model is a dynamical system consisting of three equations, one for the baby's leg movements, one for the jiggling motion of the mobile and one for the functional coupling between the two. A key mechanism in the model is positive feedback which is shown to depend sensitively on bifurcation parameters related to the infant's level of attention and inertial properties of the mobile. The implications of our model for the dynamical (and developmental) origins of agency are discussed.


Impaired sperm maturation in RNASE9 knockout mice.
Ribonuclease, RNase A family, 9 (RNASE9) is a ribonuclease A superfamily member that is expressed only in the epididymis. It is a small, secreted polypeptide, it lacks ribonuclease activity, and its function(s) is unknown. However, epididymis-specific expression suggests a role in sperm maturation. We generated Rnase9(-/-) mice to study RNASE9 function in vivo. We confirm that RNASE9 expression is restricted to the epididymis. Within the epididymis, RNASE9 is first detected in midcaput, persists through the distal caput and corpus, and wanes in the cauda. Rnase9(-/-) mice are born at the expected Mendelian ratio, have normal postnatal growth and development, and have no outwardly apparent phenotype. Spermatogenesis is normal, and Rnase9-null sperm are morphologically normal. Rnase9(-/-) males have normal fertility in unrestricted mating trials, and fertilization rates in in vitro fertilization assays are indistinguishable from wild-type mice. Visual observations coupled with analyses of sperm velocities shortly after swim out from the corpus shows that motility of Rnase9-null sperm is significantly impaired. However, no differences between wild-type and Rnase9-null sperm are detected by computer-assisted sperm analysis 10-90 min after sperm isolation from the corpus or cauda. Assessment of capacitation-dependent signaling pathways in Rnase9-null sperm showed that, while levels of tyrosine phosphorylation of sperm proteins were normal, there was decreased phosphorylation of protein kinase A substrates upon capacitation compared to wild-type mice. In conclusion, RNASE9 is dispensable for fertility, but the absence of RNASE9 during epididymal transit results in impaired sperm maturation.


Vascular endothelial growth factor signaling is necessary for expansion of medullary microvessels during postnatal kidney development.
Postnatal inhibition or deletion of angiotensin II (ANG II) AT1 receptors impairs renal medullary mircrovascular development through a mechanism that may include vascular endothelial growth factor (VEGF). The present study was designed to test if VEGF/VEGF receptor signaling is necessary for the development of the renal medullary microcirculation. Endothelial cell-specific immunolabeling of kidney sections from rats showed immature vascular bundles at postnatal day (P) 10 with subsequent expansion of bundles until P21. Medullary VEGF protein abundance coincided with vasa recta bundle formation. In human fetal kidney tissue, immature vascular bundles appeared early in the third trimester (GA27-28) and expanded in size until term. Rat pups treated with the VEGF receptor-2 (VEGFR2) inhibitor vandetanib (100 mg·kg(-1)·day(-1)) from P7 to P12 or P10 to P16 displayed growth retardation and proteinuria. Stereological quantification showed a significant reduction in total length (386 ± 13 vs. 219 ± 16 m), surface area, and volume of medullary microvessels. Vascular bundle architecture was unaffected. ANG II-AT1A/1B (-/-) mice kidneys displayed poorly defined vasa recta bundles whereas mice with collecting duct principal cell-specific AT1A deletion displayed no medullary microvascular phenotype. In conclusion, VEGFR2 signaling during postnatal development is necessary for expansion of the renal medullary microcirculation but not structural patterning of the vasa recta bundles, which occurs through an AT1-mediated mechanism.


Distinct polarity cues direct Taz/Yap and TGFβ receptor localization to differentially control TGFβ-induced Smad signaling.
We and others have shown that the Hippo pathway effectors TAZ and YAP direct Smad activity to regulate TGFβ family-induced cellular responses in stem cell and cancer biology. In polarized epithelial cells we showed that the Crumbs complex promotes Hippo-dependent cytoplasmic TAZ/YAP localization that restricts TGFβ-induced Smad nuclear accumulation and activity. In this Developmental Cell issue, basal-lateral restriction of TGFβ receptors is proposed as the sole mechanism suppressing Smad signaling in epithelial cells. Here we show that basal recruitment of TGFβ receptors occurs subsequent to Hippo-dependent suppression of Smad activity by cytoplasmic TAZ/YAP. Our results demonstrate that receptor sequestration and Hippo control of activated Smads are distinct events regulating TGFβ signaling in polarized epithelia and raise interesting questions about the function of these pathways in controlling Smad signaling in development, homeostasis, and disease. This Matters Arising Response addresses the Nallet-Staub et al. (2015) Matters Arising, published concurrently in Developmental Cell.


Roller Massage: Difference in Knee Joint Range of Motion and Pain Perception Among Experienced and Nonexperienced Individuals After Following a Prescribed Program.
Roller massage (RM) is a popular myofascial intervention. To date, no research has investigated the effects of RM on experienced and nonexperienced individuals and if there are differences between a prescribed RM program and a self-preferred program. The main objective was to measure the effects of a prescribed RM program with a foam roller on knee passive range of motion (ROM) and pressure pain threshold (PPT) among experienced and nonexperienced individuals. A secondary objective was to determine if there are differences between a prescribed RM program and a self-preferred program in experienced individuals. Pretest and posttest observational study. University kinesiology laboratory. A total of 60 healthy adults (age = 26 [5.3] y) were allocated into 3 groups of 20 subjects: experienced, nonexperienced, and control. The experienced and nonexperienced groups followed a prescribed 2-minute RM intervention. The control group did their own 2-minute self-preferred program. Knee passive ROM and PPT. For the experienced and nonexperienced, the between-group analysis revealed a statistically significant difference for ROM and PPT (P < .001). Within-group analysis revealed a posttest knee passive ROM increase of 8° for experienced and 7° for the nonexperienced. For PPT, there was a posttest increase of 180 kPa for the experienced and 169 kPa for the nonexperienced. For the prescribed versus self-preferred program, the between-group analysis (experienced vs control) revealed a statistically significant difference (P < .001). The within-group analysis revealed a posttest knee passive ROM increase of 8° for the prescribed and 5° for the self-preferred program. For PPT, there was a posttest increase of 180 kPa for the prescribed program and 137 kPa for the self-preferred program. These findings suggest that experienced and nonexperienced individuals have similar responses to a prescribed RM program. A prescribed RM program may produce better outcomes than a self-preferred program.


