Development of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves

Members of the voltage-gated K+ channel subfamily (Kv1), involved in regulating transmission between neurons or to muscles, are associated with human diseases and, thus, putative targets for neurotherapeutics. This applies especially to those containing Kv1.1 α subunits which become prevalent in murine demyelinated axons and appear abnormally at inter-nodes, underlying the perturbed propagation of nerve signals. To overcome this dysfunction, akin to the consequential debilitation in multiple sclerosis (MS), small inhibitors were sought that are selective for the culpable hyper-polarising K+ currents. Herein, we report a new semi-podand – compound 3 – that was designed based on the modelling of its interactions with the extracellular pore region in a deduced Kv1.1 channel structure. After synthesis, purification, and structural characterisation, compound 3 was found to potently (IC50 = 8 µM) and selectively block Kv1.1 and 1.6 channels. The tested compound showed no apparent effect on native Nav and Cav channels expressed in F-11 cells. Compound 3 also extensively and selectively inhibited MS-related Kv1.1 homomer but not the brain native Kv1.1- or 1.6-containing channels. These collective findings highlight the therapeutic potential of compound 3 to block currents mediated by Kv1.1 channels enriched in demyelinated central neurons

Pathways for nutrient loss to water with emphasis on phosphorus

Teagasc wishes to acknowledge the support of the Environmental Research Technological Development and Innovation (ERTDI) Programme under the Productive Sector Operational Programme which was financed by the Irish Government under the National Development Plan 2000-2006.End of project reportThe main objective of this project was to study phosphorus (P) loss from agricultural land under a range of conditions in Ireland, to quantify the main factors influencing losses and make recommendations on ways to reduce these losses. This report is a synthesis of the main conclusions and recommendations from the results of the studies. The final reports from the individual sub-projects in this project are available from the EPA (www.epa.ie).Environmental Protection Agenc

Disorder-specific functional abnormalities during temporal discounting in youth with Attention Deficit Hyperactivity Disorder (ADHD), Autism and comorbid ADHD and Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share cognitive abnormalities in temporal foresight. A key question is whether shared cognitive phenotypes are based on common or different underlying pathophysiologies and whether comorbid patients have additive neurofunctional deficits, resemble one of the disorders or have a different pathophysiology. We compared age- and IQ-matched boys with non-comorbid ADHD (18), non-comorbid ASD (15), comorbid ADHD and ASD (13) and healthy controls (18) using functional magnetic resonance imaging (fMRI) during a temporal discounting task. Only the ASD and the comorbid groups discounted delayed rewards more steeply. The fMRI data showed both shared and disorder-specific abnormalities in the three groups relative to controls in their brain-behaviour associations. The comorbid group showed both unique and more severe brain-discounting associations than controls and the non-comorbid patient groups in temporal discounting areas of ventromedial and lateral prefrontal cortex, ventral striatum and anterior cingulate, suggesting that comorbidity is neither an endophenocopy of the two pure disorders nor an additive pathology

Improving the organisation of maternal health service delivery and optimising childbirth by increasing vaginal birth after caesarean section through enhanced women-centred care (OptiBIRTH trial): study protocol for a randomised controlled trial (ISRCTN10612254)

Open Access JournalBackground The proportion of pregnant women who have a caesarean section shows a wide variation across Europe, and concern exists that these proportions are increasing. Much of the increase in caesarean sections in recent years is due to a cascade effect in which a woman who has had one caesarean section is much more likely to have one again if she has another baby. In some places, it has become common practice for a woman who has had a caesarean section to have this procedure again as a matter of routine. The alternative, vaginal birth after caesarean (VBAC), which has been widely recommended, results in fewer undesired results or complications and is the preferred option for most women. However, VBAC rates in some countries are much lower than in other countries. Methods/Design The OptiBIRTH trial uses a cluster randomised design to test a specially developed approach to try to improve the VBAC rate. It will attempt to increase VBAC rates from 25 % to 40 % through increased women-centred care and women’s involvement in their care. Sixteen hospitals in Germany, Ireland and Italy agreed to join the study, and each hospital was randomly allocated to be either an intervention or a control site. Discussion If the OptiBIRTH intervention succeeds in increasing VBAC rates, its application across Europe might avoid the 160,000 unnecessary caesarean sections that occur every year at an extra direct annual cost of more than €150 million

Health economic analysis of a cluster‐randomised trial (OptiBIRTH) designed to increase rates of vaginal birth after caesarean section

Der Artikel wurde innerhalb des EU-Projekts OptiBIRTH erstellt.This is the peer reviewed version of the following article: [Haunberger, S, Rüegger, C, Baumgartner, E. Experiences with a psychosocial screening instrument (S‐FIRST) to identify the psychosocial support needs of parents of children suffering from cancer. Psycho‐Oncology. 2019; 28: 1025‐ 1032.], which has been published in final form at https://doi.org/10.1002/pon.5045. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Objective: To perform a health economic analysis of an intervention designed to increase rates of vaginal birth after caesarean, compared with usual care. Design: Economic analysis alongside the cluster-randomised OptiBIRTH trial (Optimising childbirth by increasing vaginal birth after caesarean section (VBAC) through enhanced women-centred care). Setting: Fifteen maternity units in three European countries - Germany (five), Ireland (five), and Italy (five) - with relatively low VBAC rates. Population: Pregnant women with a history of one previous lower-segment caesarean section; sites were randomised (3:2) to intervention or control. Methods: A cost-utility analysis from both societal and health-services perspectives, using a decision tree. Main Outcome Measures: Costs and resource use per woman and infant were compared between the control and intervention group by country, from pregnancy recognition until 3 months postpartum. Based on the caesarean section rates, and maternal and neonatal morbidities and mortality, the incremental cost-utility ratios were calculated per country. Results: The mean difference in costs per quality-adjusted life years (QALYs) gained from a societal perspective between the intervention and the control group, using a probabilistic sensitivity analysis, was: €263 (95% CI €258-268) and 0.008 QALYs (95% CI 0.008-0.009 QALYs) for Germany, €456 (95% CI €448-464) and 0.052 QALYs (95% CI 0.051-0.053 QALYs) for Ireland, and €1174 (95% CI €1170-1178) and 0.006 QALYs (95% CI 0.005-0.007 QALYs) for Italy. The incremental cost-utility ratios were €33,741/QALY for Germany, €8785/QALY for Ireland, and €214,318/QALY for Italy, with a 51% probability of being cost-effective for Germany, 92% for Ireland, and 15% for Italy. Conclusion: The OptiBIRTH intervention was likely to be cost-effective in Ireland and Germany

Cardiotocography versus intermittent auscultation of fetal heart on admission to labour ward for assessment of fetal wellbeing

