Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

Heteromultimeric G protein-activated inward rectifier K+ (GIRK) channels, abundant in heart and brain, help to determine the cellular membrane potential as well as the frequency and duration of electrical impulses. The sequence arginine-glycine-aspartate (RGD), located extracellularly between the first membrane-spanning region and the pore, is conserved among all identified GIRK subunits but is not found in the extracellular domain of any other cloned K+ channels. Many integrins, which, like channels, are integral membrane proteins, recognize this RGD sequence on other proteins, usually in the extracellular matrix. We therefore asked whether GIRK activity might be regulated by direct interaction with integrin. Here, we present evidence that mutation of the RGD site to RGE, particularly on the GIRK4 subunit, decreases or abolishes GIRK current. Furthermore, wild-type channels can be co-immunoprecipitated with integrin. The total cellular amount of expressed mutant GIRK channel protein is the same as the wild-type protein; however, the amount of mutant channel protein that localizes to the plasma membrane is decreased relative to wild-type, most likely accounting for the diminished GIRK current detected. GIRK channels appear to bind directly to integrin and to require this interaction for proper GIRK channel membrane localization and function

The Formation of the Double Pulsar PSR J0737-3039A/B

Recent timing observations of the double pulsar J0737-3039A/B have shown that its transverse velocity is extremely low, only 10 km/s, and nearly in the Plane of the Galaxy. With this new information, we rigorously re-examine the history and formation of this system, determining estimates of the pre-supernova companion mass, supernova kick and misalignment angle between the pre- and post-supernova orbital planes. We find that the progenitor to the recently formed `B' pulsar was probably less than 2 MSun, lending credence to suggestions that this object may not have formed in a normal supernova involving the collapse of an iron core. At the same time, the supernova kick was likely non-zero. A comparison to the history of the double-neutron-star binary B1534+12 suggests a range of possible parameters for the progenitors of these systems, which should be taken into account in future binary population syntheses and in predictions of the rate and spatial distribution of short gamma-ray burst events.Comment: To appear in MNRAS Letters. Title typo fix only; no change to pape

Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): A multicentre, randomised, placebo-controlled trial

Published: September 26, 2017Background: Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity. The withdrawal of progesterone, either actual or functional, is thought to be an antecedent to the onset of labour. There remains limited information on clinically relevant health outcomes as to whether vaginal progesterone may be of benefit for pregnant women with a history of a previous preterm birth, who are at high risk of a recurrence. Our primary aim was to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth reduced the risk and severity of respiratory distress syndrome in their infants, with secondary aims of examining the effects on other neonatal morbidities and maternal health and assessing the adverse effects of treatment. Methods: Women with a live singleton or twin pregnancy between 18 to <24 weeks' gestation and a history of prior preterm birth at less than 37 weeks' gestation in the preceding pregnancy, where labour occurred spontaneously or in association with cervical incompetence or following preterm prelabour rupture of the membranes, were eligible. Women were recruited from 39 Australian, New Zealand, and Canadian maternity hospitals and assigned by randomisation to vaginal progesterone pessaries (equivalent to 100 mg vaginal progesterone) (n = 398) or placebo (n = 389). Participants and investigators were masked to the treatment allocation. The primary outcome was respiratory distress syndrome and severity. Secondary outcomes were other respiratory morbidities; other adverse neonatal outcomes; adverse outcomes for the woman, especially related to preterm birth; and side effects of progesterone treatment. Data were analysed for all the 787 women (100%) randomised and their 799 infants. Findings: Most women used their allocated study treatment (740 women, 94.0%), with median use similar for both study groups (51.0 days, interquartile range [IQR] 28.0-69.0, in the progesterone group versus 52.0 days, IQR 27.0-76.0, in the placebo group). The incidence of respiratory distress syndrome was similar in both study groups-10.5% (42/402) in the progesterone group and 10.6% (41/388) in the placebo group (adjusted relative risk [RR] 0.98, 95% confidence interval [CI] 0.64-1.49, p = 0.912)-as was the severity of any neonatal respiratory disease (adjusted treatment effect 1.02, 95% CI 0.69-1.53, p = 0.905). No differences were seen between study groups for other respiratory morbidities and adverse infant outcomes, including serious infant composite outcome (155/406 [38.2%] in the progesterone group and 152/393 [38.7%] in the placebo group, adjusted RR 0.98, 95% CI 0.82-1.17, p = 0.798). The proportion of infants born before 37 weeks' gestation was similar in both study groups (148/406 [36.5%] in the progesterone group and 146/393 [37.2%] in the placebo group, adjusted RR 0.97, 95% CI 0.81-1.17, p = 0.765). A similar proportion of women in both study groups had maternal morbidities, especially those related to preterm birth, or experienced side effects of treatment. In 9.9% (39/394) of the women in the progesterone group and 7.3% (28/382) of the women in the placebo group, treatment was stopped because of side effects (adjusted RR 1.35, 95% CI 0.85-2.15, p = 0.204). The main limitation of the study was that almost 9% of the women did not start the medication or forgot to use it 3 or more times a week. Conclusions: Our results do not support the use of vaginal progesterone pessaries in women with a history of a previous spontaneous preterm birth to reduce the risk of neonatal respiratory distress syndrome or other neonatal and maternal morbidities related to preterm birth. Individual participant data meta-analysis of the relevant trials may identify specific women for whom vaginal progesterone might be of benefit. Current Clinical Trials ISRCTN20269066.Caroline A. Crowther, Pat Ashwood, Andrew J. McPhee, Vicki Flenady, Thach Tran, Jodie M. Dodd, Jeffrey S. Robinson, for the PROGRESS Study Grou

