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Studies have focused on the effects of chronic alcohol consumption and the mechanisms of tissue injury underlying alcoholic hepatitis and cirrhosis, with less focus on the pathophysiological consequences of binge alcohol consumption. Alcohol binge drinking prevalence continues to rise, particularly among individuals ages 18 to 24. However, it is also frequent in individuals ages 65 and older. High blood alcohol levels achieved with this pattern of alcohol consumption are of particular concern, as alcohol can permeate to virtually all tissues in the body, resulting in significant alterations in organ function, which leads to multisystemic pathophysiological consequences. In addition to the pattern, amount, and frequency of alcohol consumption, additional factors, including the type of alcoholic beverage, may contribute differentially to the risk for alcohol-induced tissue injury. Preclinical and translational research strategies are needed to enhance our understanding of the effects of binge alcohol drinking, particularly for individuals with a history of chronic alcohol consumption. Identification of underlying pathophysiological processes responsible for tissue and organ injury can lead to development of preventive or therapeutic interventions to reduce the health care burden associated with binge alcohol drinking.

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

Following the 10 weeks ART administration period, we observed decreased frequencies of long-term hematopoietic stem cells and multipotent progenitor cells in CBA, ART naïve animals, and this deficit was not observed in ART-treated animals.

The cardiovascular effects of psychostimulant drugs (methylphenidate, amphetamine, cocaine) have been mostly associated with their noradrenergic effects. However, there is some evidence that dopaminergic effects are involved in the cardiovascular actions of these drugs. Here, we evaluated this association in humans. Positron emission tomography (PET) and [(11)C]raclopride, a dopamine (DA) D2 receptor radioligand that competes with endogenous DA for occupancy of the D2 receptors, were used to measure changes in brain DA after different doses of intravenous methylphenidate in 14 healthy subjects. Cardiovascular (heart rate and blood pressure) and catecholamine (plasma epinephrine and norepineprhine) responses were determined in parallel to assess their relationships to methylphenidate-induced changes in brain DA. Methylphenidate administration significantly increased heart rate, systolic and diastolic blood pressures and epinephrine concentration in plasma. The increases in blood pressure were significantly correlated with methylphenidate-induced increases of DA in striatum (r>0.78, P<0.001) and of plasma epinephrine levels (r>0.82, P<0.0005). In turn methylphenidate-induced DA increases in striatum were correlated with increases of epinephrine in plasma (r=0.85, P<0.0001). Subjects in whom methylphenidate did not increase DA had no change in blood pressure or in plasma epinephrine concentration. These results are consistent with the hypothesis that methylphenidate-induced increases in blood pressure are in part due to its central dopaminergic effects. They also suggest that methylphenidate's pressor effects may be in part mediated by DA-induced increases in peripheral epinephrine.

Acute alcohol intoxication is a frequent underlying condition associated with traumatic injury. Studies from our laboratory have been designed to examine the early hemodynamic, proinflammatory, and neuroendocrine alterations in responses to hemorrhagic shock in surgically catheterized, conscious, unrestrained, male Sprague–Dawley rats during acute alcohol intoxication (1.75-g/kg bolus, followed by a constant 15-h infusion at a rate of 250–300 mg/kg/h). With both fixed-pressure (40 mm Hg) and fixed-volume (50%) hemorrhagic shock, followed by fluid resuscitation with Ringer's lactate, acute (15 h) alcohol intoxication has been shown to impair significantly the immediate hemodynamic, metabolic, and inflammatory counterregulatory responses to hemorrhagic shock. Alcohol intoxication enhanced hemodynamic instability during blood loss and impaired the recovery of mean arterial blood pressure during fluid resuscitation. Activation of neuroendocrine pathways involved in restoring hemodynamic stability was significantly attenuated in alcohol-intoxicated hemorrhaged animals. The hemodynamic and neuroendocrine impairment is associated with enhanced expression of lung and spleen tumor necrosis factor, and it suppressed circulating neutrophil function. In addition, neuroimmune regulation of cytokine production by spleen-derived macrophages obtained from alcohol-intoxicated hemorrhaged animals was impaired when examined in vitro. We hypothesize that impaired neuroendocrine activation contributes to hemodynamic instability, which, in turn, prolongs tissue hypoperfusion and enhances risk for tissue injury. Specifically, the early dysregulation in counterregulatory responses is hypothesized to affect host defense mechanisms during the recovery period. We examined host response to systemic (cecal ligation and puncture) and localized (pneumonia) infectious challenge in animals recovering from hemorrhage during acute alcohol intoxication. Increased morbidity and mortality from infection were observed in alcohol-intoxicated hemorrhaged animals. Our results indicate that alcohol-induced alterations in early hemodynamic and neuroimmune responses to shock have an impact on susceptibility to an infectious challenge during the early recovery period.

