Late preconditioning by ethanol is initiated via an oxidant-dependent signaling pathway

Ingestion of alcoholic beverages at low to moderate levels 24 h prior to ischemia and reperfusion (I/R) prevents postischemic leukocyte/endothelial cell adhesive interactions, a phenomenon referred to as late ethanol preconditioning (EtOH-PC). The aim of this study was to determine whether oxidants act as initiators of late EtOH-PC. Ethanol was instilled into the stomachs of C57BL/6 mice as a bolus by gavage at a dose that produced a peak plasma concentration of 45 mg/dl 30 min after administration and returned to control levels 60 min after ingestion. Twenty four hours later, the superior mesenteric artery was occluded for 45 min followed by 70 min of reperfusion. The numbers of rolling and firmly adherent leukocytes were quantified in postcapillary venules of the small intestine in sham animals (no EtOH-PC, no I/R), in mice subjected to I/R alone or EtOH-PC + I/R, and in animals treated with Mn-TBAP (a cell-permeant superoxide dismutase mimetic), oxypurinol (a XO inhibitor), the NAD(P)H oxidase inhibitors PR-39 or apocynin, or oxypurinol plus PR39 during the period of EtOH-PC on Day 1 followed by I/R on Day 2. In separate groups of mice, oxypurinol or apocynin were also administered 1 h after ethanol ingestion on Day 1, with induction of I/R 24 h later. I/R induced marked increases in leukocyte rolling and adherence, effects that were completely prevented by EtOH-PC. Coincident treatment with Mn-TBAP, oxypurinol, PR-39, apocynin, or oxypurinol plus PR-39 with ethanol attenuated these anti-inflammatory actions of EtOH-PC. However, administration of oxypurinol or apocynin 1 h after ethanol ingestion failed to prevent these protective effects of EtOH-PC. Our results indicate that reactive oxygen species formed during the period of ethanol exposure on Day 1 trigger the development of an anti-inflammatory phenotype that renders the small bowel resistant to the proadhesive effects of I/R 24 h later.     

Interval sprint training enhances endothelial function and eNOS content in some arteries that perfuse white gastrocnemius muscle.

The purpose of this study was to test the hypothesis that interval sprint training (IST) selectively increases endothelium-dependent dilation (EDD) and endothelial nitric oxide synthase and/or superoxide dismutase-1 protein content in arteries and/or arterioles that perfuse the white portion of rat gastrocnemius muscle (WG). Male Sprague-Dawley rats completed 10 wk of IST (n = 62) or remained sedentary (Sed) (n = 63). IST rats performed six 2.5-min exercise bouts, with 4.5 min of rest between bouts (60 m/min, 15% incline), 5 days/wk. EDD was assessed from acetylcholine (ACh)-induced increases in muscle blood flow measured in situ and by ACh-induced dilation of arteries and arterioles [first to third order (1A-3A)] that perfuse red gastrocnemius muscle (RG) and WG. Artery protein content was determined with immunoblot analysis. ACh-induced increases in blood flow were enhanced in WG of IST rats. eNOS content was increased in conduit arteries, gastrocnemius feed artery, and fourth-order arterioles from WG and fifth-order arterioles of RG but not in 2As from RG. EDD was examined in 2As and 3As from a subset of IST and Sed rats. Arterioles were canulated with micropipettes, and intraluminal pressure was set at 60 cmH2O. Results indicate that passive diameter (measured in 0 calcium PSS) of WG 2As was similar in IST and Sed, whereas diameter of WG 3As was greater in IST (96 +/- 8 microm) than Sed (73 +/- 4 microm). WG 2As and 3As of IST rats exhibited greater spontaneous tone, but sensitivity to stretch, phenylephrine, and sodium nitroprusside was similar to Sed arterioles. ACh-induced dilation was enhanced by IST in WG 2As but not in RG 2As or WG 3As. We conclude that IST induces vascular adaptations nonuniformly among arteries that perfuse WG muscle.     