Ectrodactyly and lethal pulmonary acinar dysplasia associated with homozygous FGFR2 mutations identified by exome sequencing

First published: 11 July 2016Abstract not availableChristopher P. Barnett, Nathalie J. Nataren, Manuela Klingler-Hoffmann, Quenten Schwarz, Chan-Eng Chong, Young K. Lee, Damien L. Bruno, Jill Lipsett, Andrew J. McPhee, Andreas W. Schreiber, Jinghua Feng, Christopher N. Hahn, and Hamish S. Scot

Quantifying habitual levels of physical activity according to impact in older people: accelerometry protocol for the VIBE study

Physical activity (PA) may need to produce high impacts to be osteogenic. The aim of this study was to identify threshold(s) for defining high impact PA for future analyses in the VIBE (Vertical Impact and Bone in the Elderly) study, based on home recordings with triaxial accelerometers. Recordings were obtained from 19 Master Athlete Cohort (MAC; mean 67.6 years) and 15 Hertfordshire Cohort Study (HCS; mean 77.7 years) participants. Data cleaning protocols were developed to exclude artifacts. Accelerations expressed in g units were categorized into three bands selected from the distribution of positive Y-axis peak accelerations. Data were available for 6.6 and 4.4 days from MAC and HCS participants respectively, with approximately 14 hr recording daily. Three-fold more 0.5–1.0g impacts were observed in MAC versus HCS, 20-fold more 1.0–1.5g impacts, and 140-fold more impacts ≥ 1.5g. Our analysis protocol successfully distinguishes PA levels in active and sedentary older individuals

Comparing the effect of CTG+STan with CTG alone on emergency Cesarean section rate : STan Australian Randomized controlled Trial (START)

The authors would like to thank the women and their babies for participating. We would like to thank all the staff at the WCH, in particular Priya Umampathysivam, Denise Cheetham and Cecilia Heitmann for their assistance in recruitment of participants for START. We would also like to thank the members of the DSMC, Diogo Ayres-de-Campos, Scott Morris and Katherine Lee, for their oversight of START and the Clinical Information Service (CIS) team at the WCH for the comparative hospital dataPeer reviewedPublisher PD

Increased posterior cingulate functional connectivity following 6-month high-dose B-vitamin multivitamin supplementation : a randomized, double-blind, placebo-controlled trial

B vitamins are essential for optimal brain and body function, and are particularly important for cortical metabolic processes that have downstream effects on mitigating oxidative stress. Oxidative stress has been linked to poor psychological outcomes including psychological distress, which has wide-reaching implications for the community and the workplace. Given work-related stress has been associated with poor mental health outcomes, high-dose B vitamin supplementation may be effective in improving brain function and psychological outcomes via attenuation of oxidative stress. This randomized, double-blind, placebo-controlled study investigated psychological outcomes following 6-month supplementation of a high-B-vitamin multivitamin in a large sample of healthy adults (n = 108, aged 30–70 years), as well as changes in default mode network functional connectivity in a subset of the original sample (n = 28). Improvements in occupational stress, general health, perceived stress, depressive symptoms, and mood profiles were identified for both active and placebo groups over time (p < 0.05 corrected). Seed-based functional connectivity analysis centered on the posterior cingulate cortex (PCC) showed that connectivity between the PCC and the caudate increased for the active treatment group, but decreased for the placebo group (p < 0.05 corrected). These findings reveal a substantial intervention effect for both active and placebo treatments, which could in part be associated with a placebo effect in subjective measures. There was, however, a significant treatment effect in the objective measure of functional connectivity, suggesting that reduced psychological stress and high-B-vitamin multivitamin supplementation may lead to an increase in DMN and caudate functional connectivity, which might reflect a strengthening of neurocircuitry within areas associated with reward and emotion at rest. Future studies should consider a placebo run-in methodology to reduce the placebo effect on the subjective measures of stress