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The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD ≤20. Neutrophil-to-lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (≥4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case-control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD ≤20 within 90 days of death. Controls were similar LT candidates who were alive for ≥90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was ≥4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous ≥1.9, ≥4, ≥6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of ≥1.9, ≥4, ≥6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD.

Infliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.

SummaryMany compounds hold promise for pharmacologic manipulation of aging. However, such claims are difficult to investigate due to time and budget constraints. Here, we took a comparative approach, using short-lived invertebrate species, to directly test the effects of two tocopherols (vitamin E) on longevity. γ-tocopherol represents the most abundant tocopherol in the Western diet, while α-tocopherol is selectively enriched in human plasma. Both isoforms demonstrate antioxidant activity and are proposed to have anti-aging activities. We compared the effects of α-and γ-tocopherol supplementation on lifespan in three invertebrate species. γ-, but not α-, tocopherol slightly extended lifespan in nematodes, but neither significantly affected lifespan in two fly species. This study shows that a comparative approach, utilizing multiple invertebrate species, can increase the robustness of invertebrate-based pilot screens for prolongevity interventions.Pharmacological and nutritional approaches to retard aging and increase longevity have been proposed (Floyd, 2006, Joseph et al., 2005. Large-scale screens are being considered for a number of model organisms to accelerate discovery of compounds with the greatest potential for extending lifespan (Bauer et al., 2004, Wang et al., 2004. One class of compounds with potentially beneficial effects on aging are the tocopherol isomers found in Vitamin E and which are found naturally in plant oils (Ames et al., 2005). Vitamin E is a mixture of several related tocopherol and tocotrienol isomers, including the α-and γ-tocopherols. The Western diet is enriched in γ-tocopherol, but α-tocopherol is selectively retained in human plasma (Jiang et al., 2001, Tucker andTownsend, 2005). Both tocopherols are derived from fatty acids and exist within membranes, where they affect membrane fluidity and can act as antioxidants.The high antioxidant capacity of vitamin E makes it a candidate for a prolongevity therapy, since aging is correlated with increased oxidative stress in cells (Ames et al., 1993, Harman, 1 These authors contributed equally to this work. * Corresponding author: CAW: Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore MD 21224; Tel: 410-558-8566; Fax: 410-558-8323; wolkowca@grc.nia.nih.gov.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. One efficient strategy for directly examining whether these compounds have any effect on lifespan is to determine whether supplementation can affect lifespan in short-lived invertebrate species, which offer models for aging in...

We studied the membrane transporters that mediate intracellular pH (pH(i)) recovery from acidification in brainstem neurons from chemosensitive regions of neonatal rats. Individual neurons within brainstem slices from the retrotrapezoid nucleus (RTN), the nucleus tractus solitarii (NTS), and the locus coeruleus (LC) were studied using a pH-sensitive fluorescent dye and fluorescence imaging microscopy. The rate of pH(i) recovery from an NH(4)Cl-induced acidification was measured, and the effects of inhibitors of various pH-regulating transporters determined. Hypercapnia (15% CO(2)) resulted in a maintained acidification in neurons from all three regions. Recovery in RTN neurons was nearly entirely eliminated by amiloride, an inhibitor of Na(+)/H(+) exchange (NHE). Recovery in RTN neurons was blocked approximately 50% by inhibitors of isoform 1 of NHE (NHE-1) but very little by an inhibitor of NHE-3 or by DIDS (an inhibitor of HCO(3)-dependent transport). In NTS neurons, amiloride blocked over 80% of the recovery, which was also blocked approximately 65% by inhibitors of NHE-1 and 26% blocked by an inhibitor of NHE-3. Recovery in LC neurons, in contrast, was unaffected by amiloride or blockers of NHE isoforms but was dependent on Na(+) and increased by external HCO(3)(-). On the basis of these findings, pH(i) recovery from acidification appears to be largely mediated by NHE-1 in RTN neurons, by NHE-1 and NHE-3 in NTS neurons, and by a Na- and HCO(3)-dependent transporter in LC neurons. Thus, pH(i) recovery is mediated by different pH-regulating transporters in neurons from different chemosensitive regions, but recovery is suppressed by hypercapnia in all of the neurons.