Marta G. Cavalcanti

Resolution of skeletal muscle inflammation in mdx dystrophic mouse is accompanied by increased immunoglobulin and interferon-γ production

Mdx mouse, the animal model of Duchenne muscular dystrophy, develops an X‐linked recessive inflammatory myopathy with an apparent sustained capacity for muscle regeneration. We analysed whether changes in the skeletal muscle during myonecrosis and regeneration would correlate with functional alterations in peripheral lymphoid tissues. Here we show that during the height of myonecrosis, mdx mice display marked atrophy of peripheral lymph nodes and extensive muscle inflammation. In contrast, enlargement of draining lymph nodes with accumulation of CD4+ CD44+, CD4+ CD25+, CD8+ CD44+ T lymphocytes and type‐2 B cells was consistently observed during amelioration of the muscle lesion. In addition, regeneration of the muscular tissue was accompanied by concomitant increase of immunoglobulin‐secreting cells in regional lymph nodes and bone marrow. Double immunolabelling analysis revealed intense B cell proliferation and formation of germinal centre in the follicles of dystrophic regional lymph nodes. Furthermore, lymph node cells produced large amounts of IFN‐γ but not IL‐4, IL‐6 or IL‐10 after in vitro mitogen stimulation with Concanavalin A. As these alterations occurred mainly during the recovery period, we suggested that local activation of the immune system could be an influence which mitigates the myonecrosis of muscular tissue in the mdx dystrophic mouse.

MIF Participates in Toxoplasma gondii-Induced Pathology Following Oral Infection

Background Macrophage migration inhibitory factor (MIF) is essential for controlling parasite burden and survival in a model of systemic Toxoplasma gondii infection. Peroral T. gondii infection induces small intestine necrosis and death in susceptible hosts, and in many aspects resembles inflammatory bowel disease (IBD). Considering the critical role of MIF in the pathogenesis of IBD, we hypothesized that MIF participates in the inflammatory response induced by oral infection with T. gondii. Methodology/Principal Findings Mif deficient (Mif−/−) and wild-type mice in the C57Bl/6 background were orally infected with T. gondii strain ME49. Mif−/− mice had reduced lethality, ileal inflammation and tissue damage despite of an increased intestinal parasite load compared to wt mice. Lack of MIF caused a reduction of TNF-α, IL-12, IFN-γ and IL-23 and an increased expression of IL-22 in ileal mucosa. Moreover, suppressed pro-inflammatory responses at the ileal mucosa observed in Mif−/− mice was not due to upregulation of IL-4, IL-10 or TGF-β. MIF also affected the expression of matrix metalloproteinase-9 (MMP-9) but not MMP-2 in the intestine of infected mice. Signs of systemic inflammation including the increased concentrations of inflammatory cytokines in the plasma and liver damage were less pronounced in Mif−/− mice compared to wild-type mice. Conclusion/Significance In conclusion, our data suggested that in susceptible hosts MIF controls T. gondii infection with the cost of increasing local and systemic inflammation, tissue damage and death.

Molecular and serological techniques to detect co-circulation of DENV, ZIKV and CHIKV in suspected dengue-like syndrome patients

BACKGROUND Arboviruses are important emerging viruses worldwide. The signs and symptoms of Zika virus (ZIKV) infection are similar to those presented by infections with dengue virus (DENV) and chikungunya virus (CHIKV). Furthermore, diagnosis of ZIKV infection is particularly challenging in dengue endemic regions and with co-circulation of DENV, CHIKV, and ZIKV, making diagnosis based solely on clinical and epidemiological data unreliable. As these three viral infections share similar clinical manifestations, differential diagnosis is crucial. OBJECTIVES In this study, diagnoses of ZIKV, CHIKV and DENV infections were investigated in 30 patients with suspected dengue fever residing in the area of co-circulation of these three arboviruses. STUDY DESIGN The study included whole blood and/or serum samples obtained from 30 patients with suspected dengue fever. All patients were tested for DENV infection as well as for CHIKV and ZIKV infections. Assays for detecting anti-DENV IgM and DENV RNA by semi-nested RT-PCR and ZIKV and CHIKV RNA by real-time RT-PCR were performed. RESULTS DENV RNA was not detectable in any of the clinical samples, whereas ZIKV RNA was detectable in 17 samples (56.7%). Co-infection by ZIKV and CHIKV was documented in one case. Of the 17 ZIKV-positive individuals, 8 showed reactivity for anti-DENV IgM, which suggested recent DENV infection, cross-reactivity or co-infection. CONCLUSION Our findings confirm that accurate laboratory testing is of paramount importance for differential diagnosis in areas of simultaneous transmission of different arboviruses with similar clinical presentations.

Neurocysticercosis-related mortality