PKD Phosphorylation as Novel Pathway of K_V11.1 Regulation

Background/Aims: The voltage-gated potassium channel KV11.1 has been originally cloned from the brain and is expressed in a variety of tissues. The role of phosphorylation for channel function is a matter of debate. In this study, we aimed to elucidate the extent and role of protein kinase D mediated phosphorylation. Methods: We employed mass spectrometry, whole-cell patch clamp electrophysiology, confocal microscopy, site-directed mutagenesis, and western blotting. Results: Using brain tissue from rat and mouse, we mapped several phosphorylated KV11.1 residues by LC-MS mass spectrometry and identified protein kinase D (PKD1) as possible regulatory kinase. Co-expression of KV11.1 with PKD1 reduced current amplitudes without altering protein levels or surface expression of the channel. Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1. Conclusions: Our data might help mitigating a long-standing controversy in the field regarding PKC regulation of KV11.1. We propose that PKD1 mediates the PKC effects on KV11.1 and we found that PKD targets S284 in the N-terminus of the channel

Hyperthermia impairs short-term memory and peripheral motor drive transmission

The aims of this study were to determine (i) the effect of passive hyperthermia on motor drive and cognitive function, and (ii) whether head cooling can limit the hyperthermia-induced alterations. Sixteen subjects were randomly exposed for 2 h to three different conditions: control (Con, 20°C), hot (Hot, 50°C) and hot head cool (HHC – where cold packs were applied to the head under Hot conditions). Three cognitive tests measuring attention and two measuring memory were performed. Neuromuscular testing included electrically evoked muscle action potentials (M-waves) and reflex waves (H-reflex) at rest and during brief (4–5 s) and sustained (120 s) maximal voluntary contractions (MVC) of the plantar flexors. All the tests were performed in the environmental room. During brief MVC, torque was significantly lower in both Hot and HHC as compared to Con (P < 0.05). The decrease in muscle activation was significant in Hot (P < 0.05) but not in HBC (P= 0.07). This was accompanied by peripheral failures in the transmission of the neural drive at both spinal (significant decrements in H-reflexes and V-waves, P < 0.05) and neuromuscular junction (significant decrements in M-waves, P < 0.05) levels. During sustained MVC, muscle activation was further depressed (P < 0.05) without any concomitant failures in M-waves, suggesting neural activation adjustments occurring probably at the supraspinal level. Cerebral perturbations were confirmed by significant decrements in both memory tests in Hot as compared with Con (P < 0.05) but not in simple tests (attention tests) that were not affected by hyperthermia. The decrement in memory capacity suggested the existence of frontal lobe activity impairments. Thus, HHC preserved memory capacity but not the visual memory

Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales

Background Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. Methods We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. Results Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be −178.8 g (95% CI −225.43 to −134.47 g) in the Danish population and −210.08 g (95% CI −281.97 to −141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age. Conclusions CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestatio

Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality:a cluster-randomized clinical trial (TRIAGE III)

Abstract Background Risk stratification of patients in the emergency department can be strengthened using prognostic biomarkers, but the impact on patient prognosis is unknown. The aim of the TRIAGE III trial was to investigate whether the introduction of the prognostic and nonspecific biomarker: soluble urokinase plasminogen activator receptor (suPAR) for risk stratification in the emergency department reduces mortality in acutely admitted patients. Methods The TRIAGE III trial was a cluster-randomized interventional trial conducted at emergency departments in the Capitol Region of Denmark. Eligible hospitals were required to have an emergency department with an intake of acute medical and surgical patients and no previous access to suPAR measurement. Three emergency departments were randomized; one withdrew shortly after the trial began. The inclusion period was from January through June of 2016 consisting of twelve cluster-periods of 3-weeks alternating between intervention and control and a subsequent follow-up of ten months. Patients were allocated to the intervention if they arrived in interventional periods, where suPAR measurement was routinely analysed at arrival. In the control periods suPAR measurement was not performed. The main outcome was all-cause mortality 10 months after arrival of the last patient in the inclusion period. Secondary outcomes included 30-day mortality. Results The trial enrolled a consecutive cohort of 16,801 acutely admitted patients; all were included in the analyses. The intervention group consisted of 6 cluster periods with 8900 patients and the control group consisted of 6 cluster periods with 7901 patients. After a median follow-up of 362 days, death occurred in 1241 patients (13.9%) in the intervention group and in 1126 patients (14.3%) in the control group. The weighted Cox model found a hazard ratio of 0.97 (95% confidence interval, 0.89 to 1.07; p = 0.57). Analysis of all subgroups and of 30-day all-cause mortality showed similar results. Conclusions The TRIAGE III trial found no effect of introducing the nonspecific and prognostic biomarker suPAR in emergency departments on short- or long-term all-cause mortality among acutely admitted patients. Further research is required to evaluate how prognostic biomarkers can be implemented in routine clinical practice. Trial registration clinicaltrials.gov, NCT02643459. Registered 31 December 2015

Advanced parental age: Is it contributing to an increased incidence of non-syndromic craniosynostosis? A review of case-control studies

Background: Craniosynostosis (CS) is a congenital birth defect characterized by the premature fusion of one or several calvarial suture(s). CS could lead to serious complications, such as intracranial hypertension and neurodevelopmental impairment. There is an increasing trend in the prevalence of CS – 75% of which are of non-syndromic type (NSCS). In parallel, there is a steady rise in the average maternal age. The goal of this paper was to review the literature to clearly identify any associations between parental age and NSCS. This review was performed and reported in compliance with PRISMA guidelines. Methods: The PUBMED and EMBASE databases were systematically searched, and all studies that observed the relationship between maternal and/or paternal age on NSCS were included. The articles were then assessed for methodological quality using the Newcastle–Ottawa Scale (NOS). The effect of advanced maternal and/or paternal age on the incidence of NSCS was identified by the prevalence ratios reported at a confidence interval of 95%. Results: Six retrospective case-control studies, reporting on a total of 3267 cases of NSCS were included in this review. While there were some inconsistencies in the findings of the different studies, the majority reported a positive correlation between advanced maternal and/or paternal age and an increased incidence of NSCS. Conclusion: This review identified an association between advanced parental age and an increased incidence of NSCS