Digitalis for treatment of heart failure in patients in sinus rhythm

<b>Background</b><p></p> Digitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity.<p></p> <b>Objectives</b><p></p> To examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with "HF due to systolic dysfunction" versus "HF with preserved ejection fraction."<p></p> <b>Search methods</b><p></p> Searches on the following databases were updated in May 2013: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Dissertation Abstracts. Annual meeting abstracts of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology were searched from 1996 to March 2013. In addition, reference lists provided by the pharmaceutical industry (GlaxoSmithKline and Covis Pharma) were searched.<p></p> <b>Selection criteria</b><p></p> Included were randomized placebo-controlled trials of 20 or more adult participants of either sex with symptomatic HF who were studied for seven weeks or longer. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of HF such as acute ischemic heart disease or myocarditis was present.<p></p> <b>Data collection and analysis</b><p></p> Articles selected from the searches described above were evaluated in a joint effort of the review authors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE.<p></p> <b>Main results</b><p></p> No new studies were identified in the updated searches. Thirteen studies (7896 participants) are included, and major endpoints of mortality, hospitalization, and clinical status, based respectively on 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with lower rates of both hospitalization and clinical deterioration. The largest study, in which most participants were taking angiotensin-converting enzyme inhibitors, showed a significant rise in “other cardiac” deaths, possibly due to arrhythmias. However collectively, these findings were based on studies done before beta-blockers, as well as angiotensin receptor blockers and aldosterone antagonists, became widely used to treat HF.<p></p> <b>Authors' conclusions</b><p></p> The literature indicates that digitalis may have a useful role in the treatment of patients with HF who are in normal sinus rhythm. New trials are needed to elucidate the importance of the dosage of digitalis and its usefulness in the era of beta-blockers and other agents shown to be effective in treating HF.<p></p&gt

Determinants of adolescent physical activity and inactivity patterns.

Objectives. Despite recognition of the important influence of environmental determinants on physical activity patterns, minimal empirical research has been done to assess the impact of environmental/contextual determinants of physical activity. This article aims to investigate environmental and sociodemographic determinants of physical activity and inactivity patterns among subpopulations of US adolescents. We define environmental determinants as modifiable factors in the physical environment that impose a direct influence on the opportunity to engage in physical activity. The present research examines environmental and sociodemographic determinants of physical activity and inactivity with the implication that these findings can point toward societal-level intervention strategies for increasing physical activity and decreasing inactivity among adolescents

Single-cell RNAseq reveals seven classes of colonic sensory neuron.

OBJECTIVE: Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. Colonic sensory neurons activate reflex pathways and give rise to conscious sensation, but the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by a paucity of molecular markers. Here we address this by comprehensive transcriptomic profiling and unsupervised clustering of individual mouse colonic sensory neurons. DESIGN: Unbiased single-cell RNA-sequencing was performed on retrogradely traced mouse colonic sensory neurons isolated from both thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia associated with lumbar splanchnic and pelvic spinal pathways, respectively. Identified neuronal subtypes were validated by single-cell qRT-PCR, immunohistochemistry (IHC) and Ca2+-imaging. RESULTS: Transcriptomic profiling and unsupervised clustering of 314 colonic sensory neurons revealed seven neuronal subtypes. Of these, five neuronal subtypes accounted for 99% of TL neurons, with LS neurons almost exclusively populating the remaining two subtypes. We identify and classify neurons based on novel subtype-specific marker genes using single-cell qRT-PCR and IHC to validate subtypes derived from RNA-sequencing. Lastly, functional Ca2+-imaging was conducted on colonic sensory neurons to demonstrate subtype-selective differential agonist activation. CONCLUSIONS: We identify seven subtypes of colonic sensory neurons using unbiased single-cell RNA-sequencing and confirm translation of patterning to protein expression, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity. These results provide a pathway to molecular interrogation of colonic sensory innervation in health and disease, together with identifying novel targets for drug development

Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways.

KEY POINTS: Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated sodium channel subtype NaV 1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV 1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics. ABSTRACT: Voltage-gated sodium channel NaV 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV 1.7 knockout mouse (NaV 1.7Nav1.8 ) and selective small-molecule NaV 1.7 antagonist PF-5198007. NaV 1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV 1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV 1.7 (in NaV 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV 1.7 antagonist PF-5198007. Our data demonstrate that NaV 1.7 (in NaV 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.University of Granada Dr Hadwen Trust for Humane Researc

