Origin and evolution of the genus Piper in Peninsular India.
The evolution of Peninsular Indian biodiversity has been a fascinating topic of research due to historical connections of this region to the ancient Gondwanaland. We investigated the phylogeny and historical biogeography of nearly all extant species of the genus Piper reported from the region to assess the biogeographical origins and test mechanisms of lineage diversification (dispersal, vicariance and in situ radiation) of this highly diverse genus of angiosperms commonly found in the understory of evergreen forests. The phylogeny of 21 species of Piper reported from Peninsular India was reconstructed for the first time, which included three new putative species from the Western Ghats. We used BEAST for the divergence time estimations (using three constraints), and ancestral range estimations were performed with the dated phylogenetic tree using BIOGEOBEARS. Divergence dating analysis revealed that the genus Piper originated during lower Cretaceous around 110 Ma [95% highest posterior density (HPD): 116-105 Ma] and colonized Peninsular India five times independently, from Southeast Asia starting from the Oligocene. The two major dispersals into India occurred during the periods of 27.3 Ma (95% HPD: 35.8-19.9.) and 15.5 Ma (95% HPD: 24.9-7.11). This was followed by rapid radiations in some lineages with subsequent back dispersals to Southeast Asia. Our study indicates that dispersals from Southeast Asia led to the arrival of Piper to Indian subcontinent following the Indo-Eurasian collision. Members of Piper have colonized and diversified within the climatically stable habitats of Peninsular India. Furthermore, the present study provides evidence for the Miocene overland dispersal of Piper species to Africa from South Asia.


Effects of 20-s and 180-s double poling interval training in cross-country skiers.
The purpose of this study was to investigate the effect of upper body 20-s or 180-s interval training, using a double poling ergometer, on upper body power output and selected physiological and biomechanical parameters in cross-country skiers. Twenty (12 male, 8 female) well-trained cross-country skiers took part. Two intervention groups, a 20-s interval training group (IT20; n=6) and a 180-s interval training group (IT180; n=7), underwent training three times a week for 6 weeks on a double poling ergometer. A third group served as a control (CON; n=7) and followed the same training program as the IT20 and IT180 groups without the double poling ergometer interval training. The IT20 and IT180 groups significantly (P<0.05) increased both peak and mean power in a 30-s test and mean power in a 6-min test after double poling training. There was a significant improvement in work efficiency in both IT20 and IT180 (P<0.05) and, in IT180, a significant reduction (P<0.05) in blood lactate concentration at given sub-maximal workloads. VO(2peak) increased significantly during double poling in IT180 ( P<0.05) only. VO(2max) did not change significantly in either group. There were no significant changes in any of the test variables in CON. In conclusion, this study shows that 6 weeks of 20-s or 180-s double poling interval training, three times a week, significantly increases power output in both 30-s and 6-min tests, as well as in selected physiological and biomechanical parameters in well-trained cross-country skiers.


Differential effect of the 5-HTT gene-linked polymorphic region on emotional eating during stress exposure following tryptophan challenge.
Stress and negative moods, which are thought to be partly mediated by reduced brain serotonin function, often increase emotional eating in dieting women (restrainers). Because the short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) is associated with serotonin dysfunction, S allele compared to long (L) allele 5-HTTLPR genotypes may be more susceptible to stress-induced emotional eating. Consequently, serotonin challenge via tryptophan (TRP)-rich protein hydrolysate (TPH) may alleviate stress-induced emotional eating particularly in S/S allele carriers. We tested whether acute stress affects emotional eating in women with high or low dietary restraints depending on their 5-HTTLPR genotype and TPH intake. Nineteen female subjects who were homozygous for the short-allele 5-HTTLPR genotype (S'/S'=S/L(G), L(G)/L(G): restrainers vs. nonrestrainers) and 23 female subjects who were homozygous for the long-allele 5-HTTLPR genotype (L'/L'=L(A)/L(A): restrainers vs. nonrestrainers) were tested in a double-blind, placebo-controlled crossover study of stress-induced emotional eating following intake of TPH or a placebo. TPH intake significantly increased the plasma TRP/large neutral amino acid ratio (P<.0001) in the L'/L' group (70%) compared to the S'/S' group (30%). TPH reduced food intake in both groups, but in the L'/L' group, it also reduced stress-induced negative mood (P=.037) and the desire for sweet, high-fat foods (P=.011) regardless of dietary restraint. Since TPH caused a greater increase in the plasma TRP/large neutral amino acid ratio in the L'/L' group compared to S'/S' group, the exclusive beneficial effects of L'/L' genotype may be due to enhanced brain 5-HT function.


Genetic diversity of culturable Vibrio in an Australian blue mussel Mytilus galloprovincialis hatchery.
Bacillary necrosis associated with Vibrio species is the common cause of larval and spat mortality during commercial production of Australian blue mussel Mytilus galloprovincialis. A total of 87 randomly selected Vibrio isolates from various stages of rearing in a commercial mussel hatchery were characterised using partial sequences of the ATP synthase alpha subunit gene (atpA). The sequenced isolates represented 40 unique atpA genotypes, overwhelmingly dominated (98%) by V. splendidus group genotypes, with 1 V. harveyi group genotype also detected. The V. splendidus group sequences formed 5 moderately supported clusters allied with V. splendidus/V. lentus, V. atlanticus, V. tasmaniensis, V. cyclitrophicus and V. toranzoniae. All water sources showed considerable atpA gene diversity among Vibrio isolates, with 30 to 60% of unique isolates recovered from each source. Over half (53%) of Vibrio atpA genotypes were detected only once, and only 7 genotypes were recovered from multiple sources. Comparisons of phylogenetic diversity using UniFrac analysis showed that the culturable Vibrio community from intake, header, broodstock and larval tanks were phylogenetically similar, while spat tank communities were different. Culturable Vibrio associated with spat tank seawater differed in being dominated by V. toranzoniae-affiliated genotypes. The high diversity of V. splendidus group genotypes detected in this study reinforces the dynamic nature of microbial communities associated with hatchery culture and complicates our efforts to elucidate the role of V. splendidus group bacteria in vibriosis.


Photooxidative stress-inducible orange and pink water-soluble astaxanthin-binding proteins in eukaryotic microalga.
Lipid astaxanthin, a potent antioxidant known as a natural sunscreen, accumulates in eukaryotic microalgae and confers photoprotection. We previously identified a photooxidative stress-inducible water-soluble astaxanthin-binding carotenoprotein (AstaP) in a eukaryotic microalga (Coelastrella astaxanthina Ki-4) isolated from an extreme environment. The distribution in eukaryotic microalgae remains unknown. Here we identified three novel AstaP orthologs in a eukaryotic microalga, Scenedesmus sp. Oki-4N. The purified proteins, named AstaP-orange2, AstaP-pink1, and AstaP-pink2, were identified as secreted fasciclin proteins with potent 1O2 quenching activity in aqueous solution, which are characteristics shared with Ki-4 AstaP. Nonetheless, the absence of glycosylation in the AstaP-pinks, the presence of a glycosylphosphatidylinositol (GPI) anchor motif in AstaP-orange2, and highly acidic isoelectric points (pI = 3.6-4.7), differed significantly from that of AstaP-orange1 (pI = 10.5). These results provide unique examples on the use of water-soluble forms of astaxanthin in photosynthetic organisms as novel strategies for protecting single cells against severe photooxidative stresses.


Ku70, an essential gene, modulates the frequency of rAAV-mediated gene targeting in human somatic cells.
Gene targeting has two important applications. One is the inactivation of genes ("knockouts"), and the second is the correction of a mutated allele back to wild-type ("gene therapy"). Central to these processes is the efficient introduction of the targeting DNA into the cells of interest. In humans, this targeting is often accomplished through the use of recombinant adeno-associated virus (rAAV). rAAV is presumed to use a pathway of DNA double-strand break (DSB) repair termed homologous recombination (HR) to mediate correct targeting; however, the specifics of this mechanism remain unknown. In this work, we attempted to generate Ku70-null human somatic cells by using a rAAV-based gene knockout strategy. Ku70 is the heterodimeric partner of Ku86, and together they constitute an end-binding activity that is required for a pathway [nonhomologous end joining (NHEJ)] of DSB repair that is believed to compete with HR. Our data demonstrated that Ku70 is an essential gene in human somatic cells. More importantly, however, in Ku70(+/-) cells, the frequency of gene targeting was 5- to 10-fold higher than in wild-type cells. RNA interference and short-hairpinned RNA strategies to deplete Ku70 phenocopied these results in wild-type cells and greatly accentuated them in Ku70(+/-) cell lines. Thus, Ku70 protein levels significantly influenced the frequency of rAAV-mediated gene targeting in human somatic cells. Our data suggest that gene-targeting frequencies can be significantly improved in human cells by impairing the NHEJ pathway, and we propose that Ku70 depletion can be used to facilitate both knockout and gene therapy approaches.