Evaluating drug resistance in visceral leishmaniasis: the challenges.
For decades antimonials were the drugs of choice for the treatment of visceral leishmaniasis (VL), but the recent emergence of resistance has made them redundant as first-line therapy in the endemic VL region in the Indian subcontinent. The application of other drugs has been limited due to adverse effects, perceived high cost, need for parenteral administration and increasing rate of treatment failures. Liposomal amphotericin B (AmB) and miltefosine (MIL) have been positioned as the effective first-line treatments; however, the number of monotherapy MIL-failures has increased after a decade of use. Since no validated molecular resistance markers are yet available, monitoring and surveillance of changes in drug sensitivity and resistance still depends on standard phenotypic in vitro promastigote or amastigote susceptibility assays. Clinical isolates displaying defined MIL- or AmB-resistance are still fairly scarce and fundamental and applied research on resistance mechanisms and dynamics remains largely dependent on laboratory-generated drug resistant strains. This review addresses the various challenges associated with drug susceptibility and -resistance monitoring in VL, with particular emphasis on the choice of strains, susceptibility model selection and standardization of procedures with specific read-out parameters and well-defined threshold criteria. The latter are essential to support surveillance systems and safeguard the limited number of currently available antileishmanial drugs.


Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media.
Macrophages play an important role in the inflammatory responses involved with spinal cord injury (SCI). We have previously demonstrated that infiltrated bone marrow-derived macrophages (BMDMs) engulf myelin debris, forming myelin-laden macrophages (mye-Mϕ). These mye-Mϕ promote disease progression through their pro-inflammatory phenotype, enhanced neurotoxicity, and impaired phagocytic capacity for apoptotic cells. We thus hypothesize that the excessive accumulation of mye-Mϕ is the root of secondary injury, and that targeting mye-Mϕ represents an efficient strategy to improve the local inflammatory microenvironment in injured spinal cords and to further motor neuron function recovery. In this study, we administer murine embryonic stem cell conditioned media (ESC-M) as a cell-free stem cell based therapy to treat a mouse model of SCI. We showed that BMDMs, but not microglial cells, engulf myelin debris generated at the injury site. Phagocytosis of myelin debris leads to the formation of mye-Mϕ in the injured spinal cord, which are surrounded by activated microglia cells. These mye-Mϕ are pro-inflammatory and lose the normal macrophage phagocytic capacity for apoptotic cells. We therefore focus on how to trigger lipid efflux from mye-Mϕ and thus restore their function. Using ESC-M as an immune modulating treatment for inflammatory damage after SCI, we rescued mye-Mϕ function and improved functional locomotor recovery. ESC-M treatment on mye-Mϕ resulted in improved exocytosis of internalized lipids and a normal capacity for apoptotic cell phagocytosis. Furthermore, when ESC-M was administered intraperitoneally after SCI, animals exhibited significant improvements in locomotor recovery. Examination of spinal cords of the ESC-M treated mice revealed similar improvements in macrophage function as well as a shift towards a more anti-inflammatory environment at the lesion and parenchyma. The embryonic stem cell conditioned media can be used as an effective treatment for SCI to resolve inflammation and improve functional recovery while circumventing the complications involved in whole cell transplantation.


Diversity-induced resonance in the response to social norms.
In this paper we focus on diversity-induced resonance, which was recently found in bistable, excitable, and other physical systems. We study the appearance of this phenomenon in a purely economic model of cooperating and defecting agents. An agent's contribution to a public good is seen as a social norm, so defecting agents face a social pressure, which decreases if free riding becomes widespread. In this model, diversity among agents naturally appears because of the different sensitivities towards the social norm. We study the evolution of cooperation as a response to the social norm (i) for the replicator dynamics and (ii) for the logit dynamics by means of numerical simulations. Diversity-induced resonance is observed as a maximum in the response of agents to changes in the social norm as a function of the degree of heterogeneity in the population. We provide an analytical, mean-field approach for the logit dynamics and find very good agreement with the simulations. From a socioeconomic perspective, our results show that, counterintuitively, diversity in the individual sensitivity to social norms may result in a society that better follows such norms as a whole, even if part of the population is less prone to follow them.


A thymine isostere in the templating position disrupts assembly of the closed DNA polymerase beta ternary complex.
The high fidelity of the DNA polymerization process is critically important for the stability of the cellular genome. The role of template and incoming nucleotide base pairing in polymerase fidelity has recently been explored by the use of nucleotide isosteres, which preserve the steric but not the electronic properties of the corresponding bases. The DNA repair enzyme, DNA polymerase beta (Pol beta), is among the most discriminating, being inactive when the thymine isostere difluorotoluene (DFT) is present in the templating base position. To explore the physical basis for this inactivity, we have performed NMR studies on [methyl-13C]methionine-labeled Pol beta complexed with double-hairpin DNA, used to model the gapped nucleotide substrate, and having either a thymine or a DFT isostere at the templating base position. The six methionine residues distributed throughout the enzyme provide useful conformational probes of the lyase and polymerase domains and subdomains. Analysis of the proton shift of Met282 that results from formation of an abortive Pol beta-gapped DNA-dATP complex is consistent with an open to closed conformational change of the enzyme predicted from crystal structures. In contrast, the same resonance is nearly unshifted when a ternary complex is formed from dATP and gapped DNA in which a DFT isostere replaces thymine at the templating base position. Alternatively, the resonances of Met191 and Met155, located in the catalytic subdomain, show perturbations upon formation of the abortive ternary complex, which are qualitatively similar, but significantly weaker, than the changes observed when thymine is present at the templating base position. The changes in the Met155 and Met191 methyl resonances are in fact more similar to those observed in the binary Pol beta-dATP complex. These studies demonstrate that the block in catalysis is directly related to the absence of the set of conformational transitions that include the "open" to "closed" transition monitored by Met282.


