Indexing dialysis dose for gender, body size and physical activity: Impact on survival

Current practice basing dialysis dose on urea distribution volume (V) has been questioned. We explored the impact on survival of scaling dialysis dose (Kt) to parameters reflective of metabolic activity. In a multicentre prospective cohort study of 1500 patients on thrice-weekly haemodialysis, body surface area (BSA) and resting energy expenditure (REE) were estimated using validated equations and physical activity by the Recent Physical Activity Questionnaire. Total energy expenditure (TEE) was estimated from REE and physical activity data. Kt was calculated from delivered (single-pool Kt/V)*Watson V. Kt/BSA, Kt/ REE and Kt/TEE were then calculated at baseline and 6 monthly during follow-up for 2 years. In adjusted Cox models Kt/TEE, Kt/BSA, Kt/REE, in that order, had lower hazard ratios for death than single-pool Kt/V. On the basis of adjusted survival differences, putative minimum target doses were estimated for Kt/BSA as 27119 ml/m 2 and Kt/TEE as 25.79 ml/ kcal. We identified spKt/V values equivalent to these estimated targets, ranging from 1.4 to 1.8 in patient groups based on gender, body size and physical activity. For sedentary patients, the minimum target dose was 1.4 for large males, 1.5 for small males and 1.7 for women. For active patients the target was 1.8 irrespective of gender and body-weight. Patients achieving these individualised minimum targets had greater adjusted two-year survival compared to those achieving conventional minimum targets. Metabolic activity related parameters, such as Kt/TEE and Kt/BSA, may have a clinically important role in scaling haemodialysis dose. Using such parameters or their spKt/V equivalents to adjust minimum target doses based on gender, body size and habitual physical activity may have a positive impact on survival.Peer reviewe

Vaccination with live attenuated simian immunodeficiency virus causes dynamic changes in intestinal CD4+CCR5+ T cells

<p>Abstract</p> <p>Background</p> <p>Vaccination with live attenuated SIV can protect against detectable infection with wild-type virus. We have investigated whether target cell depletion contributes to the protection observed. Following vaccination with live attenuated SIV the frequency of intestinal CD4+CCR5+ T cells, an early target of wild-type SIV infection and destruction, was determined at days 3, 7, 10, 21 and 125 post inoculation.</p> <p>Results</p> <p>In naive controls, modest frequencies of intestinal CD4+CCR5+ T cells were predominantly found within the LPL T_TrM-1and IEL T_TrM-2subsets. At day 3, LPL and IEL CD4+CCR5+ T_EMcells were dramatically increased whilst less differentiated subsets were greatly reduced, consistent with activation-induced maturation. CCR5 expression remained high at day 7, although there was a shift in subset balance from CD4+CCR5+ T_EMto less differentiated T_TrM-2cells. This increase in intestinal CD4+CCR5+ T cells preceded the peak of SIV RNA plasma loads measured at day 10. Greater than 65.9% depletion of intestinal CD4+CCR5+ T cells followed at day 10, but overall CD4+ T cell homeostasis was maintained by increased CD4+CCR5- T cells. At days 21 and 125, high numbers of intestinal CD4+CCR5- naive T_Ncells were detected concurrent with greatly increased CD4+CCR5+ LPL T_TrM-2and IEL T_EMcells at day 125, yet SIV RNA plasma loads remained low.</p> <p>Conclusions</p> <p>This increase in intestinal CD4+CCR5+ T cells, following vaccination with live attenuated SIV, does not correlate with target cell depletion as a mechanism of protection. Instead, increased intestinal CD4+CCR5+ T cells may correlate with or contribute to the protection conferred by vaccination with live attenuated SIV.</p

Changes in immune cell populations in the periphery and liver of GBV-B-infected and convalescent tamarins (Saguinus labiatus)

AbstractFlaviviruses related to hepatitis C virus (HCV) in suitable animal models may provide further insight into the role that cellular immunity contributes to spontaneous clearance of HCV. We characterised changes in lymphocyte populations in tamarins with an acute GBV-B infection, a hepatitis virus of the flaviviridae. Major immune cell populations were monitored in peripheral and intra-hepatic lymphocytes at high viraemia or following a period when peripheral virus was no longer detected. Limited changes in major lymphocyte populations were apparent during high viraemia; however, the proportions of CD3+ lymphocytes decreased and CD20+ lymphocytes increased once peripheral viraemia became undetectable. Intrahepatic lymphocyte populations increased at both time points post-infection. Distinct expression patterns of PD-1, a marker of T-cell activation, were observed on peripheral and hepatic lymphocytes; notably there was elevated PD-1 expression on hepatic CD4+ T-cells during high viraemia, suggesting an activated phenotype, which decreased following clearance of peripheral viraemia. At times when peripheral vRNA was not detected, suggesting viral clearance, we were able to readily detect GBV-B RNA in the liver, indicative of long-term virus replication. This study is the first description of changes in lymphocyte populations during GBV-B infection of tamarins and provides a foundation for more detailed investigations of the responses that contribute to the control of GBV-B infection

Vaccination with live attenuated simian immunodeficiency virus for 21 days protects against superinfection

AbstractThe identification of mechanisms that prevent infection with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) would facilitate the development of an effective AIDS vaccine. In time-course experiments, protection against detectable superinfection with homologous wild-type SIV was achieved within 21 days of inoculation with live attenuated SIV, prior to the development of detectable anti-SIV humoral immunity. Partial protection against superinfection was achieved within 10 days of inoculation with live attenuated SIV, prior to the development of detectable anti-SIV humoral and cellular immunity. Furthermore, co-inoculation of live attenuated SIV with wild-type SIV resulted in a significant reduction in peak virus loads compared to controls that received wild-type SIV alone. These findings imply that innate immunity or non-immune mechanisms are a significant component of early protection against superinfection conferred by inoculation with live attenuated SIV

What is Hacking’s argument for entity realism?

According to Ian Hacking’s Entity Realism, unobservable entities that scientists carefully manipulate to study other phenomena are real. Although Hacking presents his case in an intuitive, attractive, and persuasive way, his argument remains elusive. I present five possible readings of Hacking’s argument: a no-miracle argument, an indispensability argument, a transcendental argument, a Vichian argument, and a non-argument. I elucidate Hacking’s argument according to each reading, and review their strengths, their weaknesses, and their compatibility with each othe

Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells.

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