The Epidemiology of Lung Metastases.
Introduction: Lung metastasis is usually associated with poor outcomes in cancer patients. This study was performed to characterize and analyze the population of patients with de novo (synchronous) lung metastases using the Surveillance, Epidemiology and End Results (SEER) database. Materials and Methods: Baseline characteristics of lung metastasis patients were obtained from SEER case listings. Incidence rates and counts of synchronous lung metastasis were also obtained using the SEER*Stat software. Survival outcomes were analyzed using univariate and multivariable Cox regressions, controlling for confounders. An alpha threshold of 0.05 was used for statistical significance and p-values were subject to correction for multiple comparisons. Results: The age-adjusted incidence rate of synchronous lung metastasis was 17.92 per 100,000 between 2010 and 2015. Synchronous lung metastases most commonly arose from primary lung cancers, colorectal cancers, kidney cancers, pancreatic cancers and breast cancers. During this time period, 4% of all cancer cases presented with synchronous lung metastasis. The percentage of patients presenting with synchronous lung metastasis ranged from 0.5% of all prostate cancers to 13% of all primary lung cancers. The percentage of all cancer cases presenting with synchronous lung metastasis increased over time. De novo metastatic patients with lung metastases had worse overall survival [hazard ratio = 1.22 (1.21-1.23), p < 0.001] compared to those with only extrapulmonary metastases, controlling for potential confounders. Conclusions: Synchronous lung metastasis occurs frequently and is an independent predictors of poor patient outcomes. As treatment for lung metastases becomes more complicated, patients with synchronous lung metastasis represent a high-risk population.


Resolving Rapid Radiations within Angiosperm Families Using Anchored Phylogenomics.
Despite the promise that molecular data would provide a seemingly unlimited source of independent characters, many plant phylogenetic studies are still based on only two regions, the plastid genome and nuclear ribosomal DNA (nrDNA). Their popularity can be explained by high-copy numbers and universal polymerase chain reaction (PCR) primers that make their sequences easily amplified and converted into parallel datasets. Unfortunately, their utility is limited by linked loci and limited characters resulting in low confidence in the accuracy of phylogenetic estimates, especially when rapid radiations occur. In another contribution on anchored phylogenomics in angiosperms, we presented flowering plant-specific anchored enrichment probes for hundreds of conserved nuclear genes and demonstrated their use at the level of all angiosperms. In this contribution, we focus on a common problem in phylogenetic reconstructions below the family level: Weak or unresolved backbone due to rapid radiations ($\leqslant $10 million years) followed by long divergence, using the Cariceae-Dulichieae-Scirpeae (CDS, Cyperaceae) clade as a test case. By comparing our nuclear matrix of 461 genes to a typical Sanger-sequence dataset consisting of a few plastid genes (matK, ndhF) and an nrDNA marker (ETS), we demonstrate that our nuclear data is fully compatible with the Sanger dataset and resolves short backbone internodes with high support in both concatenated and coalescence-based analyses. In addition, we show that nuclear gene tree incongruence is inversely proportional to phylogenetic information content, indicating that incongruence is mostly due to gene tree estimation error. This suggests that large numbers of conserved nuclear loci could produce more accurate trees than sampling rapidly evolving regions prone to saturation and long-branch attraction. The robust phylogenetic estimates obtained here, and high congruence with previous morphological and molecular analyses, are strong evidence for a complete tribal revision of CDS clade. The anchored hybrid enrichment probes used in this study should be similarly effective in other flowering plant groups.


Behaviour changes in dementia. 2: Are there behavioural syndromes?
To establish whether robust behavioural 'syndromes' can be identified from among the widely heterogeneous behavioural changes which occur in dementia. Longitudinal, prospective study with follow-up at 4 and 8 months. Community settings in Oxfordshire, UK. 97 elderly people with a diagnosis of Alzheimer's disease or vascular dementia (in many cases confirmed by postmortem examination) and who were living at home with a carer. Each subject's behaviour was assessed in detail at each interview using the Present Behavioural Examination to assess subject's behaviour over the preceding 4 weeks. Seventeen key behaviour items which were both common and clinically important were selected for further analysis. Three syndromes were identified: (a) overactivity (walking more, walking aimlessly, trailing the carer or checking where the carer was); (b) aggressive behaviour (physical aggression, aggressive resistance, verbal aggression); (c) psychosis (anxiety, persecutory ideas and hallucinations). The same syndromes were found using data collected at three different time points and by using a variety of statistical techniques, confirming their robustness. Overactivity, aggressive behaviour and psychosis form three distinct behavioural syndromes in dementia.


Self-management in osteoarthritis of hip or knee: a randomized clinical trial in a primary healthcare setting.
To assess in a primary healthcare setting the efficacy of a self-management program in middle-aged patients with osteoarthritis (OA). This was a 2-group randomized controlled trial, with 273 patients aged 40 to 60 years with OA of the hip(s) and/or knee(s). The experimental intervention was compared with care-as-usual. Treatments and followup measurements were performed in a general healthcare setting by general practitioners. Duration of followup was 21 months after start of the intervention. Instruction in self-management techniques was given by physiotherapists. The main outcome measures were pain severity in hips and knees, other significant complaints, and functional limitations. To begin, 297 patients were randomized: 149 as self-management and 148 controls; before the intervention 24 withdrew for practical reasons (17 self-management, 7 controls). At 3-month followup the intervention group was significantly improved on a visual analog scale (VAS) for knee pain (score 0.67; SD 2.10) and the WOMAC (score 2.46; SD 9.49), while the control group showed stable VAS knee pain (0.01; SD 2.00) and deterioration on WOMAC (-0.53; SD 9.47). At 21-month followup the differences between the groups increased in favor of the intervention group (VAS pain knee: p values from 0.023 at 3 mo to 0.004 at 21 mo; WOMAC: p values from 0.030 to 0.022). The self-management program positively influenced knee pain and self-reported functional level in this sample of patients with OA. Differences between the study groups increased during followup in favor of the intervention group.


Do common mechanisms of adaptation mediate color discrimination and appearance? Uniform backgrounds.
Color vision is useful for detecting surface boundaries and identifying objects. Are the signals used to perform these two functions processed by common mechanisms, or has the visual system optimized its processing separately for each task? We measured the effect of mean chromaticity and luminance on color discriminability and on color appearance under well-matched stimulus conditions. In the discrimination experiments, a pedestal spot was presented in one interval and a pedestal + test in a second. Observers indicated which interval contained the test. In the appearance experiments, observers matched the appearance of test spots across a change in background. We analyzed the data using a variant of Fechner's proposal, that the rate of apparent stimulus change is proportional to visual sensitivity. We found that saturating visual response functions together with a model of adaptation that included multiplicative gain control and a subtractive term accounted for data from both tasks. This result suggests that effects of the contexts we studied on color appearance and discriminability are controlled by the same underlying mechanism.


Bio-functionalisation of polydimethylsiloxane with hyaluronic acid and hyaluronic acid--collagen conjugate for neural interfacing.
In this work, polydimethylsiloxane was activated with oxygen plasma and treated with silanes bearing ethylene imine units. Hyaluronic acid was then grafted covalently onto the aminated surfaces. The influence of silane structure on surface amination was assessed and the influence of the modification on surface physiochemical properties and protein adsorption of modified polydimethylsiloxane were investigated. Collagen type I was conjugated onto the modified polydimethylsiloxane to improve its cyto-compatibility for neural applications. In vitro cultivation of rat pheochromocytoma cells on the bioactive polydimethylsiloxane showed a significant increase in cell growth and differentiation. The potential applications of the bio-functionalized polydimethylsiloxane in cochlear implant electrode arrays were discussed.


A granular activated carbon/electrochemical hybrid system for onsite treatment and reuse of blackwater.
Over 1/3 of the global population lacks access to improved sanitation, leading to disease, death, and impaired economic development. Our group is working to develop rapidly deployable, cost-effective, and sustainable solutions to this global problem that do not require significant investments in infrastructure. Previously, we demonstrated the feasibility of a toilet system that recycles blackwater for onsite reuse as flush water, in which the blackwater is electrochemically treated to remove pathogens due to fecal contamination. However, this process requires considerable energy (48-93 kJ/L) to achieve complete disinfection of the process liquid, and the disinfected liquid retains color and chemical oxygen demand (COD) in excess of local discharge standards, negatively impacting user acceptability. Granular activated carbon (GAC) efficiently reduces COD in concentrated wastewaters. We hypothesized that reduction of COD with GAC prior to electrochemical treatment would both improve disinfection energy efficiency and user acceptability of the treated liquid. Here we describe the development and testing of a hybrid system that combines these technologies and demonstrate its ability to achieve full disinfection with improved energy efficiency and liquid quality more suitable for onsite reuse and/or discharge.


Synthetic lethality in CCNE1-amplified high grade serous ovarian cancer through combined inhibition of Polo-like kinase 1 and microtubule dynamics.
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.


A Fast Likelihood Method to Reconstruct and Visualize Ancestral Scenarios.
The reconstruction of ancestral scenarios is widely used to study the evolution of characters along phylogenetic trees. One commonly uses the marginal posterior probabilities of the character states, or the joint reconstruction of the most likely scenario. However, marginal reconstructions provide users with state probabilities, which are difficult to interpret and visualize, whereas joint reconstructions select a unique state for every tree node and thus do not reflect the uncertainty of inferences. We propose a simple and fast approach, which is in between these two extremes. We use decision-theory concepts (namely, the Brier score) to associate each node in the tree to a set of likely states. A unique state is predicted in tree regions with low uncertainty, whereas several states are predicted in uncertain regions, typically around the tree root. To visualize the results, we cluster the neighboring nodes associated with the same states and use graph visualization tools. The method is implemented in the PastML program and web server. The results on simulated data demonstrate the accuracy and robustness of the approach. PastML was applied to the phylogeography of Dengue serotype 2 (DENV2), and the evolution of drug resistances in a large HIV data set. These analyses took a few minutes and provided convincing results. PastML retrieved the main transmission routes of human DENV2 and showed the uncertainty of the human-sylvatic DENV2 geographic origin. With HIV, the results show that resistance mutations mostly emerge independently under treatment pressure, but resistance clusters are found, corresponding to transmissions among untreated patients.