Mitochondrial DNA repairs double-strand breaks in yeast chromosomes.
The endosymbiotic theory for the origin of eukaryotic cells proposes that genetic information can be transferred from mitochondria to the nucleus of a cell, and genes that are probably of mitochondrial origin have been found in nuclear chromosomes. Occasionally, short or rearranged sequences homologous to mitochondrial DNA are seen in the chromosomes of different organisms including yeast, plants and humans. Here we report a mechanism by which fragments of mitochondrial DNA, in single or tandem array, are transferred to yeast chromosomes under natural conditions during the repair of double-strand breaks in haploid mitotic cells. These repair insertions originate from noncontiguous regions of the mitochondrial genome. Our analysis of the Saccharomyces cerevisiae mitochondrial genome indicates that the yeast nuclear genome does indeed contain several short sequences of mitochondrial origin which are similar in size and composition to those that repair double-strand breaks. These sequences are located predominantly in non-coding regions of the chromosomes, frequently in the vicinity of retrotransposon long terminal repeats, and appear as recent integration events. Thus, colonization of the yeast genome by mitochondrial DNA is an ongoing process.


Pay for performance and contractual choice: the case of general practitioners in England.
The Quality and Outcomes Framework (QOF) is a Pay-for-Performance scheme introduced in England in 2004 to reward primary care providers. This incentive scheme provides financial incentives that reward the overall performance of a practice, not individual effort. Consequently, an important question is how the QOF may affect contractual choices, quality provision and doctor mobility in the primary healthcare labour market. The paper provides a simple theoretical model that shows that the introduction and further strengthening of the scheme may have induced practices to compete for the best doctors and modified their choices in terms of contractual agreements with practitioners. We test the implications of this model using a linkage between Doctors Census data and practices' characteristics from 2003 to 2007. We use linear multilevel models with random intercept and we account for sample selection. We find that after the introduction of the QOF efficient doctors are more likely to become partners and mobility among doctors has increased. The strengthening of the scheme in 2005 is associated with an increase in the quality of primary care and a reduction in access to the market for new doctors.


Visualization of painful experiences believed to trigger the activation of affective and emotional brain regions in subjects with low back pain.
In the management of clinical low back pain (LBP), actual damage to lower back areas such as muscles, intervertebral discs etc. are normally targeted for therapy. However, LBP may involve not only sensory pain, but also underlying affective pain which may also play an important role overall in painful events. Therefore we hypothesized that visualization of a painful event may trigger painful memories, thus provoking the affective dimension of pain. The present study investigated neural correlates of affect processing in subjects with LBP (n = 11) and subjects without LBP (n = 11) through the use of virtual LBP stimuli. Whole brain functional magnetic resonance imaging (MRI) was performed for all subjects while they were shown a picture of a man carrying luggage in a half-crouching position. All subjects with LBP reported experiencing discomfort and 7 LBP subjects reported experiencing pain. In contrast to subjects without LBP, subjects with LBP displayed activation of the cortical area related to pain and emotions: the insula, supplementary motor area, premotor area, thalamus, pulvinar, posterior cingulate cortex, hippocampus, fusiform, gyrus, and cerebellum. These results suggest that the virtual LBP stimuli caused memory retrieval of unpleasant experiences and therefore may be associated with prolonged chronic LBP conditions.


Inhibition of Sam68 triggers adipose tissue browning.
Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis. We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.


Does hyperinsulinemia preserve bone?
Obesity and NIDDM are each associated with increased bone mineral density (BMD). We therefore hypothesize that hyperinsulinemia is an osteogenic factor. Subjects consisted of 411 men and 559 women aged 50-89 years who were participants in the Rancho Bernardo Heart and Chronic Disease Study and were not diabetic by history or oral glucose tolerance test. Fasting and 2-h postchallenge insulin were measured by radioimmunoassay. Bone mineral density was measured at the midshaft radius with single photon absorptiometry and at the lumbar spine and hip with dual energy X-ray absorptiometry. Multiple regression analyses indicated that among men, a significant insulin-BMD association at the hip was no longer apparent after adjusting for covariates. Among women, fasting insulin was significantly and positively associated with bone density of the radius and spine (P < 0.05), independent of age, BMI, waist-hip ratio, postmenopausal estrogen use, age at menopause, thiazide use, family history of diabetes, current cigarette smoking, and exercise. Each 10 microU/ml increase in fasting insulin was associated with an increase of 0.33 and 0.57 g/cm2 of the radius and spine, respectively. Hyperinsulinemia may be responsible for part of the observed association of both diabetes and obesity with BMD in women.


Epidemiology and extracutaneous comorbidities of severe acne in adolescence: a U.S. population-based study.
Little is known about the epidemiology of severe acne in the U.S. We sought to study the U.S. prevalence, determinants and comorbidities of severe acne in adolescence. We analysed data from the 2007 National Health Interview Survey, a cross-sectional questionnaire-based study of 9417 children ages 0-17 years. Prevalence of severe acne, demographics and comorbid disorders were determined. The U.S. prevalence of severe acne was virtually nil in the first decade of life, but increased in a linear fashion from 11 years [1·7% (95% confidence interval (CI) 0·4-3·0%)] to 17 years of age [12·1% (95% CI 7·8-16·5%)] (Rao-Scott Chi-square, P < 0·0001). Severe acne was more common in Whites compared with other racial groups at age 14-15 years (P = 0·0004) and girls at age 11-13 (P = 0·02). Severe acne was associated with a number of comorbid disorders. Sinopulmonary disease included sinus infection (P = 0·0003), sore throat other than strep infection (P = 0·0003), asthma (P = 0·03) and nonasthmatic lung disease (P = 0·03). Upper gastrointestinal comorbidities included reflux/heartburn (P = 0·0003), abdominal pain (P = 0·03), nausea/vomiting (P = 0·0001) and food/digestive allergy (P = 0·01). Psychological comorbidities included depression (P = 0·02), anxiety (P < 0·0001), attention deficit disorder/attention deficit hyperactivity disorder (P = 0·01) and insomnia (P = 0·02). In conclusion, severe acne was more prevalent in older age, Whites, female sex and higher socioeconomic status. Future studies are needed to confirm the associations with sinopulmonary, upper gastrointestinal and psychological disorders in adolescents.


