Learning needs, preferred learning methods and learning challenges of first five general practitioners in NHS Scotland: a qualitative study.

Objectives: To identify the learning needs and preferred learning methods of First5 general practitioners (GPs) in National Health Service (NHS) Scotland.

Design: Qualitative research study using grounded theory methods. First5 GPs were interviewed in small focus groups or individual interviews in-person, or over the telephone depending on their preference.

Barriers and facilitators to patient uptake and utilisation of digital interventions for the self-management of low back pain: a systematic review of qualitative studies.

Objectives: Low back pain (LBP) is a leading contributor to disability globally. Self-management is a core component of LBP management. We aimed to synthesise published qualitative literature concerning digital health interventions (DHIs) to support LBP self-management to: (1) determine engagement strategies, (2) identify barriers and facilitators affecting patient uptake/utilisation and (3) develop a preliminary conceptual model of barriers and facilitators to uptake/utilisation.

What helps and hinders the provision of healthcare that minimises treatment burden and maximises patient capacity? A qualitative study of stroke health professional perspectives.

Objectives: Treatment burden is the healthcare workload experienced by individuals with long-term conditions and the impact on well-being. Excessive treatment burden can negatively affect quality-of-life and adherence to treatments. Patient capacity is the ability of an individual to manage their life and health problems and is dependent on a variety of physical, psychological and social factors.

A non-randomised controlled pilot study of clinical pharmacist collaborative intervention for community dwelling patients with COPD.

UK, home-based patients with COPD receive specialist care from respiratory physicians, nurses, and general practitioners (GPs), but increasing complexity of therapeutic options and a GP/Nurse workforce crisis suggests merit in testing the role of home visits by a clinical pharmacist. We conducted a non-randomised intervention study with a contemporaneous comparator group, in Glasgow (Scotland). A clinical pharmacist (working closely with a consultant respiratory physician) visited patients with COPD living at home, assessing respiratory and other co-morbid conditions, and medicines then, with patient approval, agreed treatment modifications with a consultant physician.

Transgenic overexpression of the SUR2A-55 splice variant in mouse heart reduces infract size and promotes protective mitochondrial function.

ATP-sensitive potassium channels found in both the sarcolemma (sarcK) and mitochondria (mitoK) of cardiomyocytes are important mediators of cardioprotection during ischemic heart disease. Sulfonylurea receptor isoforms (SUR2), encoded by , an ATP-binding cassette family member, form regulatory subunits of the sarcK channel and are also thought to regulate mitoK channel activity. A short-form splice variant of SUR2 (SUR2A-55) was previously shown to target mitochondria and display diaxoxide and ATP insensitive K activity when co-expressed with the inward rectifier channels Kir6.

An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population.

Background: We have identified the cardiomyopathy-susceptibility gene vinculin () mutation M94I may account for a sudden unexplained nocturnal death syndrome (SUNDS) case. We addressed whether common variant D841H is associated with SUNDS.

Methods And Results: In 8 of 120 SUNDS cases, we detected an East Asian common VCL variant p.

Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current.

Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS.

Does Sudden Unexplained Nocturnal Death Syndrome Remain the Autopsy-Negative Disorder: A Gross, Microscopic, and Molecular Autopsy Investigation in Southern China.

Objective: To look for previously unrecognized cardiac structural abnormalities and address the genetic cause for sudden unexplained nocturnal death syndrome (SUNDS).

Methods: Data for 148 SUNDS victims and 444 controls (matched 1:3 on sex, race, and age of death within 1 year) were collected from Sun Yat-sen University from January 1, 1998, to December 31, 2014, to search morphological changes. An additional 17 patients with Brugada syndrome (BrS) collected from January 1, 2006, to December 31, 2014, served as a comparative disease cohort.

Mechanisms of sudden cardiac death: oxidants and metabolism.

Ventricular arrhythmia is the leading cause of sudden cardiac death (SCD). Deranged cardiac metabolism and abnormal redox state during cardiac diseases foment arrhythmogenic substrates through direct or indirect modulation of cardiac ion channel/transporter function. This review presents current evidence on the mechanisms linking metabolic derangement and excessive oxidative stress to ion channel/transporter dysfunction that predisposes to ventricular arrhythmias and SCD.

Mouse ERG K(+) channel clones reveal differences in protein trafficking and function.

Background: The mouse ether-a-go-go-related gene 1a (mERG1a, mKCNH2) encodes mERG K(+) channels in mouse cardiomyocytes. The mERG channels and their human analogue, hERG channels, conduct IKr. Mutations in hERG channels reduce IKr to cause congenital long-QT syndrome type 2, mostly by decreasing surface membrane expression of trafficking-deficient channels.

Diseases caused by mutations in Na1.5 interacting proteins.

Sodium current in the heart flows principally through the pore protein Na1.5, which is part of a complex of interacting proteins that serve both to target and localize the complex in the membrane, and to modulate function by such post-translational modifications as phosphorylation and nitrosylation. Multiple mutations in seven different Na1.

The effect of withdrawal and intake of nicotine on smokers' ability to ignore distractors in a number parity decision task.

Nicotine's attention enhancing effects are often attributed to enhancement of stimulus filtering by the attention networks. We investigated distractibility in 20 abstinent cigarette smokers (9 hours overnight; phase 1) and tested them again after smoking one cigarette (phase 2). Their performance was compared to 20 nonsmokers (no nicotine intake).

