Mycobacterium tuberculosis Responds to Chloride and pH as Synergistic Cues to the Immune Status of its Host Cell

PubMed ID: 23592993This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Disappearance of myocardial perfusion defects on prone SPECT imaging: Comparison with cardiac magnetic resonance imaging in patients without established coronary artery disease

<p>Abstract</p> <p>Background</p> <p>It is of great clinical importance to exclude myocardial infarction in patients with suspected coronary artery disease who do not have stress-induced ischemia. The diagnostic use of myocardial perfusion single-photon emission computed tomography (SPECT) in this situation is sometimes complicated by attenuation artifacts that mimic myocardial infarction. Imaging in the prone position has been suggested as a method to overcome this problem.</p> <p>Methods</p> <p>In this study, 52 patients without known prior infarction and no stress-induced ischemia on SPECT imaging were examined in both supine and prone position. The results were compared with cardiac magnetic resonance imaging (CMR) with delayed-enhancement technique to confirm or exclude myocardial infarction.</p> <p>Results</p> <p>There were 63 defects in supine-position images, 37 of which disappeared in the prone position. None of the 37 defects were associated with myocardial infarction by CMR, indicating that all of them represented attenuation artifacts. Of the remaining 26 defects that did not disappear on prone imaging, myocardial infarction was confirmed by CMR in 2; the remaining 24 had no sign of ischemic infarction but 2 had other kinds of myocardial injuries. In 3 patients, SPECT failed to detect small scars identified by CMR.</p> <p>Conclusion</p> <p>Perfusion defects in the supine position that disappeared in the prone position were caused by attenuation, not myocardial infarction. Hence, imaging in the prone position can help to rule out ischemic heart disease for some patients admitted for SPECT with suspected but not documented ischemic heart disease. This would indicate a better prognosis and prevent unnecessary further investigations and treatment.</p

Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study

Background: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes. Methods: All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests. Results: The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001. Conclusions: The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway

Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study

Background: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes. Methods: All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests. Results: The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001. Conclusions: The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway

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

Signaling pathways downstream of P2 receptors in human neutrophils

Extracellular nucleotides stimulate human neutrophils by activating the purinergic P2Y2 receptor. However, it is not completely understood which types of G proteins are activated downstream of this P2 receptor subtype. We investigated the G-protein coupling to P2Y2 receptors and several subsequent signaling events. Treatment of neutrophils with pertussis toxin (PTX), a Gi protein inhibitor, caused only ∼75% loss of nucleotide-induced Ca2+ mobilization indicating that nucleotides cause Ca2+ mobilization both through Gi-dependent and Gi-independent pathways. However, the PLC inhibitor U73122 almost completely inhibited Ca2+ mobilization in both nucleotide- and fMLP-stimulated neutrophils, strongly supporting the view that both the PTX-sensitive and the PTX-insensitive mechanism of Ca2+ increase require activation of PLC. We investigated the dependence of ERK phosphorylation on the Gi pathway. Treatment of neutrophils with PTX caused almost complete inhibition of ERK phosphorylation in nucleotide or fMLP activated neutrophils. U73122 caused inhibition of nucleotide- or fMLP-stimulated ERK phosphorylation, suggesting that although pertussis toxin-insensitive pathways cause measurable Ca2+ mobilization, they are not sufficient for causing ERK phosphorylation. Since PLC activation leads to intracellular Ca2+ increase and PKC activation, we investigated if these intracellular events are necessary for ERK phosphorylation. Exposure of cells to the Ca2+ chelator BAPTA had no effect on nucleotide- or fMLP-induced ERK phosphorylation. However, the PKC inhibitor GF109203X was able to almost completely inhibit nucleotide- or fMLP-induced ERK phosphorylation. We conclude that the P2Y2 receptor can cause Ca2+ mobilization through a PTX-insensitive but PLC-dependent pathway and ERK phosphorylation is highly dependent on activation of the Gi proteins

International Network for Comparison of HIV Neutralization Assays: The NeutNet Report

BACKGROUND: Neutralizing antibody assessments play a central role in human immunodeficiency virus type-1 (HIV-1) vaccine development but it is unclear which assay, or combination of assays, will provide reliable measures of correlates of protection. To address this, an international collaboration (NeutNet) involving 18 independent participants was organized to compare different assays. METHODS: Each laboratory evaluated four neutralizing reagents (TriMab, 447-52D, 4E10, sCD4) at a given range of concentrations against a panel of 11 viruses representing a wide range of genetic subtypes and phenotypes. A total of 16 different assays were compared. The assays utilized either uncloned virus produced in peripheral blood mononuclear cells (PBMCs) (virus infectivity assays, VI assays), or their Env-pseudotyped (gp160) derivatives produced in 293T cells (PSV assays) from molecular clones or uncloned virus. Target cells included PBMC and genetically-engineered cell lines in either a single- or multiple-cycle infection format. Infection was quantified by using a range of assay read-outs that included extracellular or intracellular p24 antigen detection, RNA quantification and luciferase and beta-galactosidase reporter gene expression. FINDINGS: PSV assays were generally more sensitive than VI assays, but there were important differences according to the virus and inhibitor used. For example, for TriMab, the mean IC50 was always lower in PSV than in VI assays. However, with 4E10 or sCD4 some viruses were neutralized with a lower IC50 in VI assays than in the PSV assays. Inter-laboratory concordance was slightly better for PSV than for VI assays with some viruses, but for other viruses agreement between laboratories was limited and depended on both the virus and the neutralizing reagent. CONCLUSIONS: The NeutNet project demonstrated clear differences in assay sensitivity that were dependent on both the neutralizing reagent and the virus. No single assay was capable of detecting the entire spectrum of neutralizing activities. Since it is not known which in vitro assay correlates with in vivo protection, a range of neutralization assays is recommended for vaccine evaluation

Hemodialysis vascular access options in pediatrics: considerations for patients and practitioners

Recent data indicate that the incidence of end-stage renal disease (ESRD) in pediatric patients (age 0–19 years) has increased over the past two decades. Similarly, the prevalence of ESRD has increased threefold over the same period. Hemodialysis (HD) continues to be the most frequently utilized modality for renal replacement therapy in incident pediatric ESRD patients. The number of children on HD exceeded the sum total of those on peritoneal dialysis and those undergoing pre-emptive renal transplantation. Choosing the best vascular access option for pediatric HD patients remains challenging. Despite a national initiative for fistula first in the adult hemodialysis population, the pediatric nephrology community in the United States of America utilizes central venous catheters as the primary dialysis access for most patients. Vascular access management requires proper advance planning to assure that the best permanent access is placed, seamless communication involving a multidisciplinary team of nephrologists, nurses, surgeons, and interventional radiologists, and ongoing monitoring to ensure a long life of use. It is imperative that practitioners have a long-term vision to decrease morbidity in this unique patient population. This article reviews the various types of pediatric vascular accesses used worldwide and the benefits and disadvantages of these various forms of access