Antitumor activity of fucoidan against diffuse large B cell lymphoma in vitro and in vivo.
Fucoidan is one of the major sulfated polysaccharides isolated from brown seaweeds. In this study, we determined the anti-cancer activity of fucoidan on diffuse large B cell lymphoma (DLBCL) cells both in vitro and in vivo. Fucoidan inhibited the growth of DLBCL cells in a dose- and time-dependent manner, and fucoidan treatment provoked G0/G1 cell cycle arrest, which was accompanied by p21 up-regulation and cyclin D1, Cdk4, and Cdk6 down-regulation. Fucoidan also induced caspase-dependent cell apoptosis in DLBCL cell lines and primary DLBCL cell. In addition, fucoidan treatment caused the loss of mitochondrial membrane potential and the release of cytochrome c and apoptosis-inducing factor from the mitochondria into the cytosol. Fucoidan also potentiated the activities of carfilzomib in killing DLBCL cells. Oral administration of fucoidan effectively inhibited tumor growth in xenograft mouse models. Our findings reveal the novel function of fucoidan as an anti-DLBCL agent, which can be used in the clinical treatment of DLBCL.


Deep fungal dermatitis in three inland bearded dragons (Pogona vitticeps) caused by the Chrysosporium anamorph of Nannizziopsis vriesii.
The Chrysosporium anamorph of Nannizziopsis vriesii (CANV), a keratinophilic fungus that naturally and experimentally causes severe and often fatal dermatitis in multiple reptile species, was isolated in pure culture from skin samples of three inland bearded dragons (Pogona vitticeps) with deep granulomatous dermatomycosis. The first animal presented with a focal maxillary swelling involving the skin and gingiva. This lizard died while undergoing itraconazole and topical miconazole therapy. The second presented with focally extensive discoloration and thickening of the skin of the ventrum and was euthanized after 10 weeks of itraconazole therapy. A third lizard presented with hyperkeratotic exudative dermatitis on a markedly swollen forelimb. Amputation and itraconazole therapy resulted in a clinical cure. Histopathology of tissue biopsies in all cases demonstrated granulomatous dermatitis with intralesional hyphae morphologically consistent with those produced by the CANV. The second lizard also had granulomatous hepatitis with intralesional hyphae. Evidence in this report suggests that the CANV is the etiologic agent of an emerging condition in captive bearded dragons that has been called 'yellow fungus disease'.


The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.
Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain. Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight. In the kidney, increased sodium delivery to the macula densa mediated by SGLT-2 inhibition has the potential to reduce intraglomerular pressure, which may explain why SGLT-2 inhibitors reduce albuminuria and appear to slow kidney function decline in people with diabetes. Importantly, in the trials completed to date, these benefits appeared to be maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and did not appear to be dependent on ambient hyperglycaemia. There is therefore a rationale for studying the cardio-renal effects of SGLT-2 inhibition in people at risk of CV disease and hyperfiltration (i.e. those with substantially reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes.


IPS in Europe: the EQOLISE trial.
IPS has been demonstrated to increase return to open employment significantly in individuals with mental health problems in the US. Previous experience (e.g. with ACT) has demonstrated the sensitivity of complex community mental health interventions to local social and healthcare cultures. Europe has conditions of generally greater employment security than the US and varying (generally higher) unemployment rates and welfare benefits. Evidence of the effectiveness of IPS in these conditions, and its potential variation across them, would guide local policy and provide possible insights into its mechanism. We conducted an RCT of IPS versus high-quality train-and-place vocational rehabilitation in six European centers with very different labor market and health and social care conditions. A sample of 312 individuals with psychotic illness was randomly allocated (50 per site). Inclusion criteria were a minimum of two years' illness duration, with at least one year of continuous unemployment and six months contact with their current mental health services. Follow-up was 18 months. The primary outcome was any open employment, and secondary outcomes included time to employment, duration of employment and hospital admission. IPS was more effective than the Vocational Services for all vocational outcomes. 85 IPS patients (54.5%) worked for at least one day compared to 43 Vocational Service patients (27.6). They were significantly less likely to be rehospitalized. Local unemployment rates explained a significant amount of the variation in IPS effectiveness and both national economic growth and welfare systems influenced overall employment rates in both services. IPS doubles the access to work of people with psychotic illnesses, without any evidence of increased relapse. Its effectiveness is not independent of external circumstances, particularly local unemployment rates.


Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram.
The value of heart rate variability, ambulatory electrocardiographic (ECG) variables and the signal-averaged ECG in the prediction of arrhythmic events (sudden death or life-threatening ventricular arrhythmias) was assessed before hospital discharge in 416 consecutive survivors of acute myocardial infarction. During the follow-up period (range 1 to 1,112 days), there were 24 arrhythmic events and 47 deaths. The initial relation between several prognostic factors and arrhythmic events was explored with use of the Kaplan-Meier product limit estimates of survival function. Impaired heart rate variability less than 20 ms (p less than 0.0000), late potentials (p less than 0.0000), ventricular ectopic beat frequency (p less than 0.0000), repetitive ventricular forms (p less than 0.0000), left ventricular ejection fraction less than 40% (p less than 0.02) and Killip class (p less than 0.02) were identified as significant univariate predictors of arrhythmic events. When these variables were analyzed by using a stepwise Cox regression model, only impaired heart rate variability, followed by late potentials and repetitive ventricular forms remained independent predictors of arrhythmic events. The combination of impaired heart rate variability and late potentials had a sensitivity of 58%, a positive predictive accuracy of 33% and a relative risk of 18.5 for arrhythmic events and was superior to other combinations including those incorporating left ventricular function, exercise ECG, ventricular ectopic beat frequency and repetitive ventricular forms. These results suggest that a simple method of assessment based on heart rate variability and the signal-averaged ECG can select a small subgroup of survivors of myocardial infarction at high risk of future life-threatening arrhythmias and sudden death.