Channelopathies from mutations in the cardiac sodium channel protein complex.

The cardiac sodium current underlies excitability in heart, and inherited abnormalities of the proteins regulating and conducting this current cause inherited arrhythmia syndromes. This review focuses on inherited mutations in non-pore forming proteins of sodium channel complexes that cause cardiac arrhythmia, and the deduced mechanisms by which they affect function and dysfunction of the cardiac sodium current. Defining the structure and function of these complexes and how they are regulated will contribute to understanding the possible roles for this complex in normal and abnormal physiology and homeostasis.

An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract.

Autosomal dominant congenital cataracts have been associated with mutations of genes encoding several soluble and membrane proteins. By candidate gene screening, we identified a novel mutation in MIP (c.494 G > A) that segregates with a congenital lamellar cataract within a south Indian family and causes the replacement of a highly conserved glycine by aspartate (G165D) within aquaporin0 (AQP0).

Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure.

The amino terminal domain (NT) of the connexins consists of their first 22-23 amino acids. Site-directed mutagenesis studies have demonstrated that NT amino acids are determinants of gap junction channel properties including unitary conductance, permeability/selectivity, and gating in response to transjunctional voltage. The importance of this region has also been emphasized by the identification of multiple disease-associated connexin mutants affecting amino acid residues in the NT region.

The N terminus of connexin37 contains an alpha-helix that is required for channel function.

The cytoplasmic N-terminal domain of connexins has been implicated in multiple aspects of gap junction function, including connexin trafficking/assembly and channel gating. A synthetic peptide corresponding to the first 23 amino acids of human connexin37 was prepared, and circular dichroism and nuclear magnetic resonance studies showed that this N-terminal peptide was predominantly alpha-helical between glycine 5 and glutamate 16. The importance of this structure for localization of the protein at appositional membranes and channel function was tested by expression of site-directed mutants of connexin37 in which amino acids leucine 10 and glutamine 15 were replaced with prolines or alanines.

Late Na+ current produced by human cardiac Na+ channel isoform Nav1.5 is modulated by its beta1 subunit.

Experimental data accumulated over the past decade show the emerging importance of the late sodium current (I(NaL)) for the function of both normal and, especially, failing myocardium, in which I(NaL) is reportedly increased. While recent molecular studies identified the cardiac Na(+) channel (NaCh) alpha subunit isoform (Na(v)1.5) as a major contributor to I (NaL), the molecular mechanisms underlying alterations of I(NaL) in heart failure (HF) are still unknown.

An intact connexin N-terminus is required for function but not gap junction formation.

The cytoplasmic N-termini of connexins have been implicated in protein trafficking, oligomerization and channel gating. To elucidate the role of the N-terminus in connexin37 (CX37), we studied mutant constructs containing partial deletions of its 23 N-terminal amino acids and a construct with a complete N-terminus in which residues 2-8 were replaced with alanines. All mutants containing nine or more N-terminal amino acids form gap junction plaques in transiently transfected HeLa cells, whereas most of the longer deletions do not.

Molecular identity of the late sodium current in adult dog cardiomyocytes identified by Nav1.5 antisense inhibition.

Late Na(+) current (I(NaL)) is a major component of the action potential plateau in human and canine myocardium. Since I(NaL) is increased in heart failure and ischemia, it represents a novel potential target for cardioprotection. However, the molecular identity of I(NaL) remains unclear.

Toxin-resistant sodium channels: parallel adaptive evolution across a complete gene family.

Approximately 75% of vertebrate proteins belong to protein families encoded by multiple evolutionarily related genes, a pattern that emerged as a result of gene and genome duplications over the course of vertebrate evolution. In families of genes with similar or related functions, adaptation to a strong selective agent should involve multiple adaptive changes across the entire gene family. However, we know of no evolutionary studies that have explicitly addressed this point.

An inner pore residue (Asn406) in the Nav1.5 channel controls slow inactivation and enhances mibefradil block to T-type Ca2+ channel levels.

Mibefradil is a tetralol derivative once marketed to treat hyper-tension. Its primary target is the T-type Ca(2+) channel (IC(50), approximately 0.1-0.

A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies.

Highly alternatively spliced genes may provide complex targets for disease mutations. Structural changes created by missense mutations may differentially affect the activity of alternative gene products, whereas missense, silent and non-coding mutations may alter developmental regulation of splice variant expression. CACNA1H is a human gene encoding Ca(v)3.

Flecainide sensitivity of a Na channel long QT mutation shows an open-channel blocking mechanism for use-dependent block.

A long QT mutation in the cardiac sodium channel, D1790G (DG), shows enhanced flecainide use-dependent block (UDB). The relative importance of open and inactivated states of the channel in flecainide UDB has been controversial. We used a modifiable, inactivation-deficient mutant channel that contains the F1486C mutation in the IFM motif to investigate the UDB difference between the wild-type (WT-ICM) and DG (DG-ICM) channels.

Gating of the late Na+ channel in normal and failing human myocardium.

We previously reported an ultraslow inactivating late Na+ current (INaL) in left ventricular cardiomyocytes (VC) isolated from normal (NVC) and failing (FVC) human hearts. This current could play a role in heart failure-induced repolarization abnormalities. To identify properties of NaCh contributing to INaL, we examined early and late openings in cell-attached patches of HEK293 cells expressing human cardiac NaCh alpha-subunit (alpha-HEK) and in VC of one normal and three failing human hearts.