The influence of comorbidities on achieving an N-terminal pro-b-type natriuretic peptide target: a secondary analysis of the GUIDE-IT trial.

Aims: N-terminal pro-b-type natriuretic peptide (NT-proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT-proBNP targets and clinical outcomes.

Methods: A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment trial.

Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour.

Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2).

How important is the α-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of α-adrenoceptor to urethral contractility.

Urethral smooth muscle (USM) contributes to urinary continence by contracting during the urine storage phase, which is mainly mediated by activation of postjunctional α-adrenoceptors. Males and females show differences in the functioning of the lower urinary tract and the most common urinary tract symptoms (LUTS). LUTS in men typically occur in association with bladder outlet obstruction, whereas in women urinary urge-incontinence symptoms are more common.

The reservoir-wave approach to characterize pulmonary vascular-right ventricular interactions in humans.

Using the reservoir-wave approach (RWA) we previously characterized pulmonary vasculature mechanics in a normal canine model. We found reflected backward-traveling waves that decrease pressure and increase flow in the proximal pulmonary artery (PA). These waves decrease right ventricular (RV) afterload and facilitate RV ejection.

Grading diastolic function by echocardiography: hemodynamic validation of existing guidelines.

Background: While echocardiographic grading of left ventricular (LV) diastolic dysfunction (DD) is used every day, the relationship between echocardiographic DD grade and hemodynamic abnormalities is uncertain.

Methods: We identified 460 consecutive patients who underwent transthoracic echocardiography within 24 h of elective left heart catheterization and had: normal sinus rhythm, no confounding structural heart disease, no change in medications between catheterization and echo, and complete echocardiographic data. Patients were grouped based on echocardiographic DD grade.

Blockade or deletion of transient receptor potential vanilloid 4 (TRPV4) is not protective in a murine model of sepsis.

Sepsis is a systemic inflammatory response triggered by microbial infection that can cause cardiovascular collapse, insufficient tissue perfusion and multi-organ failure. The cation channel transient receptor potential vanilloid 4 (TRPV4) is expressed in vascular endothelium and causes vasodilatation, but excessive TRPV4 activation leads to profound hypotension and circulatory collapse - key features of sepsis pathogenesis. We hypothesised that loss of TRPV4 signaling would protect against cardiovascular dysfunction in a mouse model of sepsis (endotoxaemia).

Baseline Functional Class and Therapeutic Efficacy of Common Heart Failure Interventions: A Systematic Review and Meta-analysis.

Background: New York Heart Association (NYHA) functional class provides important prognostic information and is often used to select patients for cardiovascular therapies, yet, the effect of NYHA class on therapeutic efficacy has not been systematically studied.

Methods: In this systematic review and meta-analysis we compared the relative and absolute mortality benefit of 5 common heart failure interventions (angiotensin-converting enzyme [ACE] inhibitors, β-blockers, mineralocorticoid receptor antagonists [MRAs], implantable cardioverter defibrillator [ICD], and cardiac resynchronization therapy [CRT]) across NYHA class. We included 26 randomized clinical trials of these interventions that reported all-cause mortality stratified according to baseline NYHA class in 36,406 patients.

HDAC4 is required for inflammation-associated thermal hypersensitivity.

Transcriptional alterations are characteristic of persistent pain states, but the key regulators remain elusive. HDAC4 is a transcriptional corepressor that has been linked to synaptic plasticity and neuronal excitability, mechanisms that may be involved in peripheral and central sensitization. Using a conditional knockout (cKO) strategy in mice, we sought to determine whether the loss of HDAC4 would have implications for sensory neuron transcription and nociception.

TRPA1 is essential for the vascular response to environmental cold exposure.

The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion.

Menthol inhibits detrusor contractility independently of TRPM8 activation.

Agonists such as icilin and menthol can activate the cool temperature-sensitive ion channel TRPM8. However, biological responses to menthol may occur independently of TRPM8 activation. In the rodent urinary bladder, menthol facilitates the micturition reflex but inhibits muscarinic contractions of the detrusor smooth muscle.

Development of a consensus algorithm to improve interobserver agreement and accuracy in the determination of tricuspid regurgitation severity.

Background: Multiparametric scoring of valvular regurgitation may compromise interobserver agreement, as readers weight parameters differently. The aims of this study were to quantify interobserver variability in the grading of chronic tricuspid regurgitation (TR), develop an algorithm for grading TR, and assess the effect of this algorithm on concordance and accuracy.

Methods: On the basis of current guidelines, two experts graded the severity of TR by consensus in 40 patients with a spectrum of TR severity.

Phenotype-independent effects of retroviral transduction in human dental pulp stem cells.

An immortalized human dental pulp stem cell (DPSC) line of an odontoblastic phenotype is established to circumvent the normal programmed senescence and to maintain the cell line's usefulness as a tool for further study of cellular activity. DPSCs are isolated from human dental pulp tissues and transfected using hTERT. The influence of this process on the DPSC phenotype and the mRNA expression of oncogenes involved in cellular senescence is investigated.

Insulin relaxes bladder via PI3K/AKT/eNOS pathway activation in mucosa: unfolded protein response-dependent insulin resistance as a cause of obesity-associated overactive bladder.