PrPC Undergoes Basal to Apical Transcytosis in Polarized Epithelial MDCK Cells.
The Prion Protein (PrP) is an ubiquitously expressed glycosylated membrane protein attached to the external leaflet of the plasma membrane via a glycosylphosphatidylinositol anchor (GPI). While the misfolded PrPSc scrapie isoform is the infectious agent of prion disease, the cellular isoform (PrPC) is an enigmatic protein with unclear function. Of interest, PrP localization in polarized MDCK cells is controversial and its mechanism of trafficking is not clear. Here we investigated PrP traffic in MDCK cells polarized on filters and in three-dimensional MDCK cysts, a more physiological model of polarized epithelia. We found that, unlike other GPI-anchored proteins (GPI-APs), PrP undergoes basolateral-to-apical transcytosis in fully polarized MDCK cells. Following this event full-length PrP and its cleavage fragments are segregated in different domains of the plasma membrane in polarized cells in both 2D and 3D cultures.


Discovery of a new mode of oviparous reproduction in sharks and its evolutionary implications.
Two modes of oviparity are known in cartilaginous fishes, (1) single oviparity where one egg case is retained in an oviduct for a short period and then deposited, quickly followed by another egg case, and (2) multiple oviparity where multiple egg cases are retained in an oviduct for a substantial period and deposited later when the embryo has developed to a large size in each case. Sarawak swellshark Cephaloscyllium sarawakensis of the family Scyliorhinidae from the South China Sea performs a new mode of oviparity, which is named "sustained single oviparity", characterized by a lengthy retention of a single egg case in an oviduct until the embryo attains a sizable length. The resulting fecundity of the Sarawak swellshark within a season is quite low, but this disadvantage is balanced by smaller body, larger neonates and quicker maturation. The Sarawak swellshark is further uniquely characterized by having glassy transparent egg cases, and this is correlated with a vivid polka-dot pattern of the embryos. Five modes of lecithotrophic (yolk-dependent) reproduction, i.e. short single oviparity, sustained single oviparity, multiple oviparity, yolk-sac viviparity of single pregnancy and yolk-sac viviparity of multiple pregnancy were discussed from an evolutionary point of view.


Multi-View Object Retrieval via Multi-Scale Topic Models.
The increasing number of 3D objects in various applications has increased the requirement for effective and efficient 3D object retrieval methods, which attracted extensive research efforts in recent years. Existing works mainly focus on how to extract features and conduct object matching. With the increasing applications, 3D objects come from different areas. In such circumstances, how to conduct object retrieval becomes more important. To address this issue, we propose a multi-view object retrieval method using multi-scale topic models in this paper. In our method, multiple views are first extracted from each object, and then the dense visual features are extracted to represent each view. To represent the 3D object, multi-scale topic models are employed to extract the hidden relationship among these features with respect to varied topic numbers in the topic model. In this way, each object can be represented by a set of bag of topics. To compare the objects, we first conduct topic clustering for the basic topics from two data sets, and then generate the common topic dictionary for new representation. Then, the two objects can be aligned to the same common feature space for comparison. To evaluate the performance of the proposed method, experiments are conducted on two data sets. The 3D object retrieval experimental results and comparison with existing methods demonstrate the effectiveness of the proposed method.


Fungal endosymbionts of plants reduce lifespan of an aphid secondary parasitoid and influence host selection.
Complex biotic interactions shape ecological communities of plants, herbivores and their natural enemies. In studies of multi-trophic interactions, the presence of small, invisible micro-organisms associated with plants and those of a fourth above-ground trophic level have often been neglected. Incorporating these neglected factors improves our understanding of the processes within a multi-trophic network. Here, we ask whether the presence of a fungal endosymbiont, which alters plant quality by producing herbivore-toxic substances, trickles up the food chain and affects the performance and host-selection behaviour of aphid secondary parasitoids. We simultaneously offered hosts from endophyte-free and endophyte-infected environments to secondary parasitoids. Older and more experienced parasitoid females discriminated against hosts from the endophyte-infected environment. Developing in lower quality hosts from the endophyte-infected environment reduced the lifespan of secondary parasitoids. This indicates that aphid secondary parasitoids can perceive the disadvantage for their developing offspring in parasitoids from the endophyte environment and can learn to discriminate against them. In the field, this discrimination ability may shift the success of primary parasitoids to endophyte-infected plants, which co-occur with endophyte-free plants. Ultimately, the control of aphids depends on complex interactions between primary and secondary parasitoids and their relative sensitivity to endophytic fungi.


Heart rate variability as a predictor of cardiac dysrhythmias during weaning from mechanical ventilation.
Weaning from mechanical ventilation to spontaneous breathing is associated with changes in the hemodynamic and autonomic nervous systems that are reflected by heart rate variability. Although cardiac dysrhythmias are an important manifestation of hemodynamic alterations, the impact of heart rate variability on the occurrence of dysrhythmias during weaning has not been specifically studied. To describe differences in heart rate variability spectral power and occurrence of cardiac dysrhythmias at baseline and during the initial trial of weaning from mechanical ventilation and to evaluate the impact of heart rate variability during weaning on occurrence of dysrhythmias. Continuous 3-lead electrocardiographic recordings were collected from 35 patients receiving mechanical ventilation for 24 hours at baseline and during the initial weaning trial. Heart rate variability was evaluated by using spectral power analysis. Low-frequency power increased (P = .04) and high-frequency and very-low-frequency power did not change during weaning. The mean number of supraventricular ectopic beats per hour during weaning was higher than the mean at baseline (P < .001); the mean of ventricular ectopic beats did not change. Low-frequency power was a predictor of ventricular and supraventricular ectopic beats during weaning (P < .001). High-frequency power was predictive of ventricular and supraventricular (P = .02) ectopic beats during weaning. Very-low-frequency power was predictive of ventricular ectopic beats (P < .001) only. Heart rate variability power spectra during weaning were predictive of dysrhythmias.


