Effect of CGRP and sumatriptan on the BOLD response in visual cortex

To test the hypothesis that calcitonin gene-related peptide (CGRP) modulates brain activity, we investigated the effect of intravenous CGRP on brain activity in response to a visual stimulus. In addition, we examined if possible alteration in brain activity was reversed by the anti-migraine drug sumatriptan. Eighteen healthy volunteers were randomly allocated to receive CGRP infusion (1.5 μg/min for 20 min) or placebo. In vivo activity in the visual cortex was recorded before, during and after infusion and after 6 mg subcutaneous sumatriptan by functional magnetic resonance imaging (3 T). 77% of the participants reported headache after CGRP. We found no changes in brain activity after CGRP (P = 0.12) or after placebo (P = 0.41). Sumatriptan did not affect brain activity after CGRP (P = 0.71) or after placebo (P = 0.98). Systemic CGRP or sumatriptan has no direct effects on the BOLD activity in visual cortex. This suggests that in healthy volunteers both CGRP and sumatriptan may exert their actions outside of the blood–brain barrier

Entropic Tension in Crowded Membranes

Unlike their model membrane counterparts, biological membranes are richly decorated with a heterogeneous assembly of membrane proteins. These proteins are so tightly packed that their excluded area interactions can alter the free energy landscape controlling the conformational transitions suffered by such proteins. For membrane channels, this effect can alter the critical membrane tension at which they undergo a transition from a closed to an open state, and therefore influence protein function \emph{in vivo}. Despite their obvious importance, crowding phenomena in membranes are much less well studied than in the cytoplasm. Using statistical mechanics results for hard disk liquids, we show that crowding induces an entropic tension in the membrane, which influences transitions that alter the projected area and circumference of a membrane protein. As a specific case study in this effect, we consider the impact of crowding on the gating properties of bacterial mechanosensitive membrane channels, which are thought to confer osmoprotection when these cells are subjected to osmotic shock. We find that crowding can alter the gating energies by more than $2\;k_BT$ in physiological conditions, a substantial fraction of the total gating energies in some cases. Given the ubiquity of membrane crowding, the nonspecific nature of excluded volume interactions, and the fact that the function of many membrane proteins involve significant conformational changes, this specific case study highlights a general aspect in the function of membrane proteins.Comment: 20 pages (inclduing supporting information), 4 figures, to appear in PLoS Comp. Bio

Sex-specific associations between particulate matter exposure and gene expression in independent discovery and validation cohorts of middle-aged men and women

BACKGROUND: Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases. OBJECTIVES: Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population. METHODS: Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM(10) in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM(2.5) and PM(10) exposures over 2-years were estimated for each participant’s residential address using spatiotemporal interpolation in combination with a dispersion model. RESULTS: Average long-term PM(10) was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m(3) in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM(10) and the expression of individual genes differed by sex. In the validation cohort, long-term PM(10) was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 (p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM(10) in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM(10) exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women). CONCLUSIONS: Expression of the sex-specific candidate genes identified in the discovery population predicted PM(10) exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects. CITATION: Vrijens K, Winckelmans E, Tsamou M, Baeyens W, De Boever P, Jennen D, de Kok TM, Den Hond E, Lefebvre W, Plusquin M, Reynders H, Schoeters G, Van Larebeke N, Vanpoucke C, Kleinjans J, Nawrot TS. 2017. Sex-specific associations between particulate matter exposure and gene expression in independent discovery and validation cohorts of middle-aged men and women. Environ Health Perspect 125:660–669; http://dx.doi.org/10.1289/EHP37

The handling of urinary incontinence in Danish general practices after distribution of guidelines and voiding diary reimbursement: an observational study

