A key role for STIM1 in store operated calcium channel activation in airway smooth muscle

BACKGROUND: Control of cytosolic calcium plays a key role in airway myocyte function. Changes in intracellular Ca(2+ )stores can modulate contractile responses, modulate proliferation and regulate synthetic activity. Influx of Ca(2+ )in non excitable smooth muscle is believed to be predominantly through store operated channels (SOC) or receptor operated channels (ROC). Whereas agonists can activate both SOC and ROC in a range of smooth muscle types, the specific trigger for SOC activation is depletion of the sarcoplasmic reticulum Ca(2+ )stores. The mechanism underlying SOC activation following depletion of intracellular Ca(2+ )stores in smooth muscle has not been identified. METHODS: To investigate the roles of the STIM homologues in SOC activation in airway myocytes, specific siRNA sequences were utilised to target and selectively suppress both STIM1 and STIM2. Quantitative real time PCR was employed to assess the efficiency and the specificity of the siRNA mediated knockdown of mRNA. Activation of SOC was investigated by both whole cell patch clamp electrophysiology and a fluorescence based calcium assay. RESULTS: Transfection of 20 nM siRNA specific for STIM1 or 2 resulted in robust decreases (>70%) of the relevant mRNA. siRNA targeted at STIM1 resulted in a reduction of SOC associated Ca(2+ )influx in response to store depletion by cyclopiazonic acid (60%) or histamine but not bradykinin. siRNA to STIM2 had no effect on these responses. In addition STIM1 suppression resulted in a more or less complete abrogation of SOC associated inward currents assessed by whole cell patch clamp. CONCLUSION: Here we show that STIM1 acts as a key signal for SOC activation following intracellular Ca(2+ )store depletion or following agonist stimulation with histamine in human airway myocytes. These are the first data demonstrating a role for STIM1 in a physiologically relevant, non-transformed endogenous expression cell model

In vivo tau pathology is associated with synaptic loss and altered synaptic function

BACKGROUND: The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([{18}^F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease. METHODS: Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-minV [{18}^F]flortaucipir PET, dynamic 60-min [{11}^C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [{18^}F]flortaucipir- and [{11}^C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [{18}^F]flortaucipir BPND, [{11}^C]UCB-J BP_{ND} and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. RESULTS: Across subjects, higher regional [{18}^F]flortaucipir uptake was associated with lower [{11}^C]UCB-J uptake. Within subjects, the association between [{11}^C]UCB-J and [{18}^F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [{18}^F]flortaucipir and lower [{11}^C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. CONCLUSIONS: These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction

Effects of cisplatin on olfactory function in cancer patients

A prospective analysis of olfaction was performed in 21 patients receiving cisplatin. A reduction in olfactory function was noted in only one patient. Hearing impairment was documented in nine patients, none of whom had impaired sense of smell. We conclude that cisplatin has no major deleterious effect on olfactory function at doses which cause hearing impairment

The specificity of phage testing for MAP — where might it fit into the diagnostic armoury?

The current individual tools available for the diagnosis of Johne's disease are far from suitable to tackle this endemic disease. Culture, polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) tests, when used together can be useful in managing the disease in the later stages of infection at a herd level. They are, however, ill-suited to detecting the causative agent Mycobacterium avium subsp. paratuberculosis (MAP) at the early stages of infection and at an individual level. Phage technology offers another tool in the attempt to better manage and control this disease. Phage-technology has been demonstrated to rapidly and sensitively detect and specifically identify viable MAP in the milk and blood of cattle. Although in relatively-early stages of development phage technology offers a strong addition to the armoury of tests used to detect MAP in blood and milk, and may go on to be part of ongoing control measures to reduce the burden of disease to farmers and veterinarians

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Patient attitudes towards medical students at Damascus University teaching hospitals

Background: The cooperation of patients and their consent to involve medical students in their care is vital to clinical education, but large numbers of students and lack of experience as well as loss of privacy may evoke negative attitudes of patients, which may sometimes adversely affect the clinical teaching environment. This study aimed to explore the attitudes of patients towards medical students at Damascus University hospitals, and to explore the determinants of those attitudes thus discussing possible implications applicable to clinical teaching. Methods: This cross-sectional study was conducted at three teaching hospitals affiliated to the Faculty of Medicine at Damascus University. Four hundred patients were interviewed between March and April 2011 by a trained sociologist using a structured questionnaire. Results: Of the patients interviewed, 67.8 % approved the presence of medical students during the medical consultation and 58.2 % of them felt comfortable with the presence of students, especially among patients with better socio-economic characteristics. 81.5 % of the patients agreed to be examined by students in the presence of the supervisor, while 40.2 % gave agreement even in the absence of the supervisor. Privacy was the most important factor in the patients ’ reticence towards examination by the students, whilst the relative safety and comfort if a supervisor was available determined patients ’ agreement

Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

INTRODUCTION: Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. METHODS: To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. RESULTS: Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). CONCLUSIONS: Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an attractive candidate molecular predictor of antiestrogen responsiveness

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012