The gut flora as a forgotten organ.
The intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system. Mucosal immune responses to resident intestinal microflora require precise control and an immunosensory capacity for distinguishing commensal from pathogenic bacteria. In genetically susceptible individuals, some components of the flora can become a liability and contribute to the pathogenesis of various intestinal disorders, including inflammatory bowel diseases. It follows that manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy. The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled. An improved understanding of this hidden organ will reveal secrets that are relevant to human health and to several infectious, inflammatory and neoplastic disease processes.


Methods for Development of the European Commission Initiative on Breast Cancer Guidelines: Recommendations in the Era of Guideline Transparency.
Neither breast cancer prevention and early-detection programs, nor their outcomes, are uniform across Europe. This article describes the rationale, methods, and process for development of the European Commission (EC) Initiative on Breast Cancer Screening and Diagnosis Guidelines. To be consistent with standards set by the Institute of Medicine and others, the EC followed 6 general principles. First, the EC selected, via an open call, a panel with broad representation of areas of expertise. Second, it ensured that all recommendations were supported by systematic reviews. Third, the EC separately considered important subgroups of women, included patient advocates in the guidelines development group, and focused on good communication to inform women's decisions. Fourth, EC rules on conflicts of interest were followed and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests. Fifth, it focused its recommendations on outcomes that matter to women, and certainty of the evidence is rated for each. Sixth, the EC elicited stakeholder feedback to ensure that the recommendations remain up to date and relevant to practice. This article describes the approach and highlights ways of disseminating and adapting the recommendations both within and outside Europe, using innovative information technology tools.


Surgical options for the treatment of hyperthyroidism in the cat.
Since the first description of feline hyperthyroidism in 1978, numerous treatment options for hyperthyroidism have been reported. Surgical removal of enlarged, autonomously functioning thyroid glands is one of the most commonly used treatment options. Affected cats must have a careful pre-operative evaluation to detect concurrent medical conditions such as renal disease or cardiomyopathy. Since more than 80% of hyperthyroid cats have neoplastic changes in both thyroid glands, bilateral thyroidectomy is necessary for treatment of the majority of hyperthyroid cats. Several different thyroidectomy techniques have been developed in an attempt to minimise potential post-operative complications associated with bilateral thyroidectomy such as hypocalcemia or recurrence of hyperthyroidism. Damage to or removal of all four parathyroid glands during bilateral thyroidectomy causes hypocalcemia, the most common post-operative complication. Recurrence of hyperthyroidism can occur months after initial thyroidectomy if residual adenomatous thyroid tissue is retained in the surgical site. The most effective surgical techniques for bilateral thyroidectomy involve preservation of at least one external parathyroid gland on the surface of the thyroid capsule. Additionally, the majority of the thyroid capsule must be removed to ensure that all neoplastic thyroid tissue is removed. The most recently described feline thyroidectomy techniques involve sequential removal of bilaterally affected thyroid glands. Staging a bilateral thyroidectomy allows time for ipsilateral parathyroid tissue to revascularise before the second thyroid gland is removed and the blood supply to the contralateral parathyroid glands is potentially interrupted. Thyroidectomy is a very effective treatment option for hyperthyroid cats. Surgical treatment of hyperthyroidism in cats offers permanent cure without chronic medical management. No specialised equipment other than standard surgical instrumentation and facilities are necessary. With practice, feline thyroidectomy can become a routine procedure in most veterinary hospitals.


Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy.
Pregnant mice were given a single dose (10 mug/g body weight) of diethylstilbestrol (DES) on Days 7 to 19, which correspond to the first to fifth lunar months in humans, after the authors, using a 14C-labeled compound, confirmed easy placental penetration by DES. Treatment with DES on Days 15 to 19 resulted in the induction of persistent urogenital sinus (15.8 to 92.5%) and hypertrophy of the portio vaginalis (11.8 to 73.3%) in female offspring, and treatment on Days 17 and 19 resulted in the induction of undescended testes and their hypogenesis (70.4 to 73.3%) in male offspring, although treatment with DES at other stages of pregnancy and after birth did not cause these alterations. The incidence of various tumors (lung adenoma, granulosa cell tumor, etc.) increased significantly (31.0 to 37.9%) when DES was given on Days 15 and 17, which correspond to the stage sensitive to other carcinogens. However, adenosis and adenocarcinoma of the vagina were not observed in the offspring.


Range shifts and adaptive responses to Quaternary climate change.
Tree taxa shifted latitude or elevation range in response to changes in Quaternary climate. Because many modern trees display adaptive differentiation in relation to latitude or elevation, it is likely that ancient trees were also so differentiated, with environmental sensitivities of populations throughout the range evolving in conjunction with migrations. Rapid climate changes challenge this process by imposing stronger selection and by distancing populations from environments to which they are adapted. The unprecedented rates of climate changes anticipated to occur in the future, coupled with land use changes that impede gene flow, can be expected to disrupt the interplay of adaptation and migration, likely affecting productivity and threatening the persistence of many species.


Regulation of forestomach-specific expression of the murine adenosine deaminase gene.
The maturation of stratified squamous epithelium of the upper gastrointestinal tract is a highly ordered process of development and differentiation. Information on the molecular basis of this process is, however, limited. Here we report the identification of the first murine forestomach regulatory element using the murine adenosine deaminase (Ada) gene as a model. In the adult mouse, Ada is highly expressed in the terminally differentiated epithelial layer of upper gastrointestinal tract tissues. The data reported here represent the identification and detailed analysis of a 1. 1-kilobase (kb) sequence located 3.4-kb upstream of the transcription initiation site of the murine Ada gene, which is sufficient to target cat reporter gene expression to the forestomach in transgenic mice. This 1.1-kb fragment is capable of directing cat reporter gene expression mainly to the forestomach of transgenic mice, with a level comparable to the endogenous Ada gene. This expression is localized to the appropriate cell types, confers copy number dependence, and shows the same developmental regulation. Mutational analysis revealed the functional importance of multiple transcription factor-binding sites.


