The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice

Building Babies - Chapter 16

In contrast to birds, male mammals rarely help to raise the offspring. Of all mammals, only among rodents, carnivores, and primates, males are sometimes intensively engaged in providing infant care (Kleiman and Malcolm 1981). Male caretaking of infants has long been recognized in nonhuman primates (Itani 1959). Given that infant care behavior can have a positive effect on the infant’s development, growth, well-being, or survival, why are male mammals not more frequently involved in “building babies”? We begin the chapter defining a few relevant terms and introducing the theory and hypotheses that have historically addressed the evolution of paternal care. We then review empirical findings on male care among primate taxa, before focusing, in the final section, on our own work on paternal care in South American owl monkeys (Aotus spp.). We conclude the chapter with some suggestions for future studies.Deutsche Forschungsgemeinschaft (HU 1746/2-1) Wenner-Gren Foundation, the L.S.B. Leakey Foundation, the National Geographic Society, the National Science Foundation (BCS-0621020), the University of Pennsylvania Research Foundation, the Zoological Society of San Dieg

Diabetic autonomic neuropathy: evidence for apoptosis in situ in the rat

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75065/1/j.1365-2982.2004.00524.x.pd

Dissolved noble gases and stable isotopes as tracers of preferential fluid flow along faults in the Lower Rhine Embayment, Germany

Groundwater in shallow unconsolidated sedimentary aquifers close to the Bornheim fault in the Lower Rhine Embayment (LRE), Germany, has relatively low δ2H and δ18O values in comparison to regional modern groundwater recharge, and 4He concentrations up to 1.7 × 10−4 cm3 (STP) g–1 ± 2.2 % which is approximately four orders of magnitude higher than expected due to solubility equilibrium with the atmosphere. Groundwater age dating based on estimated in situ production and terrigenic flux of helium provides a groundwater residence time of ∼107 years. Although fluid exchange between the deep basal aquifer system and the upper aquifer layers is generally impeded by confining clay layers and lignite, this study’s geochemical data suggest, for the first time, that deep circulating fluids penetrate shallow aquifers in the locality of fault zones, implying  that sub-vertical fluid flow occurs along faults in the LRE. However, large hydraulic-head gradients observed across many faults suggest that they act as barriers to lateral groundwater flow. Therefore, the geochemical data reported here also substantiate a conduit-barrier model of fault-zone hydrogeology in unconsolidated sedimentary deposits, as well as corroborating the concept that faults in unconsolidated aquifer systems can act as loci for hydraulic connectivity between deep and shallow aquifers. The implications of fluid flow along faults in sedimentary basins worldwide are far reaching and of particular concern for carbon capture and storage (CCS) programmes, impacts of deep shale gas recovery for shallow groundwater aquifers, and nuclear waste storage sites where fault zones could act as potential leakage pathways for hazardous fluids

What do patients want from their psychiatrist? A cross- sectional questionnaire based exploratory study from Karachi

<p>Abstract</p> <p>Background</p> <p>The aspects of consultation that are important for psychiatric patients have always remained a less acknowledged area. The aim of this study was to identify these aspects.</p> <p>Methods</p> <p>A Cross-sectional, questionnaire based study was carried out in a psychiatry outpatient clinic of two tertiary care hospitals in a developing country. The patients were asked to fill out the questionnaire containing a total of 11 close-ended questions plus 1 open-ended question. They graded them as not important, important, very important or do not know. Non-psychotic patients aged 18 and above, visiting the clinic were recruited into the study before they went in for their first consultation.</p> <p>Results</p> <p>The response rate of patients was 84%. More than 90% wanted the doctor to tell them the cause of their illness, talk to them about their condition, provide symptomatic relief, let them know that how long their illness would last and make the final decision about their treatment plan. Less than 20% wanted to be part of a support network. A significant 82% wanted talking therapy as part of their treatment plan.</p> <p>Conclusion</p> <p>The three issues, most important for patients were: the doctor should listen to them, make the final decision about treatment and provide symptomatic relief. Only 20% wanted to be a part of patients' support group.</p

Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae

The benzylisoquinoline alkaloids (BIAs) are a diverse class of metabolites that exhibit a broad range of pharmacological activities and are synthesized through plant biosynthetic pathways comprised of complex enzyme activities and regulatory strategies. We have engineered yeast to produce the key intermediate reticuline and downstream BIA metabolites from a commercially available substrate. An enzyme tuning strategy was implemented that identified activity differences between variants from different plants and determined optimal expression levels. By synthesizing both stereoisomer forms of reticuline and integrating enzyme activities from three plant sources and humans, we demonstrated the synthesis of metabolites in the sanguinarine/berberine and morphinan branches. We also demonstrated that a human P450 enzyme exhibits a novel activity in the conversion of (R)-reticuline to the morphinan alkaloid salutaridine. Our engineered microbial hosts offer access to a rich group of BIA molecules and associated activities that will be further expanded through synthetic chemistry and biology approaches

The Choice of the Filtering Method in Microarrays Affects the Inference Regarding Dosage Compensation of the Active X-Chromosome

The hypothesis of dosage compensation of genes of the X chromosome, supported by previous microarray studies, was recently challenged by RNA-sequencing data. It was suggested that microarray studies were biased toward an over-estimation of X-linked expression levels as a consequence of the filtering of genes below the detection threshold of microarrays.To investigate this hypothesis, we used microarray expression data from circulating monocytes in 1,467 individuals. In total, 25,349 and 1,156 probes were unambiguously assigned to autosomes and the X chromosome, respectively. Globally, there was a clear shift of X-linked expressions toward lower levels than autosomes. We compared the ratio of expression levels of X-linked to autosomal transcripts (X∶AA) using two different filtering methods: 1. gene expressions were filtered out using a detection threshold irrespective of gene chromosomal location (the standard method in microarrays); 2. equal proportions of genes were filtered out separately on the X and on autosomes. For a wide range of filtering proportions, the X∶AA ratio estimated with the first method was not significantly different from 1, the value expected if dosage compensation was achieved, whereas it was significantly lower than 1 with the second method, leading to the rejection of the hypothesis of dosage compensation. We further showed in simulated data that the choice of the most appropriate method was dependent on biological assumptions regarding the proportion of actively expressed genes on the X chromosome comparative to the autosomes and the extent of dosage compensation.This study shows that the method used for filtering out lowly expressed genes in microarrays may have a major impact according to the hypothesis investigated. The hypothesis of dosage compensation of X-linked genes cannot be firmly accepted or rejected using microarray-based data

The trochlear isometric point is different in patients with recurrent patellar instability compared to controls: a radiographical study

Purpose: The purpose of the study was to investigate the theoretical isometric point based of the curve of the femoral groove and relating it to the origin of the MPFL femoral tunnel on lateral radiograph by comparing a patellar instability cohort with a control cohort. Methods: From a Patellar Instability database the radiographs of 40 consecutive patients were analysed to define Schöttle’s point, and the arc of the circle of the trochlear groove. A comparison population of 20 radiographs from comparable patients with tibiofemoral joint disorders was used as a control. The distance from Schöttle’s point to the most anterior part of the groove (extension) was also compared to the distance to the distal end of the roof of the notch (flexion). Results: The trochlea was circular in the controls but not the Patellofemoral Instability cohort where trochlear dysplasia is usually present. The difference between the extension and flexion length was a mean of − 2.0 ± 0.5 mm in the controls and + 6.0 ± 0.5 mm in the patellofemoral cohort. In neither cohort did the centre of the circle correspond to Schöttle’s point. The extension distance correlated with the boss height. Conclusions: The dysplastic trochlea is not circular and the centre of the best matched circle was different to the control trochleae which were circular. The circle centres did not correlate with Schöttle’s point for either cohort, and was more proximal in the Patellofemoral Instability cohort. Clinical relevance: For the MPFL to have equal tension throughout flexion within the groove, the length should not change. In normal knees the MPFL does not behave isometrically. The change in length, as measured from Schöttle’s point to the trochlea, was greater for patellofemoral instability patients explaining why an isolated MPFL reconstruction in the presence of severe trochlear dysplasia risks poor outcomes

Educating and Informing Patients Receiving Psychopharmacological Medications: Are Family Physicians in Pakistan up to the Task?

