Daniel Abensur Athanazio

Carriage of Leptospira interrogans among domestic rats from an urban setting highly endemic for leptospirosis in Brazil

A survey was conducted to identify reservoirs for urban leptospirosis in the city of Salvador, Brazil. Sampling protocols were performed in the vicinity of households of severe leptospirosis cases identified during active hospital-based surveillance. Among a total of 142 captured Rattus norvegicus (Norwegian brown rat), 80.3% had a positive culture isolate from urine or kidney specimens and 68.1% had a positive serum sample by microscopic agglutination test (MAT) titre of > or = 1:100. Monoclonal antibody-based typing of isolates identified that the agent carried by rats was Leptospira interrogans serovar Copenhageni, which was the same serovar isolated from patients during hospital-based surveillance. Leptospira spp. were not isolated from 8 captured Didelphis marsupialis (Opossum), while 5/7 had a positive MAT titre against a saprophytic serogroup. R. rattus were not captured during the survey. The study findings indicate that the brown rat is a major rodent reservoir for leptospirosis in this urban setting. Furthermore, the high carriage rates of L. interrogans serovar Copenhageni in captured rats suggest that there is a significant degree of environmental contamination with this agent in the household environment of high risk areas, which in turn is a cause of transmission during urban epidemics.

Characterization of virulence of Leptospira isolates in a hamster model

Effort has been made to identify protective antigens in order to develop a recombinant vaccine against leptospirosis. Several attempts failed to conclusively demonstrate efficacy of vaccine candidates due to the lack of an appropriate model of lethal leptospirosis. The purposes of our study were: (i) to test the virulence of leptospiral isolates from Brazil, which are representative of important serogroups that cause disease in humans and animals; and (ii) to standardize the lethal dose 50% (LD(50)) for each of the virulent strains using a hamster (Mesocricetus auratus) model. Five of seven Brazilian isolates induced lethality in a hamster model, with inocula lower than 200 leptospires. Histopathological examination of infected animals showed typical lesions found in both natural and experimental leptospirosis. Results described here demonstrated the potential use of Brazilian isolates as highly virulent strains in challenge experiments using hamster as an appropriate animal model for leptospirosis. Furthermore these strains may be useful in heterologous challenge studies which aim to evaluate cross-protective responses induced by sub-unit vaccine candidates.

Morphological alterations in the kidney of rats with natural and experimental Leptospira infection.

Leptospirosis is a widespread anthropozoonosis, with a broad array of mammalian reservoirs, occurring as rural endemics, urban outbreaks related to floods, and emergent disease associated with water sports and recreational exposure in developed countries. Rats are the major source of human infection, particularly in urban areas; however few reports have focused on the pathology of leptospirosis in this host. This study reports pathological changes in 60 kidneys from captured wild rats and compares these with changes in the kidney of Wistar rats experimentally infected with Leptospira interrogans serovar Copenhageni strain FIOCRUZ L1-130. A broad range of morphological alterations were detected in the kidneys from captured rats but interstitial nephritis was the only feature reproduced under experimental conditions. The role of interstitial nephritis in the pathogenesis of leptospirosis is reviewed and it is suggested that rats may provide a potential tool for the study of colonization mechanisms and host resistance in acute leptospiral disease.

Leptospirosis-associated disturbances of blood vessels, lungs and hemostasis

The frequency of massive pulmonary hemorrhages seems to be increasing in different geographic areas; however, there is no clear explanation for this trend. Although data on the pathogenesis of such complications are scarce, recent research indicates a potential role of autoimmunity and/or multifactorial mechanisms. However, much information is already available on the disturbance of hemostasis and blood vessels in leptospirosis-related literature, even if some contradictory concepts coexist. The purpose of this review is to integrate both new and classical information from human and animal studies on severe pulmonary forms of leptospirosis and disorders of hemostasis and blood vessels. We propose that the involvement of blood vessels in leptospirosis must be understood as a sepsis-like, diffuse process of endothelial activation/damage rather than as a classical systemic vasculitis. Pulmonary hemorrhages are most likely multifactorial and there has recently been evidence against the role of autoimmunity; however, further investigation of strain variations, exposure to hydrocarbons and association with renal dysfunction is required. Thrombocytopenia is a consistent feature of leptospirosis but it is not clear whether it is attributable to sepsis-related mechanisms. In addition, further investigation is required to define whether platelet function is activated or inhibited during severe leptospirosis.

Aberrant P-cadherin expression: Is it associated with estrogen-independent growth in breast cancer?