Among the severely mentally ill, who responds to ziprasidone?
So far, demographic variables have not consistently been found to predict clinical response to antipsychotics. This study examines some differences in response to ziprasidone, which has been shown to be effective, with a better metabolic side effect profile, but was little used in New York State Hospitals. The aim was to study state hospital patients switched to ziprasidone. The results led to questions about different responses in different groups. Subjects from state hospitals who needed a change of antipsychotic participated in this openlabel 8 week trial of up to 240 mg ziprasidone. Analyses included comparisons of the very different results from two sites. Of the 36 study subjects, 12 terminated early. The 17 outpatients from Buffalo, who were older and on lower doses of antipsychotics pre-study, improved significantly. The 19 inpatients from the Bronx, overall younger and on higher pre-study doses, barely changed. Improvements in PANSS total score were significantly associated with older age, greater baseline severity, and lower doses of antipsychotics pre-study. The subjects improved on metabolic parameters. The results suggest that ziprasidone may be just as effective as previous antipsychotics taken by these severely mentally ill patients, and with fewer metabolic side effects.


Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity.
Patient-reported quality of life (QOL) is a highly prognostic and clinically relevant endpoint in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The relationships between QOL and different markers of HF severity remain unclear, particularly as they relate to functional capacity and directly measured activity levels. We hypothesized that QOL would demonstrate a stronger relationship with measures of exercise capacity and adiposity compared to other disease measures. This is a secondary analysis of the National Heart, Lung, and Blood Institute-sponsored RELAX, NEAT-HFpEF and INDIE-HFpEF trials to determine the relationships between QOL (assessed by the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire) and different domains reflecting HF severity, including maximal aerobic capacity (peak oxygen consumption), submaximal exercise capacity (6-min walk distance), volume of daily activity (accelerometry), physician-estimated functional class, resting echocardiography, and plasma natriuretic peptide levels. A total of 408 unique patients with chronic HFpEF were split into tertiles of QOL scores defined as QOLworst, QOLintermediate , QOLbest . The QOLworst HFpEF group was youngest, with a higher body mass index, greater prevalence of class II obesity and diabetes, and the lowest N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. After adjustment for age, sex and body mass index, poorer QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen consumption, 6-min walk distance and actigraphy, but was not associated with NT-proBNP or indices from resting echocardiography. QOL was similarly reduced in patients with and without prior HF hospitalization. Quality of life in HFpEF is poorest in patients who are young, obese and have diabetes, and is more robustly tied to measures reflecting functional capacity and daily activity levels rather than elevations in NT-proBNP or prior HF hospitalization. These findings have major implications for the understanding of QOL in HFpEF and for the design of future clinical trials targeting symptom improvement in HFpEF. RELAX, NCT00763867; NEAT-HFpEF, NCT02053493; INDIE-HFpEF, NCT02742129.


Second-generation corticosteroids for the treatment of Crohn's disease and ulcerative colitis: more effective and less side effects?
Systemic corticosteroids are highly effective at inducing clinical remission in cases of acute exacerbation of Crohn's disease (CD) and ulcerative colitis (UC); however, their use is limited by their frequent and sometimes severe side effects. Thus, a second generation of corticosteroids with less systemic effects has been developed. This review analyzed all of the studies on the new formulations of steroids with limited absorption (budesonide, budesonide MMX®, beclomethasone dipropionate and erythrocyte-mediated delivery of dexamethasone) in patients with CD and UC. All relevant articles published in English between September 1960 and April 2011 were reviewed. Budesonide is superior to placebo, and as effective as systemic corticosteroids in inducing clinical remission in patients with ileo-colonic CD, but evidence of mucosal healing is limited. When administered as an MMX formula, budesonide can also effectively induce clinical remission in patients with UC, but budesonide alone is not effective in maintaining clinical remission in CD or UC. Beclomethasone dipropionate seems to be effective in patients with mild-to-moderate left-sided and extensive UC, while data on erythrocyte-mediated delivery of dexamethasone are encouraging but still limited. The safety profile for all these products is good but more studies are needed. Steroids remain the mainstay for the induction of clinical remission in cases of acute relapse of both CD and UC. Second-generation corticosteroids are an interesting alternative, with the advantage of high topical activity, less systemic toxicity and limited side effects.


A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial.
The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain dietary supplement (Instaflex™ Joint Support, Direct Digital, Charlotte, NC) compared to placebo on joint pain, stiffness, and function in adults with self-reported joint pain. Instaflex™ is a joint pain supplement containing glucosamine sulfate, methylsufonlylmethane (MSM), white willow bark extract (15% salicin), ginger root concentrate, boswella serrata extract (65% boswellic acid), turmeric root extract, cayenne, and hyaluronic acid. Subjects included 100 men and women, ages 50-75 years, with a history (>3 months) of joint pain, and were randomized to Instaflex™ or placebo (3 colored gel capsules per day for 8 weeks, double-blind administration). Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs (NSAID) and all other medications and supplements targeted for joint pain. Primary outcome measures were obtained pre- and post-study and included joint pain severity, stiffness, and function (Western Ontario and McMaster Universities [WOMAC]), and secondary outcome measures included health-related quality of life (Short Form 36 or SF-36), systemic inflammation (serum C-reactive protein and 9 plasma cytokines), and physical function (6-minute walk test). Joint pain symptom severity was assessed bi-weekly using a 12-point Likert visual scale (12-VS). Joint pain severity was significantly reduced in Instaflex™ compared to placebo (8-week WOMAC, ↓37% versus ↓16%, respectively, interaction effect P = 0.025), with group differences using the 12-VS emerging by week 4 of the study (interaction effect, P = 0.0125). Improvements in ability to perform daily activities and stiffness scores in Instaflex™ compared to placebo were most evident for the 74% of subjects reporting knee pain (8-week WOMAC function score, ↓39% versus ↓14%, respectively, interaction effect P = 0.027; stiffness score, ↓30% versus ↓12%, respectively, interaction effect P = 0.081). Patterns of change in SF-36, systemic inflammation biomarkers, and the 6-minute walk test did not differ significantly between groups during the 8-week study Results from this randomized, double blind, placebo-controlled community trial support the use of the Instaflex™ dietary supplement in alleviating joint pain severity in middle-aged and older adults, with mitigation of difficulty performing daily activities most apparent in subjects with knee pain.


Evaluation of udder health parameters and risk factors for clinical mastitis in Dutch dairy herds in the context of a restricted antimicrobial usage policy.
Recently, many changes have been implemented in Dutch dairy herds. Herd sizes have increased and antimicrobial use has been reduced. Certain types of antimicrobials can only be used in specific circumstances, and the preventive use of antimicrobials in dry cows is prohibited. The aim of this study was to quantify clinical mastitis (CM), subclinical mastitis (SCM), and risk factors associated with CM in Dutch dairy herds in 2013, in the context of these changes. For this study, 240 dairy herds were randomly selected from farms that participated in test-day milk recording, used a conventional milking system, and agreed to participate in the study. Eventually, 233 Dutch dairy farmers had complete records of CM in their herds in 2013 and 224 of these farmers completed a questionnaire on management factors potentially associated with CM. All participating farmers gave consent to use their routinely collected herd data such as test-day records and cow identification and registration data. Clinical and subclinical mastitis incidence rate (CMI and SCMI, respectively) per 100 cows per year, subclinical mastitis prevalence, and average bulk tank milk somatic cell count were obtained for 2013. The risk factor analysis was conducted using a generalized linear model with a log link function and a negative binomial distribution on herd level in Stata 13.1. A median CMI of 28.6 per 100 cows at risk per year, SCMI of 70.1 per 100 cows at risk per year, SCM prevalence of 15.8%, and bulk tank milk somatic cell count of 171 × 10(3) cells/mL were observed in 2013. Factors that were significantly associated with a higher CMI were cleaning slatted floors only once per day compared with more than 4 times a day (i.e., mechanical), a higher percentage of Holstein Friesian cows present in the herd, treating less than 50% of the cows with CM with antimicrobials, postmilking teat disinfection, and treatment of cows with elevated somatic cell count with antimicrobials. The results of this study indicated that udder health had not deteriorated compared with udder health in previous Dutch studies where herd sizes were somewhat smaller and before the restrictions in antimicrobial use. Several of the risk factors that were found can be influenced by the farmer and can prevent the occurrence of CMI. Still, when cases of CM occur, treatment with antimicrobials might be necessary to cure the CM case and is beneficial for the overall udder health in the herd.


