Postconditioning protects against endothelial ischemia-reperfusion injury in the human forearm

Background: Hypoxic cell death follows interruption of blood supply to tissues. Although successful restoration of blood flow is mandatory for salvage of ischemic tissues, reperfusion can paradoxically place tissues at risk of further injury. Brief periods of ischemia applied at the onset of reperfusion have been shown to reduce ischemia-reperfusion (IR) injury, a phenomenon called postconditioning. The aim of this study was to determine whether postconditioning protects against endothelial IR injury in humans, in vivo. Methods and Results: Brachial artery endothelial function was assessed by vascular ultrasound to measure flow-mediated dilation (FMD) in response to forearm reactive hyperemia. FMD was measured before and after IR (20 minutes of arm ischemia followed by 20 minutes of reperfusion) in healthy volunteers. To test the protective effects of postconditioning, 3 cycles of reperfusion followed by ischemia (each lasting 10 or 30 seconds) were applied immediately after 20 minutes of arm ischemia. To determine whether postconditioning needs to be applied at the onset of reperfusion, a 1-minute period of arm reperfusion was allowed before the application of the 10-second postconditioning stimulus. IR caused endothelial dysfunction (FMD 9.1±1.2% pre-IR, 3.6±0.7% post-IR, P<0.001; n=11), which was prevented by postconditioning applied as 10-second cycles of reperfusion/ischemia (FMD 9.9±1.7% pre-IR, 8.3±1.4% post-IR, P=NS; n=11) and 30-second cycles of reperfusion/ischemia (FMD 10.8±1.7% pre-IR, 9.5±1.5% post-IR, P=NS; n=10) immediately at the onset of reperfusion. No protection was observed when the application of the 10-second postconditioning stimulus was delayed for 1 minute after the onset of reperfusion (FMD 9.8±1.2% pre-IR, 4.0±0.9% post-IR, P<0.001; n=8). Conclusions: This study demonstrates for the first time that postconditioning can protect against endothelial IR injury in humans. Postconditioning might reduce tissue injury when applied at the onset of reperfusion by modifying the reperfusion phase of IR

Class dealignment and the neighbourhood effect: Miller revisited

The concept of a neighbourhood effect within British voting patterns has largely been discarded, because no data have been available for testing it at the appropriate spatial scales. To undertake such tests, bespoke neighbourhoods have been created around the home of each respondent to the 1997 British Election Study survey in England and Wales, and small-area census data have been assembled for these to depict the socio-economic characteristics of voters' local contexts. Analyses of voting in these small areas, divided into five equal-sized status areas, provides very strong evidence that members of each social class were much more likely to vote Labour than Conservative in the low-status than in the high-status areas. This is entirely consistent with the concept of the neighbourhood effect, but alternative explanations are feasible. The data provide very strong evidence of micro-geographical variations in voting patterns, for which further research is necessary to identify the processes involved

Remote Ischemic Preconditioning Protects the Brain Against Injury After Hypothermic Circulatory Arrest

Background-Ischemic preconditioning (IPC) is a mechanism protecting tissues from injury during ischemia and reperfusion. Remote IPC (RIPC) can be elicited by applying brief periods of ischemia to tissues with ischemic tolerance, thus protecting vital organs more susceptible to ischemic damage. Using a porcine model, we determined whether RIPC of the limb is protective against brain injury caused by hypothermic circulatory arrest (HCA).Methods and Results-Twelve piglets were randomized to control and RIPC groups. RIPC was induced in advance of cardiopulmonary bypass by 4 cycles of 5 minutes of ischemia of the hind limb. All animals underwent cardiopulmonary bypass followed by 60 minutes of HCA at 18 degrees C. Brain metabolism and electroencephalographic activity were monitored for 8 hours after HCA. Assessment of neurological status was performed for a week postoperatively. Finally, brain tissue was harvested for histopathological analysis.Study groups were balanced for baseline and intraoperative parameters. Brain lactate concentration was significantly lower (P < 0.0001, ANOVA) and recovery of electroencephalographic activity faster (P < 0.05, ANOVA) in the RIPC group. RIPC had a beneficial effect on neurological function during the 7-day follow-up (behavioral score; P < 0.0001 versus control, ANOVA). Histopathological analysis demonstrated a significant reduction in cerebral injury in RIPC animals (injury score; mean [interquartile range]: control 5.8 [3.8 to 7.5] versus RIPC 1.5 [0.5 to 2.5], P < 0.001, t test).Conclusions-These data demonstrate that RIPC protects the brain against HCA-induced injury, resulting in accelerated recovery of neurological function. RIPC might be neuroprotective in patients undergoing surgery with HCA and improve long-term outcomes. Clinical trials to test this hypothesis are warranted. (Circulation. 2011; 123: 714-721.

Effect of methylguanidine in a model of septic shock induced by LPS

Septic shock, a severe form of sepsis, is characterized by cardiovascular collapse following microbial invasion of the body. The progressive hypotension, hyporeactivity to vasopressor agents and vascular leak leads to circulatory failure with multiple organ dysfunction and death. Many inflammatory mediators (e.g. TNF-a, IL-1 and IL-6) are involved in the pathogenesis of shock and, among them, nitric oxide (NO). The overproduction of NO during septic shock has been demonstrated to contribute to circulatory failure, myocardial dysfunction, organ injury and multiple organ failure. We have previously demonstrated with in vitro and in vivo studies that methylguanidine (MG), a guanidine compound deriving from protein catabolism, significantly inhibits iNOS activity, TNF-a release and carrageenan-induced acute inflammation in rats. The aim of the present study was to evaluate the possible anti-inflammatory activity of MG in a model of septic shock induced by lipopolysaccharide (LPS) in mice. MG was administered intraperitoneally (i.p.) at the dose of 30 mg/kg 1 h before and at 1 and 6 h after LPS-induced shock. LPS injection (10mg/kg in 0.9% NaCl; 0.1 ml/mouse; i.p.) in mouse developed a shock syndrome with enhanced NO release and liver, kidney and pancreatic damage 18 h later. NOx levels, evaluated as nitrite/nitrate serum levels, was significantly reduced in MG-treated rats (78.6%, p , 0:0001; n ¼ 10). Immunohistochemistry revealed, in the lung tissue of LPS-treated group, a positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) synthase, both of which were reduced in MG-treated mice. Furthermore, enzymatic evaluation revealed a significant reduction in liver, renal and pancreatic tissue damage andMGtreatment also improved significantly the survival rate. This study provides evidence that MG attenuates the degree of inflammation and tissue damage associated with endotoxic shock in mice. The mechanisms of the anti-inflammatory effect of MG is, at least in part, dependent on the inhibition of NO formation