Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection

Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection via the natural route, we provide evidence that regulatory T cells have modifying effects on blood-stage infection in vivo in humans. Cells with the characteristics of regulatory T cells are rapidly induced following blood-stage infection and are associated with a burst of TGF-beta production, decreased proinflammatory cytokine production, and decreased antigen-specific immune responses. Both the production of TGF-beta and the presence of CD4+CD25+FOXP3+ regulatory T cells are associated with higher rates of parasite growth in vivo. P. falciparum-mediated induction of regulatory T cells may represent a parasite-specific virulence factor.     

Vagotomy reduces obesity in MSG-treated rats

In order to study the role of vagus nerve activity at the onset of obesity induced by monosodium glutamate (MSG), 30-day-old MSG-rats were vagotomized or sham operated. Body weight and food intake were recorded until animals were 90 days old and then sacrificed. Naso-anal length was recorded for all animals. Periepididymal and retroperitoneal fat pads were isolated and weighed. Reduction of body weight and naso-anal length were registered in 30-day-old MSG-rats. Obesity could also be observed, as increase of Lee index indicated. Results were most evident in 90-day-old MSG-rats. In both groups neither body weight gain nor food intake was changed by vagotomy. However, fat accumulation on tissues was reduced by vagotomy in MSG-rats. The results showed that MSG-obesity is not related to an increment in food intake behavior. Vagotonia might play a role at the onset of MSG-obesity.     

Modulation of Cytokeratin Expression in The Hamster Thymus: Evidence For a Plasticity of The Thymic Epithelium

Cytokeratin (CK) expression was investigated, by means of immunocytochemistry, in the hamster thymic epithelium during ontogeny, as well as in primary cultures and upon glucocorticoid hormone treatment in vivo. As compared to the distribution pattern of distinct monoclonal antibody-defined cytokeratins in the normal adult thymus, CK modulation was evidenced in the three situations studied. During thymus ontogeny, both cytokeratins of simple lining epithelia, as CK8 and CK18, as well as the CK1/CK10 pair (typical marker of terminal stage of keratinization), were expressed since early stages of thymus development. They were located in the central region of thymic lobules preceding the cortical-medullary distinctions. This differed from what had been previously shown for mouse thymus ontogeny, revealing that the interspecific diversity in the distribution pattern of thymic cytokeratins occurred early in fetal life. A modulation of CK expression was also detected when hamster thymic epithelial cells (TEC) were led to grow in culture, with a down-regulation of CK19 contrasting with an enhancement of CK18 expression. This diverged from the maintenance of the in situ pattern when human TEC were cultured. Last, in vivo hydrocortisone treatment, known to increase the numbers of KL1⁺ cells in the mouse thymus medulla, promoted a cortical expression of the CK1/CK10 pair in the hamster thymus. Taken together, our findings demonstrate a continuous plasticity of the thymic epithelium, at least regarding cytokeratin expression, and enlarge the concept of interspecific diversity of intrathymic CK distribution in conditions as morphogenesis, in vitro system, and responsiveness to glucocorticoid hormone treatment.     

Autonomic nervous control of the heart rate response to dynamic incremental exercise: evaluation of the Rosenblueth-Simeone model

Summary To evaluate the validity of the Rosenblueth-Simeone model for the heart rate response to incremental dynamic exercise, 11 healthy men performed maximal exercise tests on a cycle ergometer after administration of placebo, propranolol, atropine or both propranolol and atropine. The model showed that the influence of sympathetic activity on heart rate increased at intensities up to those which resulted in a heart rate 70% maximal heart rate on placebo, and levelled off at higher intensities, while there was a progressive withdrawal of the parasympathetic activity. The ratio between heart rate predicted by the model and the recorded heart rate following placebo treatment tended to be less than 1.0 at lower exercise intensities, and approached the unit at intensities above those which resulted in a heart rate higher than 70% of maximal heart rate on placebo. There was a strong correlation (r=0.94,P<0.01) between the heart rate on placebo and the heart rate estimated by the model. Nevertheless, there was some scattering of the data around the identity line, with a standard error of the estimate for the regression line of 11 beats · min^–1. Thus, during incremental exercise, the influence of sympathetic activity on heart rate does not become progressively more important at higher exercise intensities. The application of the Rosenblueth-Simeone model shows limitations during incremental exercise, particularly at low exercise intensities.     

