Relationship between thymic function and elderly survival has been suspected, despite the fact that formal proof is elusive due to technical limitations of thymic function-related markers. The newly described sj/β-TREC ratio allows now, by overcoming these limitations, an accurate measurement of thymic output in elderly humans. Thus, the aim of this study was to determine the impact of thymic function and inflammatory markers on healthy elderly human survival. Healthy volunteers (n=151), aged over 65, were asked to participate (CARRERITAS cohort). Subjects were excluded if diagnosed of dementia or, during the last 6 months, had clinical data of infection, hospital admission, antitumor therapy, or any treatment that could influence the immune status. Thymic function (sj/β-TREC ratio), CD4:CD8 T cell ratio, C-reactive protein, interleukin-6, and neutrophilia were determined from basal samples. All basal variables and age were associated with 2-year allcause mortality. Multivariate analysis showed that only thymic function and C-reactive protein were independently associated with time to death. In conclusion, we show, for the first time, the direct role of thymic function in human survival. C-reactive protein raise is also a marker of mortality in the healthy elderly, in a thymic-independent way.

Abstract. Organic pentavalent antimonials are one of the mainstays of treatment for visceral leishmaniasis (VL). Few data are available on the toxicity and efficacy of these drugs at the dosing schedule recommended by the Centers for Disease Control and Prevention (CDC) (Atlanta, GA). We analyzed 25 VL episodes in human immunodeficiency virus (HIV)-infected patients who were treated with meglumine antimoniate (MA) at the CDC-recommended dose in southern Spain. Adverse effects were observed in 14 (56%) VL episodes. In 7 (28%), treatment with MA was permanently discontinued due to serious adverse effects that included acute pancreatitis, acute renal failure, and leukopenia. Three (12%) patients died during therapy due to severe acute pancreatitis attributable to MA. The dosing regimen of MA currently recommended for treating VL is associated with a high rate of serious side effects in HIV-1-infected patients.Visceral leishmaniasis (VL) caused by Leishmania infantum is endemic in countries bordering the Mediterranean basin. It has been increasingly recognized that it affects human immunodeficiency virus type-1 (HIV-1)-infected patients, not only in this endemic area 1 , but also in non-endemic western countries. 2,3 Organic pentavalent antimonials (Sb V ) are one of the first-line drugs recommended by the Word Health Organization (WHO) for treating VL in the Mediterranean area. 4 In 1982, WHO (unpublished data) advocated treatment with 20 mg of Sb V /kg of body weight, with a maximum dose of 850 mg/day. The Centers for Disease Control (CDC) (Atlanta, GA) recommended in 1992 to remove the upper limit dose. 5 Data that supported this recommendation stemmed from clinical trials with patients not infected with HIV. 5 It was reported that higher daily doses without an upper limit resulted in better responses. Side effects were regarded as reversible and rarely severe.Patients with VL coinfected with HIV have a poor response to Sb V therapy. 1 Microbiologic cure is observed in less than half the cases and relapses are frequent. [6][7][8][9] In this setting, toxic effects of Sb V have seldom been reported in previous studies. 6,10,11 However, the dose of Sb V used in these patients was limited to a maximum of 850 mg/day. 6-12 Therefore, we assume that a low dose was administered. Thus, few data are available on efficacy and safety of the currently recommended Sb V dosing schedule to treat VL in HIV-1-infected individuals. 1 We provide herein data on toxicity and efficacy of meglumine antimoniate (MA) at a dose of 20 mg/kg of body weight/day with no dose limit in HIV-1-infected patients with VL. PATIENTS AND METHODSPatients. Fifty-one episodes of VL were diagnosed in 46 HIV-1-infected patients attending 2 University Hospital Acquired Immunodeficiency Syndrome (AIDS) care units in Seville, Spain from October 1993 to December 1997. Based on the diagnosis of the responsible physician, 25 VL episodes (49%) were treated with MA following the dosing schedule recommended by CDC in 1992. 5 Twenty-four were initial episodes and 1 w...

SUMMARYAge is one of the main factors involved in the rapidity and the magnitude of CD4 + T cell repopulation in human immunodeficiency virus (HIV)-infected patients on highly active antiretroviral treatment (HAART). Improved thymic function has been suggested as the main factor associated with CD4 + T cell restoration after HAART. This work was undertaken to determine, among host factors, the predictor variable at baseline involved in the magnitude of short-and long-term recovery of CD4 + T cells after HAART. HIV-RNA levels and CD4 + T cell numbers were determined in 54 HIV-infected adults at baseline and at weeks 4, 12, 48 and 96 after HAART. T cell subpopulations were determined by flow cytometry, thymic volume by computed tomography, T cell receptor excision circle (TREC)-bearing cells by quantitative polymerase chian reaction (PCR) and interleukin (IL)-7 levels by enzyme linked immunosorbent assay at baseline. The phenotype of patients' isolates was determined by infecting GHOST cells expressing CCR5 and CXCR4. The possible interference of phenotype with thymic function was also analysed. Baseline thymic volume was associated independently with the magnitude of short-and long-term recovery of CD4 + T cells after HAART, despite the patients' viral phenotype. The measurement of thymic volume before therapy may predict the magnitude of T cell increase. This result could have important clinical implications not only in HIV-infected patients, but also in other scenarios of T cell depletion such as bone marrow transplantation and chemotherapy.

These data suggest that IL-7 plays an important role in thymic rebound in adult HIV-infected patients under HAART.

The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4؉ cell counts below 300 cells/mm 3 during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P ‫؍‬ 0.1 and P ‫؍‬ 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.

In general, the conventional techniques available for the diagnosis of leishmaniasis have relatively low sensitivity. This means that parasite-rich samples (which can usually only be collected by very invasive methods, such as bone-marrow aspiration) must be employed. This problem has not yet been solved even by use of the PCR-based techniques currently available. However, a new PCR-ELISA has been developed for the diagnosis of cutaneous (CL) and visceral leishmaniasis (VL) caused by Leishmania infantum. This assay appears to have sufficient sensitivity to be effective in the diagnosis of VL not only when bone-marrow aspirates are investigated but also when the samples are of peripheral blood. Overall, the ability of the PCR-ELISA to detect Leishmania, in 76 samples (22 of peripheral blood, 36 bone-marrow aspirates and 18 skin samples) from 72 patients living in a endemic region, was better than that of culture or the examination of Giemsa-stained smears. For example, L. infantum kDNA was detected by PCR-ELISA in 15 (83%) of the 18 skin samples from suspected cases of CL, whereas the combined use of several classical techniques only confirmed the presence of amastigotes in five (28%) of these samples. Similarly, only 21 individuals were diagnosed as having VL by conventional techniques whereas 30 were found Leishmania-positive in the PCR-ELISA. The new PCR-ELISA also appears to be a suitable technique for detecting leishmanial kDNA in samples of peripheral blood from cases of L. infantum-HIV co-infection. The assay is more sensitive than the combined use of several conventional techniques in the diagnosis of subclinical VL, probably because those with subclinical infection have relatively low parasitic loads that are generally undetectable using the other techniques.

Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART.

Genotyping of human immunodeficiency virus type 1 (HIV-1) for antiretroviral drug resistance is routinely used both in clinical practice, to guide the selection of options for an individual's antiretroviral therapy, and in epidemiological studies, to estimate levels of antiretroviral drug resistance in a patient population. However, reliance on results of a single test can result in an underestimation of antiretroviral drug resistance. In the present study, we quantified the prevalence of resistance-associated mutations found in recent genotypic tests of 1734 HIV-1-infected, treatment-experienced subjects who had at least 3 genotypic tests (n = 11,404 genotypic tests total; median, 5 tests/subject) and compared it with that of resistance-associated mutations ever detected in these subjects between 1996 and 2004. Single-point analyses underestimated antiretroviral drug resistance, particularly for nucleoside analogues, in both individuals and patient populations. For example, the prevalence of resistance-associated mutation M184V/I was 25.5% in the most recent genotypes and 58.8% in available historical genotypes. Our results suggest that analysis of a combined historical genotype rather than of a cross-sectional genotype may lead to more accurate estimates of antiretroviral drug resistance in individual patients and in patient populations.