BACKGROUND: The admission cardiotocograph (CTG) is a commonly used screening test consisting of a short (usually 20 minutes) recording of the fetal heart rate (FHR) and uterine activity performed on the mother's admission to the labour ward. This is an update of a review published in 2012. OBJECTIVES: To compare the effects of admission cardiotocography with intermittent auscultation of the FHR on maternal and infant outcomes for pregnant women without risk factors on their admission to the labour ward. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register to 30 November 2016 and we planned to review the reference list of retrieved papers. SELECTION CRITERIA: All randomised and quasi-randomised trials comparing admission CTG with intermittent auscultation of the FHR for pregnant women between 37 and 42 completed weeks of pregnancy and considered to be at low risk of intrapartum fetal hypoxia and of developing complications during labour. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and quality, and extracted data. Data were checked for accuracy. MAIN RESULTS: We included no new trials in this update. We included four trials involving more than 13,000 women which were conducted in the UK and Ireland and included women in labour. Three trials were funded by the hospitals where the trials took place and one trial was funded by the Scottish government. No declarations of interest were made in two trials; the remaining two trials did not mention declarations of interest. Overall, the studies were assessed as low risk of bias. Results reported in the 2012 review remain unchanged.Although not statistically significant using a strict P < 0.05 criterion, data were consistent with women allocated to admission CTG having, on average, a higher probability of an increase in incidence of caesarean section than women allocated to intermittent auscultation (risk ratio (RR) 1.20, 95% confidence interval (CI) 1.00 to 1.44, 4 trials, 11,338 women, I² = 0%, moderate quality evidence). There was no clear difference in the average treatment effect across included trials between women allocated to admission CTG and women allocated to intermittent auscultation in instrumental vaginal birth (RR 1.10, 95% CI 0.95 to 1.27, 4 trials, 11,338 women, I² = 38%, low quality evidence) and perinatal mortality rate (RR 1.01, 95% CI 0.30 to 3.47, 4 trials, 11,339 infants, I² = 0%, moderate quality evidence).Women allocated to admission CTG had, on average, higher rates of continuous electronic fetal monitoring during labour (RR 1.30, 95% CI 1.14 to 1.48, 3 trials, 10,753 women, I² = 79%, low quality evidence) and fetal blood sampling (RR 1.28, 95% CI 1.13 to 1.45, 3 trials, 10,757 women, I² = 0%) than women allocated to intermittent auscultation. There were no differences between groups in other secondary outcome measures including incidence and severity of hypoxic ischaemic encephalopathy (incidence only reported) (RR 1.19, 95% CI 0.37 to 3.90; 2367 infants; 1 trial; very low quality evidence) and incidence of seizures in the neonatal period (RR 0.72, 95% CI 0.32 to 1.61; 8056 infants; 1 trial; low quality evidence). There were no data reported for severe neurodevelopmental disability assessed at greater than, or equal to, 12 months of age. AUTHORS' CONCLUSIONS: Contrary to continued use in some clinical areas, we found no evidence of benefit for the use of the admission CTG for low-risk women on admission in labour.Furthermore, the probability is that admission CTG increases the caesarean section rate by approximately 20%. The data lacked power to detect possible important differences in perinatal mortality. However, it is unlikely that any trial, or meta-analysis, will be adequately powered to detect such differences. The findings of this review support recommendations that the admission CTG not be used for women who are low risk on admission in labour. Women should be informed that admission CTG is likely associated with an increase in the incidence of caesarean section without evidence of benefit.Evidence quality ranged from moderate to very low, with downgrading decisions based on imprecision, inconsistency and a lack of blinding for participants and personnel. All four included trials were conducted in developed Western European countries. One additional study is ongoing.The usefulness of the findings of this review for developing countries will depend on FHR monitoring practices. However, an absence of benefit and likely harm associated with admission CTG will have relevance for countries where questions are being asked about the role of the admission CTG.Future studies evaluating the effects of the admission CTG should consider including women admitted with signs of labour and before a formal diagnosis of labour. This would include a cohort of women currently having admission CTGs and not included in current trials

A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

K+ channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K+ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2′-((5,5′(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2′carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC50 ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K+ current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis

Effects of a multicomponent resistance-based exercise program with protein, vitamin D and calcium supplementation on cognition in men with prostate cancer treated with ADT: Secondary analysis of a 12-month randomised controlled trial

OBJECTIVES: The aim of this preplanned secondary analysis of a 12-month randomised controlled trial was to investigate the effects of a multicomponent exercise programme combined with daily whey protein, calcium and vitamin D supplementation on cognition in men with prostate cancer treated with androgen deprivation therapy (ADT). DESIGN: 12-month, two-arm, randomised controlled trial. SETTING: University clinical exercise centre. PARTICIPANTS: 70 ADT-treated men were randomised to exercise-training plus supplementation (Ex+ Suppl, n=34) or usual care (control, n=36). INTERVENTION: Men allocated to Ex + Suppl undertook thrice weekly resistance training with weight-bearing exercise training plus daily whey protein (25 g), calcium (1200 mg) and vitamin D (2000 IU) supplementation. PRIMARY AND SECONDARY OUTCOME MEASURES: Cognition was assessed at baseline, 6 and 12 months via a computerised battery (CogState), Trail-making test, Rey auditory-verbal learning test and Digit span. Data were analysed with linear mixed models and an intention-to-treat and prespecified per-protocol approach (exercise-training: ≥ 66%, nutritional supplement: ≥ 80%). RESULTS: Sixty (86%) men completed the trial (Ex + Suppl, n = 31; control, n = 29). Five (7.1%) men were classified as having mild cognitive impairment at baseline. Median (IQR) adherence to the exercise and supplement was 56% (37%-82%) and 91% (66%-97%), respectively. Ex + Suppl had no effect on cognition at any time. CONCLUSIONS: A 12-month multicomponent exercise training and supplementation intervention had no significant effect on cognition in men treated with ADT for prostate cancer compared with usual care. Exercise training adherence below recommended guidelines does not support cognitive health in men treated with ADT for prostate cancer. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry (ACTRN12614000317695, registered 25/03/2014) and acknowledged under the Therapeutic Goods Administration Clinical Trial Notification Scheme (CT-2015-CTN-03372-1 v1)

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy