Neuronal expression of the intermediate conductance calcium-activated potassium channel KCa3.1 in the mammalian central nervous system.

The expression pattern and functional roles for calcium-activated potassium channels of the KCa2.x family and KCa1.1 have been extensively examined in central neurons.

Effect of the Brugada syndrome mutation A39V on calmodulin regulation of Cav1.2 channels.

Background: The L-type calcium channel Cav1.2 is important for brain and heart function. The ubiquitous calcium sensing protein calmodulin (CaM) regulates calcium dependent gating of Cav1.

MicroRNA-27a/b regulates cellular cholesterol efflux, influx and esterification/hydrolysis in THP-1 macrophages.

Rationale: Macrophage cholesterol homeostasis maintenance is the result of a balance between influx, endogenous synthesis, esterification/hydrolysis and efflux. Excessive accumulation of cholesterol leads to foam cell formation, which is the major pathology of atherosclerosis. Previous studies have shown that miR-27 (miR-27a and miR-27b) may play a key role in the progression of atherosclerosis.

Survivin as a preferential target for cancer therapy.

Cancer is typically a consequence of imbalance between cell death and proliferation in a way favorable to cell proliferation and survival. Most conventional cancer therapies are based on targeting rapidly growing cancerous cells to block growth or enhance cell death, thereby, restoring the balance between these processes. In many instances, malignancies that develop resistance to current treatment modalities, such as chemotherapy, immunotherapy, and radiotherapy often present the greatest challenge in subsequent management of the patient.

Wiring the retinal circuits activated by light during early development.

Background: Light information is sorted by neuronal circuits to generate image-forming (IF) (interpretation and tracking of visual objects and patterns) and non-image-forming (NIF) tasks. Among the NIF tasks, photic entrainment of circadian rhythms, the pupillary light reflex, and sleep are all associated with physiological responses, mediated mainly by a small group of melanopsin-expressing retinal ganglion cells (mRGCs). Using Xenopus laevis as a model system, and analyzing the c-fos expression induced by light as a surrogate marker of neural activity, we aimed to establish the developmental time at which the cells participating in both systems come on-line in the retina.

Interleukin-17A in lipid metabolism and atherosclerosis.

Interleukin-17 (IL-17) A, the most important cytokine of the IL-17 family predominantly secreted by T helper 17 (Th17) cells, plays a critical role in the development of inflammatory diseases. Its receptor is an obligate heterodimer composed of IL-17 receptor (IL-17R) A and C, the main members of the IL-17R family. Binding of IL-17A to the IL-17RA/C complex can activate a variety of downstream signaling pathways such as nuclear factor kappa-B (NF-κB), activator protein 1 (AP1) and CCAAT/enhancer-binding protein (C/EBP) to induce the expression of proinflammatory cytokines and chemokines.

Measuring competence in central venous catheterization: a systematic-review.

Objectives: Central venous catheterization is a complex procedural skill. This study evaluates existing published tools on this procedure and systematically summarizes key competencies for the assessment of this technical skill.

Methods: Using a previously published meta-analysis search strategy, we conducted a systematic review of published assessment tools using the electronic databases PubMed, MEDLINE, Education Resource Information Center (ERIC), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica, and Cochrane Central Register of Controlled Trials.

Pregnane X receptor agonists enhance intestinal epithelial wound healing and repair of the intestinal barrier following the induction of experimental colitis.

The intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's disease and ulcerative colitis. It is thought that the increased permeability in patients with IBD may be driven by alterations in the epithelial wound healing response.

Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCζ/SP1 pathway in THP-1 macrophages.

Objective: The aim of this study was to determine whether ATP-binding cassette transporter A1 (ABCA1) was up-regulated by growth differentiation factor-15 (GDF-15) via the phosphoinositide 3-kinase (PI3K)/protein kinase Cζ (PKCζ)/specificity protein 1 (SP1) pathway in THP-1 macrophages.

Methods And Results: We investigated the effects of different concentrations of GDF-15 on ABCA1 expression in THP-1 macrophages. The results showed that GDF-15 dramatically increased cholesterol efflux and decreased cellular cholesterol levels.

T-type channels buddy up.

The electrical output of neurons relies critically on voltage- and calcium-gated ion channels. The traditional view of ion channels is that they operate independently of each other in the plasma membrane in a manner that could be predicted according to biophysical characteristics of the isolated current. However, there is increasing evidence that channels interact with each other not just functionally but also physically.

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: a systematic review and network meta-analysis.

Objective: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis.

Methods: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis.

A novel calmodulin site in the Cav1.2 N-terminus regulates calcium-dependent inactivation.

The L-type voltage-gated calcium channel Cav1.2 is important for excitation-contraction coupling in the heart, as well as CREB-mediated transcription in the brain. The ubiquitous calcium-binding protein calmodulin (CaM) is known to modulate calcium-dependent inactivation (CDI) of these channels, thus limiting the amount of calcium entering via Cav1.

The effects of miR-467b on lipoprotein lipase (LPL) expression, pro-inflammatory cytokine, lipid levels and atherosclerotic lesions in apolipoprotein E knockout mice.

Atherosclerosis is a lipid disorder disease characterized by chronic blood vessel wall inflammation driven by the subendothelial accumulation of macrophages. Studies have shown that lipoprotein lipase (LPL) participates in lipid metabolism, but it is not yet known whether post-transcriptional regulation of LPL gene expression by microRNAs (miRNAs) occurs in vivo. Here, we tested that miR-467b provides protection against atherosclerosis by regulating the target gene LPL which leads to reductions in LPL expression, lipid accumulation, progression of atherosclerosis and production of inflammatory cytokines in apolipoprotein E knockout (apoE(-/-)) mice.

NPC1, intracellular cholesterol trafficking and atherosclerosis.

Post-lysosomal cholesterol trafficking is an important, but poorly understood process that is essential to maintain lipid homeostasis. Niemann-Pick type C1 (NPC1), an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY), is known to accept cholesterol from NPC2 and then mediate cholesterol transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane in a vesicle- or oxysterol-binding protein (OSBP)-related protein 5 (ORP5)-dependent manner. Mutations in the NPC1 gene can be found in the majority of NPC patients, who accumulate massive amounts of cholesterol and other lipids in the LE/LY due to a defect in intracellular lipid trafficking.

Phase delays to light and gastrin-releasing peptide require the protein kinase A pathway.

Daily photic resetting of the circadian system relies on the transmission of light information from the retina to retinorecipient cells within the ventrolateral suprachiasmatic nucleus (SCN) core, and subsequent activation of rhythmic clock cells in the dorsolateral region. Some neurochemicals such as gastrin-releasing peptide (GRP) mimic the phase shifting effects of light and induce Ca(2+)-dependent gene expression in the SCN. Activation of the cAMP-response element binding protein (CREB) is necessary for Ca(2+)-dependent transcription to occur and accompanies behavioral phase shifting; however, several biochemical cascades are involved in this phenomenon.

ABCG5/ABCG8 in cholesterol excretion and atherosclerosis.

Cholesterol is essential for the growth and function of all mammalian cells, but abnormally increased blood cholesterol is a major risk factor for atherosclerotic cardiovascular disease. ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) form an obligate heterodimer that limits intestinal absorption and facilitates biliary secretion of cholesterol and phytosterols. Consistent with their function, ABCG5 and ABCG8 are located on the apical membrane of enterocytes and hepatocytes.

Family practice versus specialist care for low-risk obstetrics: examining patient satisfaction in Newfoundland and Labrador.

Objective: To investigate patient satisfaction with 3 models of low-risk obstetrics care: solo care by a GP, group care by GPs, and specialist care.

Design: Three-arm study comparing results of a self-administered, anonymous questionnaire.

Setting: Two academic family practices and the labour and delivery ward in St John's, Nfld.

Kupffer cells and activation of endothelial TLR4 coordinate neutrophil adhesion within liver sinusoids during endotoxemia.

A key pathological feature of the systemic inflammatory response of sepsis/endotoxemia is the accumulation of neutrophils within the microvasculature of organs such as the liver, where they cause tissue damage and vascular dysfunction. There is emerging evidence that the vascular endothelium is critical to the orchestration of inflammatory responses to blood-borne microbes and microbial products in sepsis/endotoxemia. In this study, we aimed to understand the role of endothelium, and specifically endothelial TLR4 activation, in the regulation of neutrophil recruitment to the liver during endotoxemia.

Microtubule dynamics control tail retraction in migrating vascular endothelial cells.

Drugs that target microtubules are potent inhibitors of angiogenesis, but their mechanism of action is not well understood. To explore this, we treated human umbilical vein endothelial cells with paclitaxel, vinblastine, and colchicine and measured the effects on microtubule dynamics and cell motility. In general, lower drug concentrations suppressed microtubule dynamics and inhibited cell migration whereas higher concentrations were needed to inhibit cell division; however, surprisingly, large drug-dependent differences were seen in the relative concentrations needed to inhibit these two processes.

Factors associated with time to diagnosis in early rheumatoid arthritis.

Early diagnosis and treatment yield optimal outcomes in rheumatoid arthritis (RA); thus, barriers to disease recognition must be identified and addressed. We determined the impact of sociodemographic factors, medical comorbidities, family history, and disease severity at onset on the time to diagnosis in early RA. The Canadian early ArThritis CoHort study data on 1,142 early RA patients were analyzed for predictors of time to diagnosis using regression analysis.

Computer order entry systems in the emergency department significantly reduce the time to medication delivery for high acuity patients.

Background: Computerized physician order entry (CPOE) systems are designed to increase safety and improve quality of care; however, their impact on efficiency in the ED has not yet been validated. This study examined the impact of CPOE on process times for medication delivery, laboratory utilization and diagnostic imaging in the early, late and control phases of a regional ED-CPOE implementation.

Setting: Three tertiary care hospitals serving a population in excess of 1 million inhabitants that initiated the same CPOE system during the same 3-week time window.

Invasion, establishment, and range expansion of two parasitic nematodes in the Canadian Arctic.

Climate warming is occurring at an unprecedented rate in the Arctic and is having profound effects on host-parasite interactions, including range expansion. Recently, two species of protostrongylid nematodes have emerged for the first time in muskoxen and caribou on Victoria Island in the western Canadian Arctic Archipelago. Umingmakstrongylus pallikuukensis, the muskox lungworm, was detected for the first time in 2008 in muskoxen at a community hunt on the southwest corner of the island and by 2012, it was found several hundred kilometers east in commercially harvested muskoxen near the town of Ikaluktutiak.

Pathoetiology of multiple sclerosis: are we barking up the wrong tree?

Despite a century of intensive investigation, the underlying cause of multiple sclerosis has eluded us. It is clear that there exists a prominent progressive degenerative phenotype together with an important autoimmune inflammatory component, and careful histopathological examination always shows, to a greater or lesser degree, concomitant degeneration/demyelination and adaptive T cell-dependent immune responses. Given this picture, it is difficult, if not impossible, to definitively say whether degeneration or autoimmunity is the initiator of the disease.

Gait characteristics over the course of a race in recreational marathon competitors.

We analyzed gait and function of the supporting limb in participants of a marathon race at three stages: prerace, midrace (18 km), and near the end of the race (36 km). We confirmed that the most successful runners were able to maintain running speed for the duration of the race with little change in speed or gait. Speed slowed progressively during the race for those with slower race times, but stride frequency-stride length relationships remained normal for the speed they ran.

Entecavir for the treatment of patients with hepatitis B virus-related decompensated cirrhosis.

Introduction: Chronic hepatitis B (CHB) infection is common and carries a significant risk for the development of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The goal of treatment in patients with CHB-related decompensated cirrhosis is to improve hepatic dysfunction and reduce mortality through the inhibition of viral replication. Several studies have now shown nucleot(s)ide analogs to be safe and effective in decompensated cirrhosis due to CHB.