Designs for mechanical circulatory support device studies.
There is increased interest in mechanical circulatory support devices (MCSDs), such as implantable left ventricular assist devices (LVADs), as "destination" therapy for patients with advanced heart failure. Because patient availability to evaluate these devices is limited and randomized trials have been slow in enrolling patients, a workshop was convened to consider designs for MCSD development including alternatives to randomized trials. A workshop was jointly planned by the Heart Failure Society of America and the US Food and Drug Administration and was convened in March 2006. One of the panels was asked to review different designs for evaluating new MCSDs. Randomized trials have many advantages over studies with no controls or with nonrandomized concurrent or historical controls. These advantages include the elimination of bias in the assignment of treatments and the balancing, on average, of known and unknown baseline covariates that influence response. These advantages of randomization are particularly important for studies in which the treatments may not differ from one another by a large amount (eg, a head-to-head study of an approved LVAD with a new LVAD). However, researchers have found it difficult to recruit patients to randomized studies because the number of clinical sites that can carry out the studies is not large. Also, there is a reluctance to randomize patients when the control device is considered technologically inferior. Thus ways of improving the design of randomized trials were discussed, and the advantages and disadvantages of alternative designs were considered. The panel concluded that designs should include a randomized component. Randomized designs might be improved by allowing the control device to be chosen before randomization, by first conducting smaller vanguard studies, and by allowing crossovers in trials with optimal medical management controls. With use of data from completed trials, other databases, and registries, alternative designs that include both a randomized component (eg, 2:1 allocation for new device versus control) and a nonrandomized component (eg, concurrent nonrandomized control, historical control, or a comprehensive cohort design) should be evaluated. This will require partnerships among academic, government, and industry scientists.


Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.
To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers. One stage meta-analysis of individual patient data. A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer. Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded. Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18). Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.


Interventions for preventing and treating low-back and pelvic pain during pregnancy.
More than two-thirds of pregnant women experience low-back pain and almost one-fifth experience pelvic pain. The two conditions may occur separately or together (low-back and pelvic pain) and typically increase with advancing pregnancy, interfering with work, daily activities and sleep. To update the evidence assessing the effects of any intervention used to prevent and treat low-back pain, pelvic pain or both during pregnancy. We searched the Cochrane Pregnancy and Childbirth (to 19 January 2015), and the Cochrane Back Review Groups' (to 19 January 2015) Trials Registers, identified relevant studies and reviews and checked their reference lists. Randomised controlled trials (RCTs) of any treatment, or combination of treatments, to prevent or reduce the incidence or severity of low-back pain, pelvic pain or both, related functional disability, sick leave and adverse effects during pregnancy. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We included 34 RCTs examining 5121 pregnant women, aged 16 to 45 years and, when reported, from 12 to 38 weeks' gestation. Fifteen RCTs examined women with low-back pain (participants = 1847); six examined pelvic pain (participants = 889); and 13 examined women with both low-back and pelvic pain (participants = 2385). Two studies also investigated low-back pain prevention and four, low-back and pelvic pain prevention. Diagnoses ranged from self-reported symptoms to clinicians' interpretation of specific tests. All interventions were added to usual prenatal care and, unless noted, were compared with usual prenatal care. The quality of the evidence ranged from moderate to low, raising concerns about the confidence we could put in the estimates of effect. For low-back painResults from meta-analyses provided low-quality evidence (study design limitations, inconsistency) that any land-based exercise significantly reduced pain (standardised mean difference (SMD) -0.64; 95% confidence interval (CI) -1.03 to -0.25; participants = 645; studies = seven) and functional disability (SMD -0.56; 95% CI -0.89 to -0.23; participants = 146; studies = two). Low-quality evidence (study design limitations, imprecision) also suggested no significant differences in the number of women reporting low-back pain between group exercise, added to information about managing pain, versus usual prenatal care (risk ratio (RR) 0.97; 95% CI 0.80 to 1.17; participants = 374; studies = two). For pelvic painResults from a meta-analysis provided low-quality evidence (study design limitations, imprecision) of no significant difference in the number of women reporting pelvic pain between group exercise, added to information about managing pain, and usual prenatal care (RR 0.97; 95% CI 0.77 to 1.23; participants = 374; studies = two). For low-back and pelvic painResults from meta-analyses provided moderate-quality evidence (study design limitations) that: an eight- to 12-week exercise program reduced the number of women who reported low-back and pelvic pain (RR 0.66; 95% CI 0.45 to 0.97; participants = 1176; studies = four); land-based exercise, in a variety of formats, significantly reduced low-back and pelvic pain-related sick leave (RR 0.76; 95% CI 0.62 to 0.94; participants = 1062; studies = two).The results from a number of individual studies, incorporating various other interventions, could not be pooled due to clinical heterogeneity. There was moderate-quality evidence (study design limitations or imprecision) from individual studies suggesting that osteomanipulative therapy significantly reduced low-back pain and functional disability, and acupuncture or craniosacral therapy improved pelvic pain more than usual prenatal care. Evidence from individual studies was largely of low quality (study design limitations, imprecision), and suggested that pain and functional disability, but not sick leave, were significantly reduced following a multi-modal intervention (manual therapy, exercise and education) for low-back and pelvic pain.When reported, adverse effects were minor and transient. There is low-quality evidence that exercise (any exercise on land or in water), may reduce pregnancy-related low-back pain and moderate- to low-quality evidence suggesting that any exercise improves functional disability and reduces sick leave more than usual prenatal care. Evidence from single studies suggests that acupuncture or craniosacral therapy improves pregnancy-related pelvic pain, and osteomanipulative therapy or a multi-modal intervention (manual therapy, exercise and education) may also be of benefit.Clinical heterogeneity precluded pooling of results in many cases. Statistical heterogeneity was substantial in all but three meta-analyses, which did not improve following sensitivity analyses. Publication bias and selective reporting cannot be ruled out.Further evidence is very likely to have an important impact on our confidence in the estimates of effect and change the estimates. Studies would benefit from the introduction of an agreed classification system that can be used to categorise women according to their presenting symptoms, so that treatment can be tailored accordingly.


