Diverse aging rates in ectothermic tetrapods provide insights for the evolution of aging and longevity.

Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.

Clinical significance of a single cerebrospinal fluid immunoglobulin band: A retrospective study.

BACKGROUND: To demonstrate an inflammatory process in the central nervous system, the presence of at least two immunoglobulin (Ig) bands in the cerebrospinal fluid (CSF) is required. So far, the presence of a single abnormal Ig band is considered as negative. OBJECTIVE: The objective was to assess retrospectively the significance of a single CSF Ig band in clinical practice. METHODS AND RESULTS: Out of 10,286 CSF analyses, we retained 214 results with single Ig. An inflammatory neurological disorder was diagnosed in 41% of patients. CONCLUSION: Despite a modest sensitivity, the presence of a single CSF Ig band may be a biomarker of an inflammatory mechanism and, as such, may prompt the clinician to repeat the analysis when the clinical context remains suggestive.

Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients.

INTRODUCTION: Septic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients. METHODS: This prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed. RESULTS: We observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4+ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration. CONCLUSIONS: These findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.

Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma.

INTRODUCTION: Major trauma is characterized by an overwhelming pro-inflammatory response and an accompanying anti-inflammatory response that lead to a state of immunosuppression, as observed after septic shock. Diminished monocyte Human Leukocyte Antigen DR (mHLA-DR) is a reliable marker of monocyte dysfunction and immunosuppression. The main objective of this study was to determine the relation between mHLA-DR expression in severe trauma patients and the development of sepsis. METHODS: We conducted a prospective observational study over 23 months in a trauma intensive care unit at a university hospital. Patients with an Injury Severity Score (ISS) over 25 and age over 18 were included. mHLA-DR was assessed by flow cytometry protocol according to standardized protocol. Mann-Whitney U-test for continuous non-parametric variables, independent paired t test for continuous parametric variables and chi-square test for categorical data were used. RESULTS: mHLA-DR was measured three times a week during the first 14 days. One hundred five consecutive severely injured patients were monitored (ISS 38 ± 17, SAPS II 37 ± 16). Thirty-seven patients (35%) developed sepsis over the 14 days post-trauma. At days 1-2, mHLA-DR was diminished in the whole patient population, with no difference with the development of sepsis. At days 3-4, a highly significant difference appeared between septic and non-septic patients. Non- septic patients showed an increase in mHLA-DR levels, whereas septic patients did not (13,723 ± 7,766 versus 9,271 ± 6,029 antibodies per cell, p = .004). Most importantly, multivariate logistic regression analysis, after adjustment for usual clinical confounders (adjusted OR 5.41, 95% CI 1.42-20.52), revealed that a slope of mHLA-DR expression between days1-2 and days 3-4 below 1.2 remained associated with the development of sepsis. CONCLUSIONS: Major trauma induced an immunosuppression, characterized by a decrease in mHLA-DR expression. Importantly, after multivariate regression logistic analysis, persistent decreased expression was assessed to be in relation with the development of sepsis. This is the first study in trauma patients showing a link between the lack of immune recovery and the development of sepsis on the basis of the standardized protocol. Monitoring immune function by mHLA-DR measurement could be useful to identify trauma patients at a high risk of infection.

Proatrial natriuretic peptide is a better predictor of 28-day mortality in septic shock patients than proendothelin-1.

BACKGROUND: Septic shock is a major health care problem that affects a heterogeneous population of patients. To improve sepsis management, a key point is to decrease this heterogeneity by stratifying patients according to specific criteria, such as appropriate biomarkers. As the early phase of septic shock is characterized by cardiovascular dysfunction, precursors of vasoactive hormones represent interesting candidates. The objective of the present study was to concomitantly assess the predictive value of C-terminal proendothelin-1 and midregional proatrial natriuretic peptide (CT-proET-1 and MR-proANP, respectively vasoconstrictor and vasodilator) on 28-day mortality following septic shock. METHODS: In this observational study which included 99 patients, concentrations of MR-proANP and CT-proET-1 were measured using an immunoluminometric assay three times within the first week after the onset of septic shock. RESULTS: While MR-proANP concentrations were significantly increased in non-survivors in comparison with survivors, no differences were noted for CT-proET-1. Increased MR-proANP concentrations were significantly associated with mortality after both univariate and multivariate analyses, adjusted for usual clinical confounders [SAPS II (simplified acute physiology score II), SOFA (sepsis-related organ failure assessment) scores and number of co-morbidities]. CONCLUSIONS: In septic shock patients, MR-proANP appears to be a good predictor of 28-day mortality, whereas CT-proET-1 does not present any predictive value during monitoring.

Percentage of regulatory T cells CD4+CD25+CD127- in HIV-infected patients is not reduced after cryopreservation.

Interest in regulatory T cells (Treg) has been continuously growing over the last 10years. In particular, a role for Treg has been recently reported in HIV. It is crucial to investigate their conservation over time, once sampled and purified. The objective of the present study was to investigate whether cryopreservation may modify recognition and measurement of relative frequency of Treg (CD4(+)CD25(+)CD127(-)) among PBMCs purified from 17 HIV-infected patients. Ours results indicate that cryopreservation does not affect this specific T lymphocyte subset.

Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients.

PURPOSE: Improvements in survival after septic shock will most likely rely on our capacity to manage individualized therapies based on the measurement of rapidly accessible biomarkers. As the early phase of septic shock is dominated by severe alterations of the cardiovascular system, the predictive value for mortality of pro-vasopressin (pro-AVP) and pro-adrenomedullin (pro-ADM), two vasoactive pro-hormones, was assessed. METHODS: In 99 consecutive patients, pro-hormone concentrations were measured (immunoluminometric assay) three times within the first week after the onset of septic shock. RESULTS: Pro-AVP and pro-ADM concentrations were significantly increased in non-survivors in comparison with survivors and were significantly associated with mortality after both univariate and multivariate analysis. Importantly, when assessed as a pair, pro-ADM and pro-AVP were even more informative. CONCLUSIONS: Both Pro-ADM and pro-AVP appear to be good biomarkers for the prediction of 28-day mortality after septic shock. However, their association in a single variable tends to improve their predictive capacity.

Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients.

PURPOSE: Sepsis syndrome represents the leading cause of death in intensive care unit. Patients present features consistent with a decline in immune responsiveness potentially contributing to mortality. We investigated whether CD4(+)CD25(+) regulatory T cells (Treg) participate in the induction of lymphocyte anergy after sepsis. METHOD: Observational study in septic shock patients and experimental study in mice. RESULTS: We took advantage of the recently described flow cytometric gating strategy using the measurement of CD25 and CD127 expressions for monitoring Treg (CD4(+)CD25(+)CD127(-)Foxp3(+)). In patients the increased circulating Treg percentage significantly correlated with a decreased lympho-proliferative response. In a murine model of sepsis mimicking these observations, the ex vivo downregulation of Foxp3 expression using siRNA was associated with a restoration of this response. CONCLUSION: The relative increase in circulating Treg might play a role in lymphocyte anergy described after septic shock and represent a standardizable surrogate marker of declining proliferative capacity after sepsis.

Decreased expression of the fractalkine receptor CX3CR1 on circulating monocytes as new feature of sepsis-induced immunosuppression.

Although it is known that septic shock rapidly induces immune dysfunctions, which contribute to the impaired clearance of microorganisms observed in patients, the mechanisms for this phenomenon remain incompletely understood. We recently observed, in a microarray study, an altered circulating leukocyte CX3CR1 mRNA expression associated with patients' mortality. As monocytes play a central role in septic shock pathophysiology and express high levels of CX3CR1, we therefore further investigated the alteration of CX3CR1 expression and of its ligand fractalkine (CX3CL1) on those cells in this clinical condition. We observed that CX3CR1 expression (both mRNA and protein) was severely down-regulated in monocytes and consequently associated with a lack of functionality upon fractalkine challenge. Importantly, nonsurvivors presented with significantly sustained lower expression in comparison with survivors. This down-regulation was reproduced by incubation of cells from healthy individuals with LPS, whole bacteria (Escherichia coli and Staphylococcus aureus), and, to a lower extent, with corticosteroids-in accordance with the concept of LPS-induced monocyte deactivation. In addition, CX3CL1 serum concentrations were elevated in patients supporting the hypothesis of increased cleavage of the membrane-anchored form expressed by endothelial cells. As CX3CR1/CX3CL1 interaction preferentially mediates arrest and migration of proinflammatory cells, the present observations may contribute to patients' inability to kill invading microorganisms. This could represent an important new feature of sepsis-induced immunosuppression.