We aimed to investigate the role of insulin in the bladder and its relevance for the development of overactive bladder (OAB) in insulin-resistant obese mice. Bladders from male individuals who were involved in multiple organ donations were used. C57BL6/J mice were fed with a high-fat diet for 10 weeks to induce insulin-resistant obesity.

Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.

Objectives: The aim of this study was to identify the best echocardiographic method for sequential quantification of left ventricular (LV) ejection fraction (EF) and volumes in patients undergoing cancer chemotherapy.

Background: Decisions regarding cancer therapy are based on temporal changes of EF. However the method for EF measurement with the lowest temporal variability is unknown.

Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice.

Obesity/metabolic syndrome are common risk factors for overactive bladder. This study aimed to investigate the functional and molecular changes of detrusor smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction.

Independent and incremental role of quantitative right ventricular evaluation for the prediction of right ventricular failure after left ventricular assist device implantation.

Objectives: This study sought to determine the utility of quantitation of right ventricular (RV) function in predicting RV failure in patients undergoing left ventricular assist device (LVAD) implantation.

Background: Clinical evaluation alone seems insufficient for predicting RV failure, an important cause of morbidity and mortality after LVAD implantation.

Methods: Clinical, hemodynamic, and echocardiographic data were collected on 117 patients undergoing LVAD implantation.

P16/p53 expression and telomerase activity in immortalized human dental pulp cells.

Introduction: Residing within human dental pulp are cells of an ectomesenchymal origin which have the potential to differentiate into odontoblast-like cells. These cells have a limited growth potential owing to the effects of cell senescence. This study examines the effects of immortalizing odontoblast-like cells on cell proliferation and mineralization by comparing transformed dental pulp stem cells (tDPSCs) and non-transformed dental pulp stem cells (nDPSCs).

Protein kinase D isoforms are expressed in rat and mouse primary sensory neurons and are activated by agonists of protease-activated receptor 2.

Serine proteases generated during injury and inflammation cleave protease-activated receptor 2 (PAR(2)) on primary sensory neurons to induce neurogenic inflammation and hyperalgesia. Hyperalgesia requires sensitization of transient receptor potential vanilloid (TRPV) ion channels by mechanisms involving phospholipase C and protein kinase C (PKC). The protein kinase D (PKD) serine/threonine kinases are activated by diacylglycerol and PKCs and can phosphorylate TRPV1.

Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice.

Exacerbated sensitivity to mechanical stimuli that are normally innocuous or mildly painful (mechanical allodynia and hyperalgesia) occurs during inflammation and underlies painful diseases. Proteases that are generated during inflammation and disease cleave protease-activated receptor 2 (PAR2) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR2-mediated mechanical hyperalgesia requires sensitization of the ion channel transient receptor potential vanilloid 4 (TRPV4).

Evidence for a novel protective role of the vanilloid TRPV1 receptor in a cutaneous contact allergic dermatitis model.

The purpose of this study was to examine the involvement of the transient receptor potential vanilloid receptor 1 (TRPV1) in inflammatory processes observed in murine allergic contact dermatitis (ACD). Oxazolone-induced ACD evoked a significant ear swelling after 24-72 h. It was augmented in TRPV1 knockout mice at all time points and supported by histological analysis and measure of TNF-alpha.

An examination of neurogenic mechanisms involved in mustard oil-induced inflammation in the mouse.

The mechanisms by which topical mustard oil causes vasodilatation in the mouse were investigated using the tachykinin NK1 receptor antagonist SR140333 and the calcitonin gene-related peptide (CGRP) antagonist BIBN4096BS, alongside alphaCGRP or NK1 receptor knockout mice. Blood flow was assessed by laser Doppler flowmetry and plasma extravasation by 125I-albumin accumulation. Mustard oil produced significant plasma extravasation and vasodilatation in wild type mice, although the plasma extravasation was less than that seen with capsaicin whilst the vasodilatation was greater.

Vascular actions of calcitonin gene-related peptide and adrenomedullin.

This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM). CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas. They share vasodilator activity, albeit to varying extents depending on species and tissue.

Tachykinins regulate the function of platelets.

Evidence has been mounting for peripheral functions for tachykinins, a family of neuropeptides including substance P (SP), neurokinin A, and neurokinin B, which are recognized for their roles in the central and peripheral nervous system. The recent discovery of 4 new members of this family, the endokinins (EKA, B, C, and D), which are distributed peripherally, adds support to the notion that tachykinins have physiologic/endocrine roles in the periphery. In the present study we report a fundamental new function for tachykinins in the regulation of platelet function.

Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback.

The concept that NK1 receptors are located pre-junctionally on substance P (SP)-containing nerves, acting as autoreceptors to inhibit SP release, has been suggested, but remains a controversial issue. To further investigate the existence of this receptor on central and peripheral terminals of primary afferent fibres, NK1 receptor knockout mice and an NK1 receptor antagonist were used in nerve-attached tissue preparations. These were the isolated dorsal horn of the spinal cord with dorsal roots attached, and the hairy skin of the hind paw with attached saphenous nerve.