Alcohol consumption contributes to increased incidence and severity of traumatic injury. Compared with patients who do not consume alcohol, alcohol-consuming patients have higher rates of long-term morbidity and mortality during recovery from injury. This can be attributed in part to an impaired immune response in individuals who consume alcohol. Acute and chronic alcohol use can affect both the innate and adaptive immune defense responses within multiple organ systems; the combination of alcohol use and injury results in increased susceptibility to bacterial and viral pathogens. This review examines the major deleterious effects of alcohol on immunity following tissue damage or traumatic injury, with a focus on alcohol's influence on the ability of the immune and major organ systems to fight disease and to repair damaged tissues following injury.

Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia. E Cersosimo , P E Molina and N N Abumrad Department of Medicine, State University of New York at Stony Brook, 11794-8154, USA. Abstract The contribution of gluconeogenic precursors to renal glucose production (RGP) during insulin-induced hypoglycemia was assessed in conscious dogs. Ten days after surgical placement of sampling catheters in the right and left renal veins and femoral artery and an infusion catheter in the left renal artery, systemic and renal glucose and glycerol kinetics were measured with peripheral infusions of [6-3H]glucose and [2-13C]glycerol. Renal blood flow was determined with a flowprobe, and the renal balance of lactate, alanine, and glycerol was calculated by arteriovenous difference. After baseline, six dogs received 2-h simultaneous infusions of peripheral insulin (4 mU x kg(-1) x min(-1)) and left intrarenal [6,6-2H]dextrose (14 micromol x kg(-1) x min(-1)) to achieve and maintain left renal normoglycemia during systemic hypoglycemia. Arterial glucose decreased from 5.3 +/- 0.1 to 2.2 +/- 0.1 mmol/l; insulin increased from 46 +/- 5 to 1,050 +/- 50 pmol/l; epinephrine, from 130 +/- 8 to 1,825 +/- 50 pg/ml; norepinephrine, from 129 +/- 6 to 387 +/- 15 pg/ml; and glucagon, from 52 +/- 2 to 156 +/- 12 pg/ml (all P < 0.01). RGP increased from 1.7 +/- 0.4 to 3.0 +/- 0.5 (left) and from 0.6 +/- 0.2 to 3.2 +/- 0.2 (right) micromol x kg(-1) x min(-1) (P < 0.01). Whole-body glycerol appearance increased from 6.0 +/- 0.5 to 7.7 +/- 0.7 micromol x kg(-1) x min(-1)(P < 0.01); renal conversion of glycerol to glucose increased from 0.13 +/- 0.04 to 0.30 +/- 0.10 (left) and from 0.11 +/- 0.03 to 0.25 +/- 0.05 (right) micromol x kg(-1) x min(-1), (P < 0.05). Net renal gluconeogenic precursor uptake increased from 1.5 +/- 0.4 to 5.0 +/- 0.4 (left) and from 0.9 +/- 0.2 to 3.8 +/- 0.4 (right) micromol x kg(-1) x min(-1) (P < 0.01). Renal lactate uptake could account for approximately 40% of postabsorptive RGP and for 60% of RGP during hypoglycemia. These results indicate that gluconeogenic precursor extraction by the kidney, particularly lactate, is stimulated by counterregulatory hormones and accounts for a significant fraction of the enhanced gluconeogenesis induced by hypoglycemia.

Renal glucose production during insulin-induced hypoglycemia. E Cersosimo , P E Molina and N N Abumrad Department of Medicine, State University of New York at Stony Brook 11794-8154, USA. Abstract Recent in vivo studies have rekindled interest in the role of the kidney in glucose metabolism. We therefore undertook the present study to evaluate the contribution of the kidney to systemic glucose production and utilization rates during insulin-induced hypoglycemia using arteriovenous balance combined with a tracer technique. Ten days after the surgical placement of sampling catheters in the right and left renal veins and femoral artery and of an infusion catheter in the left renal artery of dogs, systemic and renal glucose kinetics were measured with the peripheral infusion of [6-3H]glucose. Renal blood flow was determined with a flowprobe. After baseline, six dogs received 2-h simultaneous infusions of peripheral insulin (4 mU x kg(-1) x min(-1)) and left intrarenal [6,6-2H]dextrose (14 micromol x kg(-1) x min(-1)) to achieve and maintain left renal normoglycemia during systemic hypoglycemia. Arterial glucose decreased from 5.3 +/- 0.1 to 2.2 +/- 0.1 mmol/l; insulin increased from 46 +/- 5 to 1,050 +/- 50 pmol/l; epinephrine increased from 130 +/- 8 to 1,825 +/- 50 pg/ml; norepinephrine increased from 129 +/- 6 to 387 +/- 15 pg/ml; and glucagon increased from 52 +/- 2 to 156 +/- 12 pg/ml (all P < 0.01). Systemic glucose appearance increased from 16.6 +/- 0.4 micromol x kg(-1) x min(-1) in the baseline to 24.2 +/- 0.6 micromol x kg(-1) x min(-1) during hypoglycemia when endogenous glucose production was 10.2 +/- 1.0 micromol x kg(-1) x min(-10 (P < 0.01). In the baseline, the liver accounted for 80% (13.3 +/- 0.8 micromol x kg(-1) x min(-1)) and each kidney contributed 10% (1.6 +/- 0.2 micromol x kg(-1) x min(-1)) to endogenous glucose production. During hypoglycemia, however, hepatic glucose production decreased to 4.0 +/- 0.4 micromol x kg(-1) x min(-1), whereas right renal glucose production doubled to 3.2 +/- 0.2 micromol x kg(-1) x min(-1) (P < 0.01). Left renal glucose production was 17 +/- 2 micromol x kg(-1) x min(-1), 14 of which were derived from the exogenous infusion. These results indicate that glucose production by the kidney is stimulated by counterregulatory hormones and represents an important component of the body's defense against insulin-induced hypoglycemia.

Although stress is an extensively investigated phenomenon, the effects of specific stressors on the pharmacologic activity of routinely administered drugs are less well characterized. We designed the present study to investigate the effect of handling stress on catecholaminergic responsivity following an acute methylphenidate (MP, Ritalin) challenge in the medial prefrontal cortex (mPFC). Norepinephrine (NE) and dopamine (DA) levels were simultaneously measured in 15-min samples of PFC dialysate using HPLC coupled with electrochemical detection. Sprague-Dawley rats were handled for 15 min, which produced an increase from basal extracellular DA and NE levels. Handling stress attenuates the DA response when administered 2 h prior to IP MP, whereas handling stress enhances the DA response when administered simultaneously with IG MP. These findings suggest that persistent alterations in mesocorticolimbic DA-ergic activity are induced by a short exposure to restraint stress as evidenced by the altered response to MP challenge.

Until recently the Antarctic continent and Peninsula have been little impacted by non-native species, compared to other regions of the Earth. However, reports of species introductions are increasing as awareness of biological invasions as a major conservation threat, within the context of increased human activities and climate change scenarios, has grown within the Antarctic community. Given the recent increase in documented reports, here we provide an up-to-date inventory of known terrestrial non-native species introductions, including those subsequently removed since the 1990s, within the Antarctic Treaty area. This builds on earlier syntheses of records published in the mid-2000s, which focused largely on the sub-Antarctic islands, given the dearth of literature available at that time from the continental and maritime Antarctic regions. Reports of non-native species established in the natural environment (i.e. non-synanthropic) are mainly located within the Antarctic Peninsula region and Scotia Arc, with Deception Island, South Shetland Islands, the most impacted area. Non-native plants have generally been removed from sites of introduction, but no established invertebrates have yet been subject to any eradication attempt, despite a recent increase in reports. Legislation within the Protocol on Environmental Protection to the Antarctic Treaty has not kept pace with environmental best practice, potentially presenting difficulties for the practical aspects of non-native species control and eradication. The success of any eradication attempt may be affected by management practices and the biology of the target species under polar conditions. Practical management action is only likely to succeed with greater co-operation and improved communication and engagement by nations and industries operating in the region.