Knowledge and attitudes of students at a Caribbean offshore medical school towards sexually transmitted infections and use of condoms.
Sexually transmitted infections remain one of the predominant health issues that affect young adults. The aim of this study is to assess the level of knowledge, the attitudes and misconceptions of medical students at a Caribbean University towards STIs and condom use. A cross-sectional descriptive study was carried out among medical students by employing semi-structured questionnaires. Out of 150 questionnaires, 130 were completed, showing a response rate of 87%. The ages of the respondents ranged from 19 to 45 years with a mean age of 26 (SD 5.2) years. The findings indicated that the knowledge of students concerning STIs is high (95.4%). Twenty-four (18.5%) of the respondents had experienced vaginal/penile discharge following sexual intercourse over the last 6 months. The correlation of beliefs in condom usage and risky behaviour gives an odds ratio of 0.19 indicating a lower use of condoms among the students. A negative attitude towards condom usage was seen in 3.8% of the respondents. The main reason for condom usage was to prevent unwanted pregnancy and not to prevent contracting sexually transmitted infections. The knowledge of students about STIs in this study was found to be high, however risky behaviour such as having sexual intercourse with commercial sex-workers and regular unprotected sexual activities were identified although the prevalence of such behaviour was found to be low. We therefore recommend that behaviour modification programmes with regard to sex education and condom usage be implemented for the medical students as they are to be the future educators of the public on these matters.


Association between polypharmacy and the persistence of delirium: a retrospective cohort study.
Although the association between polypharmacy and the occurrence of delirium has been well studied, the influence of polypharmacy on the persistence of delirium remains unclear. We aimed to explore the effect of polypharmacy on the persistence of delirium. This retrospective cohort study was conducted at a tertiary hospital. The medical records of patients diagnosed with delirium who were referred to the Department of Psychosomatic Medicine were reviewed. Presentation with delirium on day 3 was set as the outcome in this study. We counted the number of drugs prescribed on the date of referral, excluding general infusion fluids, nutritional or electrolytic products, and psychotropics. To define polypharmacy, we developed a classification and regression tree (CART) model and drew a receiver operating characteristic (ROC) curve. The odds ratio (OR) of polypharmacy for the persistence of delirium on day 3 was calculated using a logistic regression model with the propensity score as a covariate. We reviewed the data of 113 patients. The CART model and ROC curve indicated an optimal polypharmacy cutoff of six drugs. Polypharmacy was significantly associated with the persistence of delirium both before [OR, 3.02; 95% confidence interval (CI), 1.39-6.81; P = 0.0062] and after (OR, 3.19; 95% CI, 1.32-8.03; P = 0.011) propensity score adjustment. We discovered an association between polypharmacy and worsening courses of delirium and hypothesize that polypharmacy might be a prognostic factor for delirium.


Microarray analysis of neural stem cell differentiation in the striatum of the fetal rat.
1. Gene expression profiles in neural stem cell differentiation in vitro were determined by cDNA microarray analysis. 2. Total RNA was extracted and reverse transcripted into cDNA from differentiated and undifferentiated neural stem cells. The 33P labeled cDNA was hybridized with a cDNA microarray consisting of 14,000 human genes. 3. The results showed that a total of 1406 genes were differentially expressed, of which 148 genes exhibited more than twofold differences. Some genes were obviously activated while others were strongly repressed. These changes in gene expression suggest that differentiation is regulated by different genes at different expressional levels. By biological classification, the differentially expressed genes were divided into four functional categories: molecular function, biological process, cellular component, and new functional genes or ESTs. 4. These findings will be a valuable contribution for gene expression profiling and elucidation of neural stem cell differentiation mechanisms.


Problem-based learning in academic health education. A systematic literature review.
Problem based learning (PBL) arguably represents the most significant development in education over the past five decades. It has been promoted as the curriculum of choice, and since its introduction in the 1960's, has been widely adopted by many medical and dental schools. PBL has been the subject of much published literature but ironically, very little high quality evidence exists to advocate its efficacy and subsequently justify the widespread curriculum change. The purpose of this review is to classify and interpret the available evidence and extract relevant conclusions. In addition, it is the intent to propose recommendations regarding the relative benefits of PBL compared with conventional teaching. The literature was searched using PubMed, ERIC and PsycLIT. Further articles were retrieved from the reference lists of selected papers. Articles were chosen and included according to specific selection criteria. Studies were further classified as randomised controlled trials (RCTs) or comparative studies. These studies were then analysed according to intervention type: whole curricula comparisons and single educational interventions of shorter duration. At the level of RCTs and comparative studies (whole curricula), no clear difference was observed between PBL and conventional teaching. Paradoxically, it was only comparative studies of single PBL intervention in a traditional curriculum that yielded results that were consistently in favour of PBL. Further research is needed to investigate the possibility that multiple PBL interventions in a traditional curriculum could be more effective than an exclusively PBL programme. In addition, it is important to address the potential benefits of PBL in relation to life-long learning of health care professionals.


Mobile phone and cordless phone use and the risk for glioma - Analysis of pooled case-control studies in Sweden, 1997-2003 and 2007-2009.
We made a pooled analysis of two case-control studies on malignant brain tumours with patients diagnosed during 1997-2003 and 2007-2009. They were aged 20-80 years and 18-75 years, respectively, at the time of diagnosis. Only cases with histopathological verification of the tumour were included. Population-based controls, matched on age and gender, were used. Exposures were assessed by questionnaire. The whole reference group was used in the unconditional regression analysis adjusted for gender, age, year of diagnosis, and socio-economic index. In total, 1498 (89%) cases and 3530 (87%) controls participated. Mobile phone use increased the risk of glioma, OR=1.3, 95% CI=1.1-1.6 overall, increasing to OR=3.0, 95% CI=1.7-5.2 in the >25 year latency group. Use of cordless phones increased the risk to OR=1.4, 95% CI=1.1-1.7, with highest risk in the >15-20 years latency group yielding OR=1.7, 95% CI=1.1-2.5. The OR increased statistically significant both per 100h of cumulative use, and per year of latency for mobile and cordless phone use. Highest ORs overall were found for ipsilateral mobile or cordless phone use, OR=1.8, 95% CI=1.4-2.2 and OR=1.7, 95% CI=1.3-2.1, respectively. The highest risk was found for glioma in the temporal lobe. First use of mobile or cordless phone before the age of 20 gave higher OR for glioma than in later age groups.