β-adrenergic inhibition prevents action potential and calcium handling changes during regional myocardial ischemia

β-adrenergic receptor (β-AR) blockers may be administered during acute myocardial infarction (MI), as they reduce energy demand through negative chronotropic and inotropic effects and prevent ischemia-induced arrhythmogenesis. However, the direct effects of β-AR blockers on ventricular electrophysiology and intracellular Ca2+ handling during ischemia remain unknown. Using optical mapping of transmembrane potential (with RH237) and sarcoplasmic reticulum (SR) Ca2+ (with the low-affinity indicator Fluo-5N AM), the effects of 15 min of regional ischemia were assessed in isolated rabbit hearts (n = 19). The impact of β-AR inhibition on isolated hearts was assessed by pre-treatment with 100 nM propranolol (Prop) prior to ischemia (n = 7). To control for chronotropy and inotropy, hearts were continuously paced at 3.3 Hz and contraction was inhibited with 20 μM blebbistatin. Untreated ischemic hearts displayed prototypical shortening of action potential duration (APD80) in the ischemic zone (IZ) compared to the non-ischemic zone (NI) at 10 and 15 min ischemia, whereas APD shortening was prevented with Prop. Untreated ischemic hearts also displayed significant changes in SR Ca2+ handling in the IZ, including prolongation of SR Ca2+ reuptake and SR Ca2+ alternans, which were prevented with Prop pre-treatment. At 5 min ischemia, Prop pre-treated hearts also showed larger SR Ca2+ release amplitude in the IZ compared to untreated hearts. These results suggest that even when controlling for chronotropic and inotropic effects, β-AR inhibition has a favorable effect during acute regional ischemia via direct effects on APD and Ca2+ handling

Differentiation, Distribution and γδ T Cell-Driven Regulation of IL-22-Producing T Cells in Tuberculosis

Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB) granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vγ2Vδ2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNγ-producing Vγ2Vδ2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNγ neutralizing Ab treatment reversed the HMBPP-mediated down-regulation effect on IL-22-producing T cells, suggesting that Vγ2Vδ2 T-cell-driven IFNγ-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vγ2Vδ2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB

Alcohol-Related Diagnoses and All-Cause Hospitalization Among HIV-Infected and Uninfected Patients: A Longitudinal Analysis of United States Veterans from 1997 to 2011.

Individuals with HIV infection are living substantially longer on antiretroviral therapy, but hospitalization rates continue to be relatively high. We do not know how overall or diagnosis-specific hospitalization rates compare between HIV-infected and uninfected individuals or what conditions may drive hospitalization trends. Hospitalization rates among United States Veterans were calculated and stratified by HIV serostatus and principal diagnosis disease category. Because alcohol-related diagnoses (ARD) appeared to have a disproportional effect, we further stratified our calculations by ARD history. A multivariable Cox proportional hazards model was fitted to assess the relative risk of hospitalization controlling for demographic and other comorbidity variables. From 1997 to 2011, 46,428 HIV-infected and 93,997 uninfected patients were followed for 1,497,536 person-years. Overall hospitalization rates decreased among HIV-infected and uninfected patients. However, cardiovascular and renal insufficiency admissions increased for all groups while gastrointestinal and liver, endocrine, neurologic, and non-AIDS cancer admissions increased among those with an alcohol-related diagnosis. After multivariable adjustment, HIV-infected individuals with an ARD had the highest risk of hospitalization (hazard ratio 3.24, 95 % CI 3.00, 3.49) compared to those free of HIV infection and without an ARD. Still, HIV alone also conferred increased risk (HR 2.08, 95 % CI 2.04, 2.13). While decreasing overall, risk of all-cause hospitalization remains higher among HIV-infected than uninfected individuals and is strongly influenced by the presence of an ARD

Rapid Syphilis Testing Uptake for Female Sex Workers at Sex Venues in Southern China: Implications for Expanding Syphilis Screening

: Accessibility of syphilis testing services is critical in syphilis control programs for female sex workers (FSWs), but few FSWs attend public STI clinics or other testing sites. Introduction of free rapid syphilis testing (RST) into outreach programs for FSWs will help improve test uptake. : Commercial sex venues were identified in two cities in South China. In cooperation with health advocacy organizations, health outreach teams from local public health or medical facilities approached all types of sex venues in study areas to offer free RST. Acceptability and uptake of RST among FSWs were evaluated. : A total of 2812 FSWs were offered RST and 2670 (95.0%) accepted syphilis testing. 182 (6.8%) FSWs had a positive RST result among whom 136 (74.7%) were willing to attend an STD clinic for confirmatory testing and treatment. More than half (89, 66.4%) of those with syphilis were not willing to notify their sex partners. Multivariate logistic analysis showed that syphilis test uptake was associated with residing in Jiangmen (AOR, 1.78; 95% CI, 1.15-2.77), older age (AOR, 2.11, 95% CI, 1.17-3.79 for age of 31 years or above), and not working at a service venue (AOR, 1.60; 95% CI, 1.10-2.34). : RST at sex venues is well accepted by FSWs when it is integrated into ongoing outreach services. Such programs provide excellent opportunities for expanding syphilis screening efforts among specific subgroups of FSW who are difficult to reach through clinic-based programs.<br/

Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts

Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff‐perfused rabbit and mouse hearts. Dual optical mapping with voltage‐ and Ca2+‐sensitive dyes allowed for analysis of spatio‐temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9 ± 5.1 ms at t = 0 s vs. 60.6 ± 4.1 ms at t = 15 s, P &lt; 0.05) followed by shortening (46.5 ± 9.1 ms at t = 60 s, P = NS vs. t = 0). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by β‐adrenergic activation. Simulations with species‐specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight‐or‐flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly