Influence of Testosterone in Neglected Tropical Diseases: Clinical Aspects in Leprosy and In Vitro Experiments in Leishmaniasis.

Neglected tropical diseases encompass a group of chronic and debilitating infectious diseases that primarily affect marginalized populations. Among these diseases, leprosy and leishmaniasis are endemic in numerous countries and can result in severe and disfiguring manifestations. Although there have been reports indicating a higher incidence of leprosy and leishmaniasis in males, the underlying factors contributing to this observation remain unclear. Therefore, the objective of this study was to examine both clinical and experimental evidence regarding the role of testosterone in leprosy and leishmaniasis. A prospective clinical study was conducted to compare the clinical forms of leprosy and assess circulating testosterone levels. Additionally, the impact of testosterone on Leishmania amazonensis-infected macrophages was evaluated in vitro. The findings demonstrated that serum testosterone levels were higher in women with leprosy than in the control group, irrespective of the multi- or pauci-bacillary form of the disease. However, no differences in testosterone levels were observed in men when comparing leprosy patients and controls. Interestingly, increasing doses of testosterone in macrophages infected with L. amazonensis resulted in a higher proportion of infected cells, decreased CD40 expression on the cell surface, elevated expression of SOCS1, and decreased expression of IRF5. These findings provide biological evidence to support the influence of testosterone on intracellular infections, though the interpretation of clinical evidence remains limited.

SARS-CoV-2 and splenic infarction: a rarely described thromboembolic presentation.

We report the case of a COVID-19 patient presenting with fever, headache and dyspnea, evolving with severe acute abdominal pain. A contrast-enhanced computed tomography (CT) scan diagnosed splenic infarction. We emphasize the importance of seeking the identification of complications of SARS-CoV-2 infection, notably thromboembolic events, with the potential to reduce the morbidity and mortality of the disease. Studies on radiological aspects involving the spleen and splenic infarctions associated with COVID-19 are rare.

Population-based, spatiotemporal modeling of social risk factors and mortality from schistosomiasis in Brazil between 1999 and 2018.

Schistosomiasis remains a significant public health concern in Brazil. To identify areas at, and social determinants of health (SDH) associated with, high-risk for schistosomiasis-related mortality from Brazil, we conducted a spatial and spatiotemporal modeling assessing all deaths confirmed in Brazil between 1999 and 2018. We used the segmented log-linear regression model to assess temporal trends, and the local empirical Bayesian estimator, the Global and Local Moran Index for spatial analysis. A total of 12,251 schistosomiasis-related deaths were reported in this period. Within the Mortality Information System (SIM) of the Brazilian Ministry of Health, the states of Alagoas (AL), Pernambuco (PE) and Sergipe (SE) recording the highest mortality rates: 2.21, 1.92 and 0.80 deaths/100,000 inhabitants, respectively. Analyses revealed an increase in the mean age of schistosomiasis-related deaths over the time assessed (APC = 0.9; p-value<0.05). Spatial analysis identified a concentration of municipalities presenting high risk of schistosomiasis-related mortality along the coastline of PE and AL. Similarly, we identified the formation of high space-time clusters in municipalities in the states of PE, AL, SE, Bahia, and Minas Gerais. Finally, mortality rates showed a significant correlation with 96.96% of SDH indices. The data reveal additional important changes in schistosomiasis-related deaths in Brazil between 1999 and 2018, such as a slow reduction among males (unlike females that displayed no change). Regardless, our analyses indicates that schistosomiasis continues to have the greatest detrimental impact in poor regions of Brazil and suggest the need for enhancement of current control measures to accelerate progress.

Epidemiological aspects and spatial distribution of human and canine visceral leishmaniasis in an endemic area in northeastern Brazil.

Visceral leishmaniasis (VL) is a systemic disease endemic in tropical countries and transmitted through sand flies. In particular, Canis familiaris (or domesticated dogs) are believed to be a major urban reservoir for the parasite causing the disease Leishmania. The average number of human VL cases was 58 per year in the state of Sergipe. The city of Aracaju, capital of Sergipe in Northeastern Brazil, had 159 cases of VL in humans. Correlatively, the percentage of serologically positive dogs for leishmaniasis increased from 4.73% in 2008 to 12.69% in 2014. Thus, these studies aimed to delineate the spatial distribution and epidemiological aspects of human and canine VL as mutually supportive for increased incidence. The number of human cases of VL and the frequency of canine positive serology for VL both increased between 2008 and 2014. Spatial distribution analyses mapped areas of the city with the highest concentration of human and canine VL cases. The neighbourhoods that showed the highest disease frequency were located on the outskirts of the city and in urbanised areas or subjected to development. Exponential increase in VL-positive dogs further suggests that the disease is expanding in urban areas, where it can serve as a reservoir for transmission of dogs to humans via the sand fly vector.

Is the WHO disability grading system for leprosy related to the level of functional activity and social participation?

To investigate the relationship between the WHO disability grading system for leprosy with the limitations to perform daily functional activities and the decrease in social participation in participants with leprosy. Participants with a diagnosis of leprosy were recruited at the dermatology ambulatory clinic of the University Hospital of Sergipe. In order to investigate the association of WHO disability grading system for leprosy with activities of daily living measured with the Screening Activity Limitation and Safety Awareness (SALSA) scale and with the social participation (P-scale), we performed an analysis with the Kruskal-Wallis test and the Spearman coefficient. Thirty-six patients diagnosed with leprosy participated in the study. Most of participants had mild to moderate daily activity limitations and 58% of participants did not have any restriction participation. The findings demonstrated that the WHO grading is associated with the level of activity (P < 0·0001; p = 0·58), but not with the level of participation (P <0·05; p = 0·27). Although the WHO grading system is used in Brazil and worldwide as an epidemiological indicator to explain the burden of leprosy, the results of this study demonstrated that in our sample the WHO grading system was not associated with participation. Participation is a complex construct with the influence of different psychosocial factors. In order to determine social participation damage of infectious diseases such as leprosy, it is necessary to develop new index of classification based on a broader definition of disability. Health professionals should consider the international classification of function and health (ICF) to develop such index.