Breast carcinomas represent a heterogeneous group of tumors, with a diverse biologic behavior, outcome, and response to therapy. Recent studies have demonstrated that alterations in the expression of adhesion molecules in cancer cells are related to aggressiveness and poor prognosis. The aim of our study was to investigate the expression of P-cadherin in breast carcinomas and correlate it with estrogen receptor (ER) status. We selected 73 ductal carcinomas in situ (DCIS) and 149 invasive carcinomas of the breast, and assessed the expression of P-cadherin as well as other biologic markers. P-cadherin expression showed a strong inverse correlation with ER expression in both types of breast carcinoma (in situ and invasive). P-cadherin-positive and ER-negative tumors were related to a higher histologic grade, a high proliferation rate, and expression of c-erbB-2. We demonstrated that P-cadherin identifies a subgroup of breast carcinomas that lacks ER expression, and correlates with higher proliferation rates and other predictors of aggressive behavior. We believe that these tumors represent an advanced step in cancer progression, and our data support the hypothesis that an estrogen-independent pathway regulates P-cadherin expression.

Renal involvement in leptospirosis: new insights into pathophysiology and treatment

Acute renal failure (ARF) is one of the most common complications of leptospirosis although the causal mechanisms are still unclear. Diverse mechanisms are implicated in leptospiral nephropathy and new data supports the role of peculiar ion transport defects. Besides antibiotic therapy, ARF management in leptospirosis requires dialytic therapy which is most efficient when started early. Dialysis is the standard supportive therapy even though recent evidence suggests clinical benefit from alternative treatments such as plasmapheresis and hemofiltration. Renal recovery is achieved soon after clinical improvement. The comprehension of the primary mechanisms of renal dysfunction will be helpful in the development of additional therapeutic tools for improving supportive therapy for leptospiral nephropathy. This review discusses new insights into mechanisms implicated in leptospiral ARF and recent advances in treatment.

Different outcomes of experimental leptospiral infection in mouse strains with distinct genotypes.

The mouse disease model has the advantage of a broad array of immunological and genetic tools available for basic research. Some studies on transgenic and/or mutant mouse strains as models for experimental leptospirosis have been reported; however, the wider use of such models is hampered by a poor understanding of the outcome of experimental leptospiral infection among the different mouse strains available. Here, the outcome of infection by a virulent strain of Leptospira interrogans serogroup Icterohaemorrhagiae strain Cop was studied in four commonly used wild-type mouse strains: A, CBA, BALB/c and C57BL/6. The end points evaluated in this study were survival, presence of kidney lesions, leptospiral load in kidney samples, microscopic agglutination test titre and anti-leptospiral IgG antibody levels. As expected, none of the mouse strains were susceptible to lethal leptospirosis. However, these strains developed specific pathologies associated with sublethal leptospirosis. The A and C57BL/6 strains exhibited a high leptospiral load in kidney samples and the CBA and C57BL/6 strains developed severe inflammatory lesions, whilst the BALB/c strain proved to be the most resistant to subclinical leptospirosis.

NK and NKT cell dynamics after rituximab therapy for systemic lupus erythematosus and rheumatoid arthritis

Biomarkers of clinical response to rituximab (RTX) therapy and early predictors of outcome are still under investigation. We report a flow cytometric immunophenotyping analysis from peripheral blood leukocyte subpopulations of two patients with systemic lupus erythematosus (SLE) associated thrombocytopenia and one patient with rheumatoid arthritis (RA), before and after 6 weeks of treatment with RTX. Our results show a reduced population of CD19+ expressing cells (B cells) after RTX treatment in all three patients. Increased frequency of peripheral regulatory CD4+CD25high T cell subset and the CD3−CD16−CD56bright NK cell subset after RTX therapy were also observed in all patients, the latter being more pronounced in the SLE patient with sustained clinical response. In addition, an increased population of NKT cell subsets was observed in the patients with clinical response. This is the first evaluation of NK and NKT cells as biomarkers of clinical response after rituximab therapy in rheumatic diseases.

Anti-C1q Antibodies: Association With Nephritis and Disease Activity in Systemic Lupus Erythematosus

Background: Anti‐C1q antibodies have been described in systemic lupus erythematosus (SLE) as well as in other connective tissue diseases. They have been considered as a marker for disease activity and presence of nephritis.

Leptospira noguchii and human and animal leptospirosis, Southern Brazil.

To the Editor: Pathogenic leptospires, the causative agents of leptospirosis, exhibit wide phenotypic and genotypic variations. They are currently classified into 17 species and >200 serovars (1,2). Most reported cases of leptospirosis in Brazil are of urban origin and caused by Leptospira interrogans (3). Brazil underwent a dramatic demographic transformation due to uncontrolled growth of urban centers during the last 60 years. Urban slums are sites of poor sanitation that favors rat-borne transmission of leptospirosis among humans. Thus, this may explain the major involvement of serovar Copenhageni (L. interrogans). The predominance of L. interrogans is likely due to the underestimation of rural cases of leptospirosis.