Children with major depression show reduced rapid eye movement latencies.
A substantial body of research in adults has established that certain sleep polysomnographic abnormalities are commonly found in depressed patients, including sleep continuity disturbances, reduced slow-wave sleep, shortened rapid eye movement (REM) latency, and increased REM density. To date, these abnormalities have not been documented in depressed children compared with age-matched controls. Three consecutive nights of polysomnographic recordings were obtained in 25 hospitalized depressed children and 20 age-matched healthy controls. The depressed patients had reduced REM latencies. The shortest single-night REM latency of each individual was the most sensitive discriminating value between depressed subjects and controls. The influence of different scoring criteria in distinguishing depressed children from healthy children is discussed. In addition, depressed children had an increased sleep latency and increased REM time but did not have stage 4 differences.


Correlates of health-related quality of life in primary caregivers of perinatally HIV infected and HIV exposed uninfected adolescents at the Kenyan Coast.
Mothers and other primary caregivers play a crucial role in looking after perinatally HIV infected, and HIV exposed uninfected adolescents in sub-Saharan Africa. Day- to-day caregiving in the context of limited instrumental support and added biomedical risk (HIV seropositivity) may expose these caregivers to adverse states of health. Unfortunately, very few studies have examined their health-related quality of life (HRQoL). Our study documents the HRQoL profile, and associated factors in primary caregivers of perinatally HIV infected, perinatally HIV exposed but uninfected and HIV unexposed/uninfected adolescents aged 12-17 years at the Kenyan Coast. This was a cross-sectional analysis of 485 primary caregivers: 195 of perinatally HIV infected adolescents, 128 of perinatally HIV exposed but uninfected adolescents and 162 of HIV unexposed/uninfected adolescents. All caregivers completed a self-report measure of HRQoL (having 8 subscales), depressive symptoms, and parenting stress. They also provided their sociodemographic information and that of the care recipients. We used one-way analysis of variance to assess statistical differences among the groups. Linear regression analyses were used to identify correlates of HRQoL. Overall, caregivers of HIV unexposed/uninfected adolescents reported significantly higher mean HRQoL scores than the other caregivers in the overall HRQoL domain and majority of the subscales. There were no statistical differences in the overall HRQoL scores and most subscales between caregivers of HIV exposed adolescents. Linear regression analyses across the sample indicated that depressive symptoms, increasing age of caregiver, and caring for an adolescent perinatally exposed to HIV were significantly associated with reduced HRQoL at both the overall and sub-scale level. Having a professional job relative to subsistence farming was the only factor associated with improved overall HRQoL. At subscale level, higher socioeconomic status correlated positively with HRQoL while being a grandparent, level of education, parenting stress were negatively associated with HRQoL. Caregivers in this sample, especially those who are ageing, at risk of mental ill-health, and taking care of adolescents perinatally exposed to HIV, appear to be vulnerable to poor quality of life. Inclusive and multi-component interventions tailored to the caregivers' psychosocial and mental needs will potentially enhance their quality of life.


Association between surgical procedures under general anesthesia in infancy and developmental outcomes at 1 year: the Japan Environment and Children's Study.
The neurotoxicity of general anesthesia to the developing human brains is controversial. We assessed the associations between surgery under general anesthesia in infancy and development at age 1 year using the Japan Environment and Children's Study (JECS), a large-scale birth cohort study. In the JECS, 103,062 pregnancies and 104,065 fetuses were enrolled between January 2011 and March 2014. Of the 100,144 registered live births, we excluded preterm or post-term infants, multiple births, and infants with chromosomal anomalies and/or anomalies of the head or brain. Data on surgical procedures under general anesthesia in infancy were collected from self-administered questionnaires by parents at the 1-year follow-up. Developmental delay at age 1 year was assessed using the Japanese translation of the Ages and Stages Questionnaires, Third Edition (J-ASQ-3), comprising five developmental domains. Among the 64,141 infants included, 746 infants had surgery under general anesthesia once, 90 twice, and 71 three or more times. The percentage of developmental delay in the five domains of the J-ASQ-3 significantly increased with the number of surgical procedures. After adjusting for potential confounding factors, the risk of developmental delays in all five domains was significantly increased in infants who had surgery under general anesthesia three times or more (adjusted odds ratios: for communication domain 3.32; gross motor domain 4.69; fine motor domain 2.99; problem solving domain 2.47; personal-social domain 2.55). Surgery under general anesthesia in infancy was associated with an increased likelihood of developmental delay in all five domains of the J-ASQ-3, especially the gross motor domain at age 1 year. The neurodevelopment with the growth should be further evaluated among the children who had surgery under general anesthesia. UMIN Clinical Trials Registry (number: UMIN000030786 ).


Dating violence and substance use among ethnically diverse adolescents.
Teen dating violence is a serious public health concern with numerous and long-lasting consequences. Although alcohol and drug use have been associated with dating violence, little is known about the role of specific substances, especially the use of club drugs and the nonmedical use of prescription drugs. Thus, the authors examined the association between dating violence victimization and the use of a variety of licit and illicit substances among 1,565 ethnically diverse and economically disadvantaged high school students in southeast Texas. Past year dating violence victimization was reported by 14.1% of boys and 11.3% of girls. Compared to their nonabused counterparts, youth who experienced dating violence were more likely to smoke cigarettes, drink alcohol, binge drink alcohol, sniff glue to get high, use marijuana, use ecstasy, use Vicodin, and use Xanax. However, with the exception of alcohol and cigarettes, all substances were reduced to nonsignificance in multivariate analyses. No differences were found in the rate of dating violence between African American, White, and Hispanic adolescents.


Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab.
Because acute rejection is associated with inferior outcomes in lung transplantation, we have routinely employed OKT3, anti-thymocyte globulin (ATG), or daclizumab as adjuncts to reduce rejection. We performed a 4-year prospective, controlled clinical trial of these 3 therapies to determine differences in post-operative infection, rejection, survival, and bronchiolitis obliterans syndrome (BOS). Eighty-seven consecutive lung transplant patients received OKT3 (n = 30), ATG (n = 34), and daclizumab (n = 23) as induction agents. The groups had similar demographics and immunosuppression protocols differing only in induction agents used. No differences were observed in immediate post-operative outcomes such as length of hospitalization, ICU stay, or time on ventilators. Twelve months post-transplant, OKT3 had more infections per patient than the other agents, a difference that only became significant 2 months post-operatively (p = 0.009). The most common infection was bacterial and OKT3 had more bacterial infections than any other agent. Daclizumab had more patients remain infection free in the first year (p = 0.02), having no fungal infections and a low rate of viral infections. No patient receiving daclizumab developed drug specific side-effects. Only those patients with episodes of acute rejection developed BOS. There were no significant differences in the freedom from acute rejection or BOS between the groups. The 2-year survival for the entire cohort was 68%, with no differences observed in patient survival. This study again reveals the importance of acute rejection in the subsequent development of BOS. Although daclizumab offers a low risk of post-transplant infection and drug specific side-effects, no drug is superior in delaying rejection or BOS or in prolonging long-term survival.


Pax2 and homeodomain proteins cooperatively regulate a 435 bp enhancer of the mouse Pax5 gene at the midbrain-hindbrain boundary.
Pax and homeodomain transcription factors are essential for the formation of an organizing center at the midbrain-hindbrain boundary (mhb) which controls the genesis of the midbrain and cerebellum in the vertebrate embryo. Pax2 and Pax5 are sequentially activated in this brain region, with Pax2 expression preceding that of Pax5. Using a transgenic reporter assay, we have now identified a conserved 435 bp enhancer in the 5' flanking region of mammalian Pax5 genes which directs lacZ expression in the correct temporal and spatial pattern at the mhb. This minimal enhancer is composed of two distinct elements, as shown by protein-binding assays with mhb-specific extracts. The proximal element contains overlapping consensus binding sites for members of the Pax2/5/8 and POU protein families, whereas a distal element is bound by homeodomain and zinc finger transcription factors. Expression analysis of transgenes carrying specific mutations in these recognition motifs identified the Pax- and homeodomain-binding sites as functional elements which cooperatively control the activity of the mhb enhancer. lacZ genes under the control of either the minimal enhancer or the endogenous Pax5 locus were normally expressed at the mhb in Pax5 mutant embryos, indicating that this enhancer does not depend on autoregulation by Pax5. In Pax2 mutant embryos, expression of the endogenous Pax5 gene was, however, delayed and severely reduced in lateral aspects of the neural plate which, on neural tube closure, becomes the dorsal mhb region. This cross-regulation by Pax2 is mediated by the Pax-binding site of the minimal enhancer which, upon specific mutation, resulted in severely reduced transgene expression in the dorsal part of the mhb. Together these data indicate that Pax2 and homeodomain proteins directly bind to and cooperatively regulate the mhb enhancer of Pax5.


IOHexperimenter: Benchmarking Platform for Iterative Optimization Heuristics.
We present IOHexperimenter, the experimentation module of the IOHprofiler project. IOHexperimenter aims at providing an easy-to-use and customizable toolbox for benchmarking iterative optimization heuristics such as local search, evolutionary and genetic algorithms, and Bayesian optimization techniques. IOHexperimenter can be used as a stand-alone tool or as part of a benchmarking pipeline that uses other modules of the IOHprofiler environment. IOHexperimenter provides an efficient interface between optimization problems and their solvers while allowing for granular logging of the optimization process. Its logs are fully compatible with existing tools for interactive data analysis, which significantly speeds up the deployment of a benchmarking pipeline. The main components of IOHexperimenter are the environment to build customized problem suites and the various logging options that allow users to steer the granularity of the data records.


Reforming Cardiovascular Care in the United States towards High-Quality Care at Lower Cost with Examples from Model Programs in the State of Michigan.
Despite its status as a world leader in treatment innovation and medical education, a quality chasm exists in American health care. Care fragmentation and poor coordination contribute to expensive care with highly variable quality in the United States. The rising costs of health care since 1990 have had a huge impact on individuals, families, businesses, the federal and state governments, and the national budget deficit. The passage of the Affordable Care Act represents a large shift in how health care is financed and delivered in the United States. The objective of this review is to describe some of the economic and social forces driving health care reform, provide an overview of the Patient Protection and Affordable Care Act (ACA), and review model cardiovascular quality improvement programs underway in the state of Michigan. As health care reorganization occurs at the federal level, local and regional efforts can serve as models to accelerate improvement toward achieving better population health and better care at lower cost. Model programs in Michigan have achieved this goal in cardiovascular care through the systematic application of evidence-based care, the utilization of regional quality improvement collaboratives, community-based childhood wellness promotion, and medical device-based competitive bidding strategies. These efforts are examples of the direction cardiovascular care delivery will need to move in this era of the Affordable Care Act.


Novel metrics for quantifying bacterial genome composition skews.
Bacterial genomes have characteristic compositional skews, which are differences in nucleotide frequency between the leading and lagging DNA strands across a segment of a genome. It is thought that these strand asymmetries arise as a result of mutational biases and selective constraints, particularly for energy efficiency. Analysis of compositional skews in a diverse set of bacteria provides a comparative context in which mutational and selective environmental constraints can be studied. These analyses typically require finished and well-annotated genomic sequences. We present three novel metrics for examining genome composition skews; all three metrics can be computed for unfinished or partially-annotated genomes. The first two metrics, (dot-skew and cross-skew) depend on sequence and gene annotation of a single genome, while the third metric (residual skew) highlights unusual genomes by subtracting a GC content-based model of a library of genome sequences. We applied these metrics to 7738 available bacterial genomes, including partial drafts, and identified outlier species. A phylogenetically diverse set of these outliers (i.e., Borrelia, Ehrlichia, Kinetoplastibacterium, and Phytoplasma) display similar skew patterns but share lifestyle characteristics, such as intracellularity and biosynthetic dependence on their hosts. Our novel metrics appear to reflect the effects of biosynthetic constraints and adaptations to life within one or more hosts on genome composition. We provide results for each analyzed genome, software and interactive visualizations at http://db.systemsbiology.net/gestalt/ skew_metrics .


Adaptation of a bacterial membrane permeabilization assay for quantitative evaluation of benzalkonium chloride as a membrane-disrupting agent.
We describe the use of the ortho-nitrophenyl-β-galactoside (ONPG) assay developed by Lehrer et al. to which a new mathematical data treatment was applied. In this simplified assay, only one enzymatic assay is needed to provide direct evidence of the kinetics of Escherichia coli membrane permeabilization induced by different concentrations of benzalkonium chloride (BAC). Analysis of the data obtained from the revised ONPG assay with our adapted mathematical formula indicates that BAC induces permeabilization of the bacterial outer and inner membranes in a two-step process. The two effective concentration (EC50) values obtained in this study, combined with the results from an outer membrane permeabilization assay, suggest that the two steps observed in the permeabilization process are related to the two different bacterial membranes. We show that membrane permeabilization occurs very fast upon the addition of bacterial cells to the BAC solutions and demonstrate that sub-lethal concentrations of BAC disturb the integrity of the Gram-negative bacterial membranes. Overall, our work broadens our knowledge on the mode of action of BAC on bacterial cells and emphasizes that BAC, and quaternary ammonium compounds in general, should not be used at sub-lethal concentrations in order to lower the risk of bacterial tolerance and resistance to antibiotics.


Carrier-mediated auxin transport.
1. Auxin (IAA) transport was investigated using crown gall suspension tissue culture cells. We have shown that auxin can cross the plasmalemma both by transport of IAA anions on a saturable carrier and by passive (not carriermediated) diffusion of the lipid-soluble undissociated IAA molecules (pK=4.7). The pH optimum of the carrier for auxin influx is about pH 6 and it is half-saturated by auxin concentrations in the region of 1-5 μM. We found that the synthetic auxin 2,4D specifically inhibited carrier-mediated IAA anion influx, and possibly also efflux. Other lipid-soluble weak acids which are not auxins, such as 3,4-dichlorobenzoic acid, had no effect on auxin transport. By contrast, we found that TIBA, an inhibitor of polar auxin transport in intact tissues inhibited only the carrier-mediated efflux of IAA. 2. When the pH outside the cells is maintained below that of the cytoplasm (pH 7), auxin can be accumulated by the cells: In the initial phase of uptake, the direction of the auxin concentration gradient allows both passive carrier-mediated anion influx (inhibited by 2,4D) and a passive diffusion of undissociated acid molecules into the cells. Once inside the cytoplasm, the undissociated molecules ionise, producing IAA anions, to a greater extent than in the more acidic extracellular environment. Uptake by passive diffusion continues as long as the extracellular concentration of undissociated acid remains higher than its intra-cellular concentration. Thus, the direction of the auxin anion concentration gradient is reversed after a short period of uptake and auxin accumulates within the cells. The carrier is now able to mediate passive IAA anion efflux (inhibited by TIBA) down this concentration gradient even though net uptake still proceeds because the carrier is saturable whereas passive diffusion is not. 3. Auxin "secretion" from cells is regarded as a critical step in polar auxin transport. The evidence which we present is consistent with the view that auxin "secretion" depends on a passive carrier-mediated efflux of auxin anions which accumulate within the cells when the extra-cellular pH is below that of the cytoplasm. The implications of this view for theories of polar auxin transport are discussed.


[Ming of the presence of schistocytes in blood smear of preeclamptic pregnant women].
to evaluate the significance of schistocytes' presence in peripheral blood smear of pregnant women with pre-eclampsia, identifying and correlating them with other markers of hemolysis and of the disease severity. Seventh six glass slides of peripheral blood smear of pregnant women with pre-eclampsia have been evaluated. After the smear, the slides have been stained with Leishman's dye and stored till they were examined with a Leica, model DLMB microscope, provided with the Qwin Lite 2.5 software that made it possible to record the images of selected fields in CD-ROM. Ten fields with approximately 100 erythrocytes were counted in each glass slide. Schistocytes (irregular fragment or helmet-shaped, bite-shaped or triangular) were considered as present, when their percentage was equal or higher than 0.2%, their presence being correlated with other hemolysis markers (hemoglobin, total bilirubin, lactic desidrogenasis and reticulocytes), pre-eclampsia markers (proteinuria and platelet number). The Statistical Package in Social Science for Windows (SPSS), 10.0 version has been used for statistical analysis, at p<0.05. schistocytes have been present in 31.6% of the pregnant women with pre-eclampsia. In most (75%) of the blood smears there have been three or four schistocytes. There has been no correlation between schistocyte presence and any other hemolysis marker, any pre-eclampsia marker or disease severity. schistocytes have been identified in a small number and in less than a third of the pregnant women with pre-eclampsia. There has been no correlation with other hemolysis marker parameters or with the disease severity. This way, the presence of schistocytes is not a marker of the clinical evolution of pre-eclampsia.


Fighting microbial pathogens by integrating host ecosystem interactions and evolution.
Successful therapies to combat microbial diseases and cancers require incorporating ecological and evolutionary principles. Drawing upon the fields of ecology and evolutionary biology, we present a systems-based approach in which host and disease-causing factors are considered as part of a complex network of interactions, analogous to studies of "classical" ecosystems. Centering this approach around empirical examples of disease treatment, we present evidence that successful therapies invariably engage multiple interactions with other components of the host ecosystem. Many of these factors interact nonlinearly to yield synergistic benefits and curative outcomes. We argue that these synergies and nonlinear feedbacks must be leveraged to improve the study of pathogenesis in situ and to develop more effective therapies. An eco-evolutionary systems perspective has surprising and important consequences, and we use it to articulate areas of high research priority for improving treatment strategies.


Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo.
Disruption of the intestinal epithelial barrier occurs in many intestinal diseases, but neither the mechanisms nor the contribution of barrier dysfunction to disease pathogenesis have been defined. We utilized a murine model of T cell-mediated acute diarrhea to investigate the role of the epithelial barrier in diarrheal disease. We show that epithelial barrier dysfunction is required for the development of diarrhea. This diarrhea is characterized by reversal of net water flux, from absorption to secretion; increased leak of serum protein into the intestinal lumen; and altered tight junction structure. Phosphorylation of epithelial myosin II regulatory light chain (MLC), which has been correlated with tight junction regulation in vitro, increased abruptly after T cell activation and coincided with the development of diarrhea. Genetic knockout of long myosin light chain kinase (MLCK) or treatment of wild-type mice with a highly specific peptide MLCK inhibitor prevented epithelial MLC phosphorylation, tight junction disruption, protein leak, and diarrhea following T cell activation. These data show that epithelial MLCK is essential for intestinal barrier dysfunction and that this barrier dysfunction is critical to pathogenesis of diarrheal disease. The data also indicate that inhibition of epithelial MLCK may be an effective non-immunosuppressive therapy for treatment of immune-mediated intestinal disease.


Economic impact of switching to fixed-dose combination therapy for Japanese hypertensive patients: a retrospective cost analysis.
The prescription of fixed-dose combinations (FDC) of antihypertensive drugs has increased rapidly since the relaxation of the prescription-term restriction. In this study, we used the opportunity of this policy change in Japan as an instrument to assess the causal impact of switching to FDC on hypertensive treatment costs. Claims data from 64 community pharmacies located in Tokyo were used to identify hypertensive patients under continuous treatment with angiotensin-receptor blockers (ARBs). Patients switching to FDC between December 2010 and April 2011 were compared to patients who did not receive FDC (control group). Changes in annual antihypertensive drug costs were compared using a difference-in-differences approach to adjust for patient characteristics and use of concomitant medication. Subpopulation analyses were also performed, taking into account pre-index treatment patterns and prescribers' characteristics. There were 542 patients who switched to FDC and 9664 patients in the control group. No significant differences were observed between the 2 groups, except for antihypertensive drug use patterns before the policy change and prescribers' characteristics. The switch to FDC was associated with an annual saving of 10,420 yen (US$112.0) in antihypertensive drug costs. Approximately 20% of the FDC patients, however, switched from ARB alone, and their drug costs increased by 2376 yen (US$25.5). For hypertensive patients who required ARB-based combination therapy, switching to FDC drugs had a significant cost-saving effect. However, the policy change of relaxing the prescription-term restriction could encourage aggressive treatment, i.e., switching to a combination therapy from monotherapy, regardless of medical conditions. Further research is required to evaluate the possible negative aspects of FDC drugs.


On being new to an insurance plan: health care use associated with the first years in a health insurance plan.
We wanted to compare health care utilization and costs in the first year of being in a health insurance plan with those of subsequent years. We used claims data from an independent practitioner association (IPA)-style managed care organization in the Rochester, NY, metropolitan area from 1996 through 1999. Cross-sectional and panel analyses of up to 4 years of claims data were conducted, involving 335,547 adult patients assigned to the panels of 687 primary care physicians (internists and family physicians). Multivariate analyses, adjusting for age, sex, case mix, and socioeconomic status derived from ZIP codes, examined the relationship between the first year of health insurance and Papanicolaou tests, mammograms in women older than 40 years, physician use, avoidable hospitalization, and expenditures. After multivariate adjustment, the first year of insurance was associated with a higher risk of not getting a mammogram, a higher risk of avoidable hospitalization, greater likelihood of visiting a physician, and higher expenditures, especially for testing. There was no relationship, however, between Papanicolaou test compliance and year of enrollment. The findings suggest there might be adverse clinical and financial implications associated with changing insurance.


Effects of Hypobaric Hypoxia on Rat Retina and Protective Response of Resveratrol to the Stress.
High-altitude retinopathy represents retinal functional changes associated with environmental challenges imposed by hypobaric hypoxia, but the detailed cellular and molecular mechanism underlying this process remains unclear. Our current investigation was to explore the effect of hypobaric hypoxia on the rat retina and determine whether resveratrol has a protective efficacy on the hypoxic damage to the retina. Experiment rats were randomly grouped as the control group, hypoxia group and resveratrol intervention group. The hypoxia group and the resveratrol intervention group were maintained in a low-pressure oxygen cabin, and the resveratrol intervention group was given daily intraperitoneal injections with resveratrol. We found that hypobaric hypoxia increased thioredoxin 1 (Trx1) and thioredoxin 2 (Trx2) expression in retinas, and resveratrol treatment significantly reversed these changes (P < 0.05, P < 0.05 respectively). In comparison with controls, hypoxia upregulated the mRNA expression levels of caspase3 (P < 0.001), caspase9 (P < 0.01), heat shock protein 70 (Hsp70) (P < 0.05), heat shock protein 90 (Hsp90) (P < 0.001) and hypoxia-inducible factor-1 (HIF-1) (P < 0.05). Resveratrol administration caused a significant decrease in the gene expression of caspase3 (P< 0.001), HSP90 (P < 0.05) and HIF-1 mRNA (P < 0.01) as well as an increase in HSP70 mRNA when compared with the hypoxia group. These findings indicated that resveratrol exerted an anti-oxidative role by modulating hypoxia stress- associated genes and an anti-apoptosis role by regulating apoptosis-related cytokines. In conclusion, hypobaric hypoxia may have a pathological impact on rat retinas. The intervention of resveratrol reverses the effect induced by hypobaric hypoxia and elicits a protective response to the stress.


Update to device-related pressure ulcers: SECURE prevention. COVID-19, face masks and skin damage.
The 2019 novel coronavirus disease (COVID-19) pandemic has brought the effects of device-related pressure ulcers (DRPU) into sharp focus. With the increased use of personal protective equipment (PPE), including face masks, continuous positive airway pressure (CAPP) masks and other devices, the incidence of DRPUs among health professionals and patients alike has risen starkly. As such, the Journal of Wound Care (JWC) consensus document, Device-related pressure ulcers: SECURE prevention, published in February 2020, is more relevant than ever. To help support patients and frontline health professionals, JWC is republishing the consensus in a digital format, along with a new introductory article outlining the DRPU risks posed by PPE and other medical devices used by patients and health professionals during the pandemic, and how the skin damage can be avoided. The aim is to provide frontline staff with a clear, simple strategy on how to prevent the risk of personal skin damage and/or DRPU during the pandemic, as well as point them in the direction of more indepth guidance on long-term strategies for prevention, for both themselves and patients.


Effect of arbuscular mycorrhizal fungi and soil phosphorus level on expression of protein and activity of peroxidase on passion fruit roots.
The effects of mycorrhizal inoculation and increasing soil P levels on the expression of total proteins and peroxidase activity on passion fruit roots were evaluated. The experimental design was entirely at random, with four treatments of inoculation (a--control; b--Gigaspora albida; c--Scutellospora heterogama; d--mixture of G. albida, G. margarita, S. heterogama, and Glomus clarum) x three levels of soil P (4, 11, and 30 mg/dm3 of soil), each with three replicates. Plants were harvested 70 days after inoculation, when root colonization, shoot P level, protein content, and enzymatic activity of peroxidase (PAGE--7%) on root extract were evaluated. Regarding protein, there was no significant difference among the treatments, except between those roots receiving mixed inoculum and 11 mg P/dm3 of soil. Effect of P on protein concentration, when compared with the inoculation effect was observed. For peroxidase, there was an eletrophoretic band common to all treatments (rf: 0.43) and another that was absent only in noncolonized plants, grown in soil with lower P (rf: 0.46). Mycorrhizal specific bands were not present but a small decrease of intensity of bands in noncolonized plants was observed. Conversely, the control roots presented a single band (rf: 0.33) not observed in the other extracts, that may demonstrate an inhibitory effect of AMF on some host activities. The data showed the influence of P level in soil on the protein expression of roots, suggesting the influence of this nutrient on root genetic expression as well as on the mechanisms of symbiotic control/recognition.


The "social brain" is highly sensitive to the mere presence of social information: An automated meta-analysis and an independent study.
How the human brain processes social information is an increasingly researched topic in psychology and neuroscience, advancing our understanding of basic human cognition and psychopathologies. Neuroimaging studies typically seek to isolate one specific aspect of social cognition when trying to map its neural substrates. It is unclear if brain activation elicited by different social cognitive processes and task instructions are also spontaneously elicited by general social information. In this study, we investigated whether these brain regions are evoked by the mere presence of social information using an automated meta-analysis and confirmatory data from an independent study of simple appraisal of social vs. non-social images. Results of 1,000 published fMRI studies containing the keyword of "social" were subject to an automated meta-analysis (http://neurosynth.org). To confirm that significant brain regions in the meta-analysis were driven by a social effect, these brain regions were used as regions of interest (ROIs) to extract and compare BOLD fMRI signals of social vs. non-social conditions in the independent study. The NeuroSynth results indicated that the dorsal and ventral medial prefrontal cortex, posterior cingulate cortex, bilateral amygdala, bilateral occipito-temporal junction, right fusiform gyrus, bilateral temporal pole, and right inferior frontal gyrus are commonly engaged in studies with a prominent social element. The social-non-social contrast in the independent study showed a strong resemblance to the NeuroSynth map. ROI analyses revealed that a social effect was credible in 9 out of the 11 NeuroSynth regions in the independent dataset. The findings support the conclusion that the "social brain" is highly sensitive to the mere presence of social information.


Chromogranin A and B in adenomas of the pituitary. An immunohistochemical study of 42 cases.
Forty-two pituitary adenomas (10 prolactinomas; three ACTH-, nine GH-, two FSH- and two TSH-secreting adenomas; and 16 clinically nonfunctioning null cell adenomas) were investigated immunohistochemically with antibodies against chromogranin A and B as well as ACTH, GH, prolactin (PRL), FSH, LH, TSH, and alpha-HCG antibodies. For the demonstration of chromogranin B, two different antibodies were used--e.g., a polyclonal antihuman antibody and an antiserum against a synthetic peptide (DK-21, chromogranin B 306-326) present in the chromogranin B amino acid sequence. All tumors were positive for both chromogranin B antibodies. Chromogranin A was found in FSH- (two of two) and TSH- (two of two) secreting adenomas; it was also found in a focal distribution in ACTH- (one of three) and GH- (four of nine) secreting adenomas. Thirteen of 16 null cell adenomas contained chromogranin A, whereas no chromogranin A was found in prolactinomas. We conclude that null cell adenomas may arise either from FSH/LH or TSH cells (null cell adenomas with both chromogranin A and B positivity) or from ACTH, GH, or PRL cells (the respective tumors are only positive for chromogranin B). Chromogranin B may be used as a universal marker for pituitary adenomas.