Soluble CD40 Ligand in Sera of Subjects Exposed to Leishmania infantum Infection Reduces the Parasite Load in Macrophages.

BACKGROUND: While CD40L is typically a membrane glycoprotein expressed on activated T cells and platelets that binds and activates CD40 on the surface on antigen presenting cells, a soluble derivative (sCD40L) that appears to retain its biological activity after cleavage from cell membrane also exists. We recently reported that sCD40L is associated with clinical resolution of visceral leishmaniasis and protection against the disease. In the present study we investigated if this sCD40L is functional and exerts anti-parasitic effect in L. infantum-infected macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Macrophages from normal human donors were infected with L. infantum promastigotes and incubated with either sera from subjects exposed to L. infantum infection, monoclonal antibodies against human CD40L, or an isotype control antibody. We then evaluated infection by counting the number of infected cells and the number of parasites in each cell. We also measured a variety of immune modulatory cytokines in these macrophage culture supernatants by Luminex assay. The addition of sCD40L, either recombinant or from infected individuals' serum, decreased both the number of infected macrophages and number of intracellular parasites. Moreover, this treatment increased the production of IL-12, IL-23, IL-27, IL-15, and IL1ß such that negative correlations between the levels of these cytokines with both the infection ratio and number of intracellular parasites were observed. CONCLUSIONS/SIGNIFICANCE: sCD40L from sera of subjects exposed to L. infantum is functional and improves both the control of parasite and production of inflamatory cytokines of infected macrophages. Although the mechanisms involved in parasite killing are still unclear and require further exploration, these findings indicate a protective role of sCD40L in visceral leishmaniasis.

Micronutrients influencing the immune response in leprosy.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an intracellular bacillus of airborne transmission. The disease affects the skin and peripheral nerves and can cause neurological sequelae. The bacillus multiplies slowly in the host and the disease probably occurs due to malfunctioning in host immune response. This review addresses the role of some specific micronutrients in the immune response, such as Vitamins A, D, E, C, Zinc and Selenium, detailing their mechanisms of actions in infectious diseases, and in leprosy. The immune response to pathogens releases harmful substances, which lead to tissue damage. This review discusses how a decreased level of antioxidants may contribute to an increased oxidative stress and complications of infectious diseases and leprosy. As the nutrients have a regulatory effect in the innate and adaptative immune responses, a perfect balance in their concentrations is important to improve the immune response against the pathogens.

Pentoxifylline down modulate in vitro T cell responses and attenuate pathology in Leishmania and HTLV-I infections.

Tumor necrosis factor-alpha (TNF-alpha) is known to have numerous biological properties relating to inflammation. This cytokine participates in the tissue damage of chronic inflammatory, autoimmune and infectious diseases. Pentoxifylline is a methylxanthine that inhibits phosphodiesterase IV, which inhibits the degradation of the cAMP and prostanoids. The increased intracellular concentration of the cAMP leads to a negative regulation of NF-kappaB and NF-AT transcription factors and suppresses TNF-alpha production. This review describes studies that support evidences that TNF-alpha is involved in the pathogenesis of HTLV-1 associated myelopathy and of cutaneous and mucosal leishmaniasis. Additionally, it demonstrates the effect of pentoxifylline in vitro in inhibiting TNF-alpha and IFN-gamma spontaneous production in PBMC from HTLV-1-infected patients, as well as its in vivo effect in inhibiting TNF-alpha in sera from mucosal leishmaniasis patients. Moreover, we review the results of clinical studies from the last 10 years using pentoxifylline to treat HTLV-1 associated myelopathy and cutaneous and mucosal leishmaniasis.

Up-regulation of Th1-type responses in mucosal leishmaniasis patients.

The cytokine profile produced by peripheral blood mononuclear cells (PBMC) in response to leishmania antigens and the ability of interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) to modulate the immune response were evaluated in 21 mucosal leishmaniasis patients. Patients with mucosal disease exhibited increased gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) secretion and decreased IL-10 secretion compared to patients with classical cutaneous leishmaniasis. CD4(+) Th1 cells were the main source of IFN-gamma and TNF-alpha production in mucosal leishmaniasis patients. Evaluation of cytokine gene expression in PBMC of these patients showed that there was strong up-regulation of IFN-gamma transcripts upon stimulation with leishmania antigen, in contrast to the baseline levels of IL-10 mRNA. IL-10 suppressed IFN-gamma production by 48% in cell cultures from cutaneous leishmaniasis patients and by 86% in cell cultures from healthy subjects stimulated with purified protein derivative, whereas in similar conditions IL-10 suppressed IFN-gamma production by 19% in cell cultures from mucosal leishmaniasis patients stimulated with leishmania antigen. TGF-beta suppressed IFN-gamma levels to a greater extent in healthy subjects than in mucosal leishmaniasis and cutaneous leishmaniasis patients. These data indicate that a poorly modulated T-cell response in mucosal leishmaniasis patients leads to production of high levels of proinflammatory cytokines, such as IFN-gamma and TNF-alpha, as well as a decreased ability of IL-10 and TGF-beta to modulate this response. These abnormalities may be the basis for the pathological findings observed in this disease.