Introduction: Studies have shown a high prevalence of psychiatric illnesses among Patients in primary health care settings. Family physicians have a fundamental role in managing psychiatric illness with psychopharmacological medications. Providing information about the disease, its management and the potential adverse effects of the medications is an important part of the management of mental illnesses. Our objective was to determine if Patients who were prescribed psychopharmacological drugs by family physicians at a community health center in Karachi, Pakistan were provided adequate education about their disease and its management. Methods: A cross-sectional study was conducted at the Community Health Centre (CHC), Aga Khan University Hospital Karachi, Pakistan. Details about the prescriptions and Patient education were acquired from the Patients after their consultations. Results: A total of 354 adult Patients were interviewed during 3 days. Among them, 73 (20.6%) were prescribed psychopharmacological medications. Among Patients receiving psychopharmacological medicines, 37 (50.7%) did not know their diagnosis, 50 (68.5%) were unaware of the disease process, 52 (71.2%) were unaware of alternative treatments, 63 (86.3%) were not cautioned about the potential adverse effects of the drugs, 24 (32.9%) were unaware of the duration of treatment and in 60 (82.2%) of the participants an appropriate referral had not been discussed. For all aspects of education, Patients prescribed psychopharmacological medications knew less as compared to those Patients that were prescribed other medications. Discussion: The practice of imparting information to Patients who receive psychopharmacological medications seems to be inadequate in Pakistan. We have hypothesized about the possible reasons for our findings, and identified a need for further research to determine the cause for such findings and to address them accordingly. At the same time there is a need to educate family physicians in Pakistan about the special importance of providing adequate information to such Patients

People’s understanding of verbal risk descriptors in patient information leaflets : a cross-sectional national survey of 18- to 65-year-olds in England

Introduction Evidence suggests the current verbal risk descriptors used to communicate side effect risk in patient information leaflets (PILs) are overestimated. Objectives The aim was to establish how people understand the verbal risk descriptors recommended for use in PILs by the European Commission (EC), and alternative verbal risk descriptors, in the context of mild and severe side effects. Methods A cross-sectional online survey was carried out by a market research company recruiting participants aged between 18 and 65 years living in England. Data were collected between 18 March and 1 April 2016. Participants were given a hypothetical scenario regarding the risk of mild or severe medication side effects and asked to estimate how many out of 10,000 people would be affected for each of the verbal risk descriptors being tested. Results A total of 1003 participants were included in the final sample. The risks conveyed by the EC recommended verbal risk descriptors were greatly overestimated by participants. Two distinct distributions were apparent for participant estimates of side effect risks: those for ‘high risk’ verbal descriptors (e.g. ‘common’, ‘likely’, ‘high chance’) and those for ‘low risk’ verbal descriptors (e.g. ‘uncommon’, ‘unlikely’, ‘low chance’). Within these two groups, the distributions were near to identical regardless of what adverb (e.g. very, high, fair) or adjective (e.g. common, likely, chance) was used. The EC recommended verbal risk descriptors were more likely to be understood in accordance with their intended meanings when describing severe side effects. Very few demographic or psychological factors were consistently associated with how well participants understood the EC recommended verbal risk descriptors. Discussion The current verbal risk descriptors used in PILs are ineffective at best and misleading at worst. Discontinuing the use of verbal risk descriptors would limit the likelihood of people overestimating the risk of side effects