Ethical Considerations in Ending Exploratory Brain-Computer Interface Research Studies in Locked-in Syndrome.
Brain-computer interface (BCI) is a promising technology for restoring communication in individuals with locked-in syndrome (LIS). BCI technology offers a potential tool for individuals with impaired or absent means of effective communication to use brain activity to control an output device such as a computer keyboard. Exploratory studies of BCI devices for communication in people with LIS are underway. Research with individuals with LIS presents not only technological challenges, but ethical challenges as well. Whereas recent attention has been focused on ethical issues that arise at the initiation of studies, such as how to obtain valid consent, relatively little attention has been given to issues at the conclusion of studies. BCI research in LIS highlights one such challenge: How to decide when an exploratory BCI research study should end. In this article, we present the case of an individual with presumed LIS enrolled in an exploratory BCI study. We consider whether two common ethical frameworks for stopping randomized clinical trials-equipoise and nonexploitation-can be usefully applied to elucidating researcher obligations to end exploratory BCI research. We argue that neither framework is a good fit for exploratory BCI research. Instead, we apply recent work on clinician-researcher fiduciary obligations and in turn offer some preliminary recommendations for BCI researchers on how to end exploratory BCI studies.


Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress.
Mastocytosisis a rare disease associated with chronic symptoms related to mast cell mediator release. Patients with mastocytosis display high level of negative emotionality such as depression and stress sensibility. Brain mast cells are mainly localized in the diencephalon, which is linked to emotion regulatory systems. Negative emotionality has been shown to be associated with telomere shortening. Taken together these observations led us to hypothesize that mast cells activity could be involved in both negative emotionality and telomere shortening in mastocytosis. To demonstrate a possible relationship between negative emotionality in mastocytosis and leukocytes telomere length. Leukocyte telomere length and telomerase activity were measured among mastocytosis patients and were correlated with perceived stress and depression assessed by the Beck Depression Inventory revised and the Perceived Stress Scale. Mild-severe depression scores were frequent (78.9%) as well as high perceived stress (42.11%). Telomere length was correlated to perceived stress (r=0.77; p=0.0001) but not to depression in our population. Patients displaying Wild-type KIT significantly presented higher perceived stress levels. Patients with the D816VC KIT mutation who had high perceived stress scores displayed significantly shorter telomere but not if they had high depression scores. These findings suggest that high perceived stress in mastocytosis could accelerate the rate of leukocytes telomere shortening. Since mastocytosis is, by definition, a mast cell mediated disease; these cells could be involved in this phenomenon. Mechanistic causal relationships between these parameters need to be investigated.


Rhinosporidiosis in Central India: A cross-sectional study from a tertiary care hospital in Chhattisgarh.
Chhattisgarh is an endemic region for rhinosporidiosis infection in Central India. This high prevalence can be explained by suitable hot tropical environment as well as social practice of common bathing of public with animals outdoor, mainly in ponds and river. There are more than 200 ponds in and around Bilaspur district, mainly in Ratanpur region. However, due to limited literature describing rhinosporidiosis from this part of India, it remains neglected and still not recognized as a serious health-care issue and any definite government or private measures/initiatives are not taken to counter this problem. It is a retrospective demographic study analyzing 113 consecutive biopsies received from different clinical departments in a tertiary care center with a histological diagnosis of rhinosporidiosis over a period of 7 years from January 2011 to December 2017. Most of the patients presented in the otorhinolaryngology (86.7%) department, followed by ophthalmology (10.6%). The mean age of the patients was 23.4 years, with a range of 3-70 years. A male-to-female ratio of about 3:2 was noted. Nasal cavity was the most common site of involvement (90/113), followed by conjunctiva (7/113), nasal cavity with oropharynx (6/113), and eyelid (3/113). Patients' complaints showed a varying range from nasal block, nasal mass, bleeding, bleed on touch, difficulty in breathing, and conjunctival mass. Two of the cases presented as recurrent rhinosporidiosis. Rhinosporidiosis is endemic and possesses a great health-care burden in Chhattisgarh. The socioeconomic status, outdoor bathing, and cultural practice in rural areas are the major factors contributing to newer cases. An urgent government initiative to decontaminate public water bodies and public health education through health-care workers and nongovernment organizations is the need of the hour to curtail the incidence of rhinosporidiosis.


Burnout among workers in emergency Departments in Palestinian hospitals: prevalence and associated factors.
Working in Emergency Departments (EDs) entails high work pressure and stress due to witnessing human suffering and the unpredictable nature of the work. This environment puts personnel at risk of burnout. This analysis aims to assess burnout levels and associated risk factors among health workers in EDs in Palestinian hospitals. Also, it examines the association between burnout and workplace violence, as well as with job turnover. Cross-sectional design utilising a self-administered questionnaire was used to collect data from all workers at 14 EDs; 8 from the West Bank and 6 from the Gaza Strip. Burnout was measured using Maslach Burnout Inventory-Human Services Survey. A total of 444 workers (response rate 74.5%) participated: 161(36.3%) nurses, 142(32.0%) physicians and 141(31.7%) administrative personnel. Results showed high levels of burnout among EDs workers; 64.0% suffered from high emotional exhaustion, 38.1% from high depersonalization and 34.6% from low personal accomplishment. In addition, high levels of emotional exhaustion (72.3%) was significantly prevalent among physicians compared to nurses (69.8%) and administrative workers (51.4%) (p < 0.05). In comparison, high levels of depersonalization was significantly prevalent among nurses (48.8%) compared to physicians (32.1%) and administrative workers (31.9%) (p < 0.05). However, there were no significant differences in the levels of personal accomplishment burnout among the three groups (p > 0.05). Moreover, high degree of burnout was more prevalent among EDs workers in the West Bank than among those working in the Gaza Strip (OR 2.02, 95% CI = 1.11-3.69, p = 0.019), and higher among younger workers (aged ≤30 years old) than their older counterparts (OR 2.4, 95% CI = 1.302-4.458, p = 0.005). Exposure to physical violence was significantly associated with having a high degree of burnout (OR 2.017 95% CI = 1.121-3.631, p = 0.019), but no association was observed with regards to exposure to verbal violence (p > 0.05). Finally, burnout was significantly associated with workers' intention to leave work at EDs (p < 0.05). Burnout is considerably prevalent among EDs' workers, especially nurses and physicians. Burnout is positively associated with job turnover intention and also with exposure to workplace violence. Therefore, there is a need for prevention and management strategies to address occupational burnout and reduce negative consequences on workers, patients and organisations.


A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer.
Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER(+) breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.


Pulmonary manifestations of malaria : recognition and management.
Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysiologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum infections as part of a severe systemic illness or as the main feature of acute malaria. P.vivax and P.ovale have also rarely caused pulmonary edema.Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the parasitemia is falling. Pregnant women are particularly prone to developing pulmonary edema. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. Malaria must be treated with effective drugs, but current choices are few: e.g. parenteral artemisinins, intravenous quinine or quinidine (in the US only). A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Respiratory compromise should be managed on its merits and may require mechanical ventilation.Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications, notably coma and acute renal failure. ALI/ARDS may also be related to a coincidental bacterial sepsis that may not be clinically obvious. Clinicians should employ a low threshold for starting broad spectrum antibacterials in such patients, after taking pertinent microbiologic specimens. Despite optimal management, the prognosis of severe malaria with ARDS is poor.ALI/ARDS in pediatric malaria appears to be rare. However, falciparum malaria with severe metabolic acidosis or acute pulmonary edema may present with a clinical picture of pneumonia, i.e. with tachypnea, intercostal recession, wheeze or inspiratory crepitations. This results in diagnostic confusion and suboptimal treatment. Whilst this is increasingly being recognized in malaria-endemic countries, clinicians in temperate zones should be aware that malaria may be a possible cause of 'pneumonia' in a visiting or returning child.


The Cut-off Values for the Diagnosis of Hamstring Shortness and Related Factors
Hamstrings are one of the most frequently evaluated muscle groups for flexibility in the lower extremity. Passive and active knee extension angle values are used as an indirect indicator of hamstring flexibility. However, the lack of consensus on the cut-off values leads to the use of inconsistent angle values in determining the hamstring tightness. To establish the normative and cut-off values of the passive and active knee extension angles for healthy young adults and to determine the associated factors including the quadriceps strength. A cross-sectional study. A total of 123 volunteer university students, aged 18-24 years, who met the inclusion criteria were included in this study. Passive and active knee extension assessments of the subjects were performed. Subsequently, on the next day, both knee extensor concentric muscle strength of the participants was measured in the isokinetic system. The knee extension angles and the knee extensor strength were recorded as the mean values of the right and the left sides. Passive knee extension angles of 17.1°±9.1° and 9.8°±5.7° and active knee extension angles of 17.8°±9.1° and 13.4°±6° were described as normative values in men and women, respectively. The cut-off values for the diagnosis of hamstring shortness were as follows: passive knee extension angle >32.2° for males and >19.2° for females and active knee extension angle >33.0° for males and >23.4° for females. A significant positive correlation was observed between knee extension angles and isokinetic knee extensor muscle strength in all participants. The knee extension angle and hamstring flexibility were not affected by dominance. The knee extension angles of healthy young people seem to be lower than the results currently reported in the literature. There s a positive correlation between knee extension angles and isokinetic knee extensor muscle strength.