Childhood obesity and community food environments in Alabama's Black Belt region

BackgroundChildhood obesity has been rising rapidly in the USA. The rate is higher among those at a lower socioeconomic status and racial/ethnic minority groups. In Alabama, nearly half of the children from rural African American families are overweight or obese. Studies suggest that children's eating behaviours and weight could be influenced by surrounding food environments. The purpose of this paper is to assess the community food environment and examine the associations with childhood obesity in Alabama's Black Belt region.MethodsThis research uses both qualitative and quantitative methods. Weight status of 613 African American students in four elementary schools in a rural county of Alabama was assessed. We examined community food environments around children's home through GIS (Geographic Information System) and statistical methods. The interrelations between children's weight and community food environments are explored with multi‐level models.ResultsApproximately 42.1% of surveyed children were overweight or obese, much higher than the national average, 30.6%. In Model 1, convenience stores (3.44; P < 0.01), full service restaurants (8.99; P < 0.01) and supermarkets (−37.69; P < 0.01) were significantly associated with the percentile of body mass index. Fast food stores (−0.93; P = 0.88) were not related to children's weight. In Model 2, the additions of sociodemographic factors and school effects cause significant changes of the relationships between children's weight and four types of food outlets. The percentage of African American population (90.23, P < 0.01) and school (6.68, P < 0.01) were positively associated with children's weight; while median household income (−39.6; P < 0.01) was negatively related to it.ConclusionChildren's weight is influenced by community food environments, sociodemographic factors and school context. Findings suggest that policymakers and planners need to improve community food environments of low‐income minority communities. Parents and schools should pay more attention to reduce the negative impacts of food environments on children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113139/1/cch12204.pd

Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.We would like to thank the EPSRC (SVL, grant nº EP/K0099494/1 and nº EP/K039520/1) for financial support.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ml500507v

Selenium inclusion decreases oxidative stress indicators and muscle injuries in sea bass larvae fed high-DHA microdiets

The objective of the present study was to determine the effect of Se inclusion in high-DHA and vitamin E microdiets (5 g DHA/100 g dry weight and 300 mg vitamin E/100 g dry weight; 5 g DHA/100 g dry weight and 300 mg vitamin E/100 g dry weight supplemented with Se) in comparison with a control diet (1 g DHA/100 g dry weight and 150 mg vitamin E/100 g dry weight) on sea bass larval growth, survival, biochemical composition, malonaldehyde (MDA) content, muscle morphology and antioxidant enzymes (AOE), insulin-like growth factors (IGF) and myosin expression. For a given DHA and vitamin E dietary content, Se inclusion favoured larval total length and specific growth rate, and reduced the incidence of muscular lesions, MDA contents and AOE gene expression. In contrast, IGF gene expression was elevated in the 5/300 larvae, suggesting an increased muscle mitogenesis that was corroborated by the increase in mRNA copies of myosin heavy chain. The results of the present study denoted the beneficial effect of Se not only in preventing oxidative stress, as a glutathione peroxidase cofactor, but probably due to other as yet unknown physiological functions

Thyroid control over biomembranes: VI. Lipids in liver mitochondria and microsomes of hypothyroid rats

The lipids of liver mitochondria prepared from normal rats and from rats made hypothyroid by thyroidectomy and injection with131INa contained similar amounts, per mg protein, of total lipids, phospholipids, neutral lipids and lipid phosphorus. Hypothyroidism caused a doubling of the relative amounts of mitochondrial cardiolipins (CL; to 20.5% of the phospholipid P) and an accompanying trend (although statistically not significant) toward decreased amounts of both phosphatidylcholines (PC) and phosphatidylserines (PS), with phosphatidylethanolamines (PE) remaining unchanged. The pattern of elevated 18∶2 fatty acyl content and depleted 20∶4 acyl groups of the mitochondrial phospholipids of hypothyroid preparations was reflected to varying degrees in the resolved phospholipids, with PC showing greater degrees of abnormality than PE, and CL showing none. Hypothyroidism produced the same abnormal pattern of fatty acyl distributions in liver microsomal total lipids as was found in the mitochondria. Hypothyroid rats, when killed 6 hr after injection of [1‐14C] labeled linoleate, showed the following abnormalities: the liver incorporated less label into lipids, and converted 18∶2 not exclusively to 20∶4 (as normals do) but instead incorporated the label mainly into saturated fatty acids. These data, together with the known decrease in β‐oxidation, suggest that hypothyroidism involves possible defective step(s) in the conversion of 18∶2 to 20∶4.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142296/1/lipd0328.pd

Extra-curricular physical activity and socioeconomic status in Italian adolescents

BACKGROUND: The relationship between physical activity and health status has been thoroughly investigated in several studies, while the relation between physical activity and socio-economic status (SES) is less investigated. The aim of this study was to measure the extra-curricular physical activity of adolescents related to the socio-economic status (SES) of their families. METHODS: The survey was carried out by submitting an anonymous questionnaire to junior high school students in the following Regions: Lazio, Abruzzo, Molise, Campania, Puglia, during the school year 2002–2003. Extra-curriculum physical activity was evaluated considering whether or not present and hours of activity weekly conducted. 2411 students agreed to participate in the study. RESULTS: Participants were 1121 males (46.5%) and 1290 females (53.5%), aged between 11 and 17 years (median age: 12 years). 71.1% of the students reported to practice extra-curricular physical activity. Parents' educational levels and work activities play an important role in predicting students' physical activity, with the more remunerative activities and higher educational levels being more predictive. CONCLUSION: The results confirm the relationship between adolescents' physical activity and their families' SES. In particular, a positive relationship between participation in extra-curricular physical activity and their families high SES was found. These data will be useful for school administrators and for politicians in order to reduce the gap between adolescents from the least and most disadvantaged families