BACKGROUND: Though urinary incontinence (UI) is a bothersome condition for the individual patient, the patients tend not to inform their physician about UI and the physician tend not to ask the patient. Recently different initiatives have been established in Danish general practices to improve the management of UI. The aim of this study was to identify the handling of urinary incontinence (UI) in Danish general practices after distribution of clinical guidelines and reimbursement for using a UI diary. METHODS: In October 2001, a questionnaire was sent to 243 general practitioners (GPs) in Frederiksborg County following distribution of clinical guidelines in July 1999 (UI in general practice) and September 2001 (UI in female, geriatric, or neurological patients). A policy for a small reimbursement to GPs for use of a fluid intake/voiding diary in the assessment of UI in general practice was implemented in October 2001. Information concerning monthly reimbursement for using a voiding diary, prescribed drugs (presumably used for treating UI), UI consultations in outpatient clinics, and patient reimbursement for pads was obtained from the National Health Service County Registry. RESULTS: Of the 132 (54%) GPs who replied, 87% had read the guidelines distributed 2 years before, but only 47% used them daily. The majority (69%) of the responding GPs had read and appreciated 1–3 other UI guidelines distributed before the study took place. Eighty-three percent of the responding GPs sometimes or often actively asked their patients about UI, and 92% sometimes or often included a voiding diary in the UI assessment. The available registry data concerning voiding diary reimbursement, prescribed UI drugs, UI consultations in outpatient clinics, and patient reimbursement for pads were insufficient or too variable to determine significant trends. CONCLUSION: GPs management of UI in a Danish county may be reasonable, but low response rate to the questionnaire and insufficient registry data made it difficult to evaluate the impact of different UI initiatives

The Accuracy of Survival Time Prediction for Patients with Glioma Is Improved by Measuring Mitotic Spindle Checkpoint Gene Expression

Identification of gene expression changes that improve prediction of survival time across all glioma grades would be clinically useful. Four Affymetrix GeneChip datasets from the literature, containing data from 771 glioma samples representing all WHO grades and eight normal brain samples, were used in an ANOVA model to screen for transcript changes that correlated with grade. Observations were confirmed and extended using qPCR assays on RNA derived from 38 additional glioma samples and eight normal samples for which survival data were available. RNA levels of eight major mitotic spindle assembly checkpoint (SAC) genes (BUB1, BUB1B, BUB3, CENPE, MAD1L1, MAD2L1, CDC20, TTK) significantly correlated with glioma grade and six also significantly correlated with survival time. In particular, the level of BUB1B expression was highly correlated with survival time (p<0.0001), and significantly outperformed all other measured parameters, including two standards; WHO grade and MIB-1 (Ki-67) labeling index. Measurement of the expression levels of a small set of SAC genes may complement histological grade and other clinical parameters for predicting survival time

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Postpartum women’s use of medicines and breastfeeding practices: a systematic review

The objectives of this article are to systematically review i) the extent of medicine use in postpartum women, and ii) the impact of maternal medicine use (excluding contraceptives and galactogogues) on breastfeeding outcomes (initiation and/or duration). PubMed, Medline (Ovid), Scopus (Elsevier), Cinahl (EBSCO), PsycINFO (Ovid), Embase (Ovid) and Web of Science (ISI) databases were searched to find original studies on medicine use in women after the birth. Additional studies were identified by searching Google Scholar, Wiley Online Library, Springer Link, selected journals and from the reference list of retrieved articles. Observational studies with information about postpartum women’s use of any type of medicine either for chronic or acute illnesses with or without breastfeeding information were included. The majority of relevant studies suggest that more than 50 % of postpartum women (breastfeeding or not) required at least one medicine. Due to the lack of uniform medication use reporting system and differences in study designs, settings and samples, the proportion of medicine use by postpartum women varies widely, from 34 to 100 %. Regarding the impact of postpartum women’s medicine use on breastfeeding, a few studies suggest that women’s use of certain medicines (e.g. antiepileptics, propylthiouracil, antibiotics) during lactation can reduce initiation and/ or duration of breastfeeding. These studies are limited by small sample size, and with one exception, all were conducted in Canada more than a decade ago. Large scale studies are required to establish the relationship between maternal medicine use and breastfeeding, considering type of illness, period of use and total duration of medicine use