Ventilatory sensitivity to inhaled carbon dioxide around the control point during exercise.
Rapid steady-state CO2 responses were determined in five normal adults at rest and at up to six levels of exercise by injecting pure CO2 at a constant flow into the inspiratory limb of a breathing circuit. Ventilation (V) was measured with a dry gas meter and PCO2 at the mouth was recorded by a mass spectrometer. Mean alveolar PCO2 (PACO2) was taken as equal to end-tidal PCO2 at rest, and during exercise was derived graphically from the sloping alveolar plateaus. The accuracy of the latter method was checked in separate experiments against arterial PCO2 (PaCO2). The mean results showed a linear relationship between change in PACO2 and change in V for work loads ranging from rest to 75 W (r = 0.94-0.98). Above 75 W the response became concave down with an initial essentially isocapnic phase. This suggests that during exercise there is a large increase in CO2 sensitivity about the control point.


Prenatal diagnosis of placenta accreta: sonography or magnetic resonance imaging?
The purpose of this study was to compare the accuracy of transabdominal sonography and magnetic resonance imaging (MRI) for prenatal diagnosis of placenta accreta. A historical cohort study was undertaken at 3 institutions identifying women at risk for placenta accreta who had undergone both sonography and MRI prenatally. Sonographic and MRI findings were compared with the final diagnosis as determined at delivery and by pathologic examination. Thirty-two patients who had both sonography and MRI prenatally to evaluate for placenta accreta were identified. Of these, 15 had confirmation of placenta accreta at delivery. Sonography correctly identified the presence of placenta accreta in 14 of 15 patients (93% sensitivity; 95% confidence interval [CI], 80%-100%) and the absence of placenta accreta in 12 of 17 patients (71% specificity; 95% CI, 49%-93%). Magnetic resonance imaging correctly identified the presence of placenta accreta in 12 of 15 patients (80% sensitivity; 95% CI, 60%-100%) and the absence of placenta accreta in 11 of 17 patients (65% specificity; 95% CI, 42%-88%). In 7 of 32 cases, sonography and MRI had discordant diagnoses: sonography was correct in 5 cases, and MRI was correct in 2. There was no statistical difference in sensitivity (P = .25) or specificity (P = .5) between sonography and MRI. Both sonography and MRI have fairly good sensitivity for prenatal diagnosis of placenta accreta; however, specificity does not appear to be as good as reported in other studies. In the case of inconclusive findings with one imaging modality, the other modality may be useful for clarifying the diagnosis.


Locked-In Syndrome Following Cervical Manipulation by a Chiropractor: A Case Report.
Vertebrobasilar occlusion poses difficult diagnostic issues and even when properly diagnosed has a poor prognosis. Newer studies highlight a better outcome when thrombectomy was carried out between six and twenty-four hours after an initial diagnosis of stroke. This paper reports a case where a patient suffered a vertebrobasilar stroke secondary to a traumatic bilateral vertebral arteries dissection was treated with late thrombectomy. A 34-year-old woman was manipulated on the cervical spinal column by a chiropractor. Following three weeks of cervical pain, she presented with severe aphasia and quadriplegia (NIHSS = 28). An MRI scan indicated ischemia of the vertebrobasilar system. Thirty-one hours after the onset of these symptoms, a thrombectomy was performed. After one month, the patient could move her head and the proximal part of her limbs but remained confined to bed (NIHSS = 13). The current case illustrates the benefit of late mechanical thrombectomy for a posterior cerebral circulation infarct. Although there was a delay in treatment, partial recovery ensued.


Conformational properties of the third variable loop of HIV-1AD8 envelope glycoprotein in the liganded conditions.
The conformational dynamics of the HIV-1 envelope glycoprotein gp120 and gp41 (Env) remains poorly understood. Here we examined how the V3 loop conformation is regulated in the liganded state using a panel of recombinant HIV-1NL4-3 clones bearing HIV-1AD8 Env by two experimental approaches, one adopting a monoclonal neutralizing antibody KD-247 (suvizumab) that recognizes the tip of the V3 loop, and the other assessing the function of the V3 loop. A significant positive correlation of the Env-KD-247 binding was detected between the liganded and unliganded conditions. Namely, the mutation D163G located in the V2 loop, which enhances viral susceptibility to KD-247 by 59.4-fold, had little effect on the sCD4-induced increment of the virus-KD-247 binding. By contrast, a virus with the S370N mutation in the C3 region increased the virus-KD-247 binding by 91.4-fold, although it did not influence the KD-247-mediated neutralization. Co-receptor usage and the susceptibility to CCR5 inhibitor Maraviroc were unaffected by D163G and S370N mutations. Collectively, these data suggest that the conformation of the liganded V3-loop of HIV-1AD8 Env is still under regulation of other Env domains aside from the V3 loop, including V2 and C3. Our results give an insight into the structural properties of HIV-1 Env and viral resistance to entry inhibitors by non-V3 loop mutations.


Validating e-learning in continuing pharmacy education: user acceptance and knowledge change.
Continuing pharmacy education is becoming mandatory in most countries in order to keep the professional license valid. Increasing number of pharmacists are now using e-learning as part of their continuing education. Consequently, the increasing popularity of this method of education calls for standardization and validation practices. The conducted research explored validation aspects of e-learning in terms of knowledge increase and user acceptance. Two e-courses were conducted as e-based continuing pharmacy education for graduated pharmacists. Knowledge increase and user acceptance were the two outcome measured. The change of knowledge in the first e-course was measured by a pre- and post-test and results analysed by the Wilcoxon signed-rank test. The acceptance of e-learning in the second e-course was investigated by a questionnaire and the results analysed using descriptive statistics. Results showed that knowledge increased significantly (p < 0.001) by 16 pp after participation in the first e-course. Among the participants who responded to the survey in the second course, 92% stated that e-courses were effective and 91% stated that they enjoyed the course. The study shows that e-learning is a viable medium of conducting continuing pharmacy education; e-learning is effective in increasing knowledge and highly accepted by pharmacists from various working environments such as community and hospital pharmacies, faculties of pharmacy or wholesales.


Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.
In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient's circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.


Comparison of the metabolic effects of GIP receptor antagonism and PYY(3-36) receptor activation in high fat fed mice.
Glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY) are secreted from the intestinal K- and L-cells, respectively, following a meal. Both peptides are believed to play a key role in glucose homeostasis and energy expenditure. This study investigated the effects of daily administration of the stable and specific GIP-R antagonist, (Pro(3))GIP (25 nmol/kg) and the endogenous truncated form of PYY, PYY(3-36) (50 nmol/kg), in mice fed with a high fat diet. Daily i.p. injection of (Pro(3))GIP, PYY(3-36) or combined peptide administration over 24 days significantly (P<0.05-0.01) decreased body weight compared with saline-treated controls without change in food intake. Plasma glucose levels and glucose tolerance were significantly (P<0.05) lowered by (Pro(3))GIP treatment alone, and in combination with PYY(3-36). These changes were accompanied by a slight improvement of insulin sensitivity in all of the treatment groups. (Pro(3))GIP treatment significantly reduced plasma corticosterone (P<0.05), while combined administration with PYY(3-36) significantly lowered serum glucagon (P<0.05). No appreciable changes were observed in either circulating or glucose-stimulated insulin secretion in all treatment groups. (Pro(3))GIP-treated mice had significantly (P<0.01) lowered fasting glucose levels and an improved (P<0.05) glycemic response to feeding. These comparative data indicate that chemical ablation of GIP receptor action using (Pro(3))GIP provides an especially effective means of countering obesity and related abnormalities induced by consumption of high fat energy rich diet.


Co-ingestion of prescription opioids and other drugs among high school seniors: results from a national study.
The objective of this study was to determine the past-year prevalence rates and behavioral correlates of co-ingestion of prescription opioids and other drugs among high school seniors in the United States. Nationally representative probability samples of high school seniors in the United States were surveyed as a part of the Monitoring the Future (MTF) study. Data were collected in schools via self-administered paper-and-pencil questionnaires during the spring of each cohort's senior year. The sample consisted of five cohorts (senior years of 2002-2006) made up of 12,441 high school seniors (modal age 18), of which 53% were women. The estimated prevalence of any past-year co-ingestion of prescription opioids and other drugs for these cohorts was 4.4%, and 69.8% among nonmedical users of prescription opioids. The substances most commonly co-ingested with prescription opioids included marijuana (58.5%), alcohol (52.1%), cocaine (10.6%), tranquilizers (10.3%), and amphetamines (9.5%). Nonmedical users who co-ingested prescription opioids with other drugs were more likely to report intranasal administration, recreational motives, oxycodone use, and greater subjective high when using prescription opioids than nonmedical users who did not co-ingest prescription opioids and other drugs. Nearly 7 out of every 10 nonmedical users of prescription opioids reported co-ingestion of prescription opioids and other drugs in the past year. The findings indicate that the co-ingestion of prescription opioids and other drugs by high school seniors in the United States serves as a marker for substance abuse and represents a significant public health concern.


Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation.
Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis. ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium. Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.