Inflammatory responses to ischemia,and reperfusion in skeletal muscle

Skeletal muscle ischemia and reperfusion is now recognized as one form of acute inflammation in which activated leukocytes play a key role. Although restoration of flow is essential in alleviating ischemic injury, reperfusion initiates a complex series of reactions which lead to neutrophil accumulation, microvascular barrier disruption, and edema formation. A large body of evidence exists which suggests that leukocyte adhesion to and emigration across postcapillary venules plays a crucial role in the genesis of reperfusion injury in skeletal muscle. Reactive oxygen species generated by xanthine oxidase and other enzymes promote the formation of proinflammatory stimuli, modify the expression of adhesion molecules on the surface of leukocytes and endothelial cells, and reduce the bioavailability of the potent antiadhesive agent nitric oxide. As a consequence of these events, leukocytes begin to form loose adhesive interactions with postcapillary venular endothelium (leukocyte rolling). If the proinflammatory stimulus is sufficient, leukocytes may become firmly adherent (stationary adhesion) to the venular endothelium. Those leukocytes which become firmly adherent may then diapedese into the perivascular space. The emigrated leukocytes induce parenchymal cell injury via a directed release of oxidants and hydrolytic enzymes. In addition, the emigrating leukocytes also exacerbate ischemic injury by disrupting the microvascular barrier during their egress across the vasculature. As a consequence of this increase in microvascular permeability, transcapillary fluid filtration is enhanced and edema results. The resultant increase in interstitial tissue pressure physically compresses the capillaries, thereby preventing microvascular perfusion and thus promoting the development of the no-reflow phenomenon. The purpose of this review is to summarize the available information regarding these mechanisms of skeletal muscle ischemia/reperfusion injury.     

Postischemic anti-inflammatory effects of bradykinin preconditioning

We sought to determine the mechanisms whereby brief administration of bradykinin (bradykinin preconditioning, BK-PC) before prolonged ischemia followed by reperfusion (I/R) prevents postischemic microvascular dysfunction. Intravital videomicroscopic approaches were used to quantify I/R-induced leukocyte/endothelial cell adhesive interactions and microvascular barrier disruption in single postcapillary venules of the rat mesentery. I/R increased the number of rolling, adherent, and emigrated leukocytes and enhanced venular albumin leakage, effects that were prevented by BK-PC. The anti-inflammatory effects of BK-PC were largely prevented by concomitant administration of a B(2)-receptor antagonist but not by coincident B(1) receptor blockade, nitric oxide (NO) synthase inhibition, or cyclooxygenase blockade. However, NO synthase blockade during reperfusion after prolonged ischemia was effective in attenuating the anti-inflammatory effects of BK-PC. Pan protein kinase C (PKC) inhibition antagonized the beneficial effects of BK-PC but only when administered during prolonged ischemia. In contrast, specific inhibition of the conventional PKC isotypes failed to alter the effectiveness of BK-PC. These results indicate that bradykinin can be used to pharmacologically precondition single mesenteric postcapillary venules to resist I/R-induced leukocyte recruitment and microvascular barrier dysfunction by a mechanism that involves B(2) receptor-dependent activation of nonconventional PKC isotypes and subsequent formation of NO.     

“They See Us As Machines:” The Experience of Recent Immigrant Women in the Low Wage Informal Labor Sector

This study explores the organization of work and occupational health risk as elicited from recently immigrated women (n = 8) who have been in the US for less than three years and employed in informal work sectors such as cleaning and factory work in the greater Boston area in Massachusetts. Additional interviews (n = 8) with Community Key Informants with knowledge of this sector and representatives of temporary employment agencies in the area provides further context to the interviews conducted with recent immigrant women. These results were also compared with our immigrant occupational health survey, a large project that spawned this study. Responses from the study participants suggest health outcomes consistent with being a day-laborer scholarship, new immigrant women are especially at higher risk within these low wage informal work sectors. A difference in health experiences based on ethnicity and occupation was also observed. Low skilled temporary jobs are fashioned around meeting the job performance expectations of the employer; the worker’s needs are hardly addressed, resulting in low work standards, little worker protection and poor health outcomes. The rising prevalence of non-standard employment or informal labor sector requires that policies or labor market legislation be revised to meet the needs presented by these marginalized workers.     

Job Sharing in the Endomembrane System: Vacuolar Acidification Requires the Combined Activity of V-ATPase and V-PPase

The presence of a large central vacuole is one of the hallmarks of a prototypical plant cell, and the multiple functions of this compartment require massive fluxes of molecules across its limiting membrane, the tonoplast. Transport is assumed to be energized by the membrane potential and the proton gradient established by the combined activity of two proton pumps, the vacuolar H⁺-pyrophosphatase (V-PPase) and the vacuolar H⁺-ATPase (V-ATPase). Exactly how labor is divided between these two enzymes has remained elusive. Here, we provide evidence using gain- and loss-of-function approaches that lack of the V-ATPase cannot be compensated for by increased V-PPase activity. Moreover, we show that increased V-ATPase activity during cold acclimation requires the presence of the V-PPase. Most importantly, we demonstrate that a mutant lacking both of these proton pumps is conditionally viable and retains significant vacuolar acidification, pointing to a so far undetected contribution of the trans-Golgi network/early endosome-localized V-ATPase to vacuolar pH.     

Influence of age on cardiac baroreflex function during dynamic exercise in humans

We investigated the influence of aging on cardiac baroreflex function during dynamic exercise in seven young (22 +/- 1 yr) and eight older middle-aged (59 +/- 2 yr) healthy subjects. Carotid-cardiac baroreflex function was assessed at rest and during moderate-intensity steady-state cycling performed at 50% heart rate reserve (HRR). Five-second pulses of neck pressure and neck suction from +40 to -80 Torr were applied to determine the operating point gain (G(OP)) and maximal gain (G(MAX)) of the full carotid-cardiac baroreflex function curve and examine baroreflex resetting during exercise. At rest, mean arterial pressure (MAP) and heart rate were similar between the younger and older subjects. In contrast, the resting G(OP) and G(MAX) were significantly lower in the older subjects. The increase in MAP from rest to exercise was greater in the older subjects (Delta +20 +/- 2 older vs. Delta +6 +/- 3 younger mmHg; P < 0.001). However, the G(OP) was similar in both groups during exercise because of a reduction in the younger subjects. In contrast, G(MAX) was unchanged from rest and therefore remained lower in older subjects (-0.19 +/- 0.05 older vs. -0.42 +/- 0.05 younger beats.min(-1).mmHg(-1); 50% HRR; P < 0.001). Furthermore, exercise resulted in an upward and rightward resetting of the cardiac baroreflex function curve in both groups. Collectively, these findings suggest that the cardiac baroreflex function curve appropriately resets during exercise in older subjects but operates at a reduced G(MAX) primarily because of age-related reductions in carotid-cardiac control manifest at rest.     

Effective control of Schistosoma haematobium infection in a Ghanaian community following installation of a water recreation area

Background

Urogenital schistosomiasis caused by Schistosoma haematobium was endemic in Adasawase, Ghana in 2007. Transmission was reported to be primarily through recreational water contact.

Methods

We designed a water recreation area (WRA) to prevent transmission to school-aged children. The WRA features a concrete pool supplied by a borehole well and a gravity-driven rainwater collection system; it is 30 m² and is split into shallow and deep sections to accommodate a variety of age groups. The WRA opened in 2009 and children were encouraged to use it for recreation as opposed to the local river. We screened children annually for S. haematobium eggs in their urine in 2008, 2009, and 2010 and established differences in infection rates before (2008–09) and after (2009–10) installation of the WRA. After each annual screening, children were treated with praziquantel and rescreened to confirm parasite clearance.

Principal Findings

Initial baseline testing in 2008 established that 105 of 247 (42.5%) children were egg-positive. In 2009, with drug treatment alone, the pre-WRA annual cumulative incidence of infection was 29 of 216 (13.4%). In 2010, this incidence rate fell significantly (p<0.001, chi-squared) to 9 of 245 (3.7%) children after installation of the WRA. Logistic regression analysis was used to determine correlates of infection among the variables age, sex, distance between home and river, minutes observed at the river, low height-for-age, low weight-for-age, low Body Mass Index (BMI)-for-age, and previous infection status.

Conclusion/Significance

The installation and use of a WRA is a feasible and highly effective means to reduce the incidence of schistosomiasis in school-aged children in a rural Ghanaian community. In conjunction with drug treatment and education, such an intervention can represent a significant step towards the control of schistosomiasis. The WRA should be tested in other water-rich endemic areas to determine whether infection prevalence can be substantially reduced.     

Canonical labeling of proteome maps

We propose a canonical labeling of proteome maps, which enables one to sort and catalog the maps in a simple way. The canonical label of a proteome map is based on the canonical labeling of vertexes of Hasse diagram embedded in the map resulting in the adjacency matrix, the rows of which when viewed as binary numbers are the smallest possible such numbers. The use of the approach in documentation is illustrated with the proteome maps of liver cells of healthy male Fisher F344 rats and the rats treated with different peroxisome proliferators.