Serotonergic-1a activity and contingent negative variation

While cholinergic, dopaminergic, noradrenergic, and gabaergic effects on contingent negative variation (CNV) have been largely described, little is known about serotonergic influence. Therefore, the relationship between CNV and serotonergic activity as reflected by prolactin (PRL) response to flesinoxan, a 5-HT(1A) full agonist, has been investigated in 28 healthy volunteers. To investigate the clinical implications of the relationship between CNV and serotonergic-1a activity, a group of 43 depressed patients was included in the study. Results among healthy volunteers showed a significant negative relationship between PRL response to flesinoxan and CNV amplitude at Fz, but no relationship for the other electrodes (Cz and Pz). In depressed patients, the relationships were not significant. Overall, this study does not support serotonergic effects on CNV. However, this information is indirect (correlations) and is limited to 5-HT(1A) activity.     

Mechanisms of uterine specificity of vaginal progesterone

Endometrial transformations achieved by vaginal progesterone exceed those normally expected from the circulating concentrations obtained, this suggests some degree of direct vagina to uterus transport. We speculate on the different mechanisms involved in uterine specificity of vaginal progesterone and report data of a preliminary randomized study comparing progesterone concentrations in serum and endometrial tissue obtained from hysterectomy specimens after vaginal or i.m. administration. Eight post-menopausal women undergoing transabdominal hysterectomy were randomized to receive either vaginal progesterone gel, 90 mg, or i.m. progesterone formulation, 50 mg, at 08.00 and 20.00 on the day before surgery and at 06.00 on the day of surgery. Venous blood samples for progesterone measurement were drawn at 08.00 on the day before surgery and during the surgery. Endometrial progesterone concentrations were markedly higher in women who received vaginal progesterone (1.38+/-0.66 and 0.38+/-0.19 ng/mg protein, for vaginal and i.m. groups respectively) (P < 0.02) despite lower serum concentrations (4.17 < 0.56 and 32.32+/-11.06 ng/ml, for vaginal and i.m. groups respectively) (P < 0.001). The vaginal route induces endometrial progesterone concentrations that far exceed those expected from the serum progesterone concentrations achieved.     

Establishing phenotypic features associated with morbidity in human T-cell lymphotropic virus type 1 infection

The human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HT). Although it is widely believed that virus infection and host immune response are involved in the pathogenic mechanisms, the role of the immune system in the development and/or maintenance of HT remains unknown. We performed an analysis of the peripheral blood leukocyte phenotype for two different subcohorts of HTLV-1-infected individuals to verify the existence of similar immunological alterations, possible laboratory markers for HT. The leukocyte population balance, the activation status of the T lymphocytes, and the cellular migratory potential of T lymphocytes, monocytes, and neutrophils were evaluated in the peripheral blood of HTLV-1-infected individuals classified as asymptomatic individuals, oligosymptomatic individuals, and individuals with HT. Data analysis demonstrated that a decreased percentage of B cells, resulting in an increased T cell/B cell ratio and an increase in the CD8+ HLA-DR+ T lymphocytes, exclusively in the HT group could be identified in both subcohorts, suggesting its possible use as a potential immunological marker for HT for use in the laboratory. Moreover, analysis of likelihood ratios showed that if an HTLV-1-infected individual demonstrated B-cell percentages lower than 7.0%, a T cell/B cell ratio higher than 11, or a percentage of CD8+ HLA-DR+ T lymphocytes higher than 70.0%, this individual would have, respectively, a 12-, 13-, or 22-times-greater chance of belonging to the HT group. Based on these data, we propose that the T cell/B cell ratios and percentages of circulating B cells and activated CD8+ T lymphocytes in HTLV-1-infected patients are important immunological indicators which could help clinicians monitor HTLV-1 infection and differentiate the HT group from the asymptomatic and oligosymptomatic groups.     

Purification of the paraflagellar rod of the trypanosomatid Herpetomonas megaseliae and identification of some of its minor components

The paraflagellar rod (PFR) is a component of the flagellar cytoskeleton of trypanosomatid protozoa, representing a filamentous structure that runs alongside the common 9 + 2 microtubular axoneme. The high degree of ultrastructural complexity and organization of the PFR suggests that it might be formed by numerous biochemical components. However, biochemical analysis of the PFR has revealed, to date, a modest degree of complexity in what concerns both major and minor PFR proteins. In this paper the preparation of purified PFR fractions by a combination of conventional cell-fractionation procedures, non-ionic detergent treatment and limited proteolysis is described. Comparative SDS-PAGE analysis of the different purification steps indicates that the purified PFR fractions possess high amounts of the well-known major PFR proteins (77 and 83 kDa). Also, bands of 147, 139, 129 and 122 kDa are clearly enriched in such fractions and may correspond to minor PFR components. A slight enrichment in a specific fraction of a doublet of bands of 181/188 kDa suggest the participation of these proteins in the composition of the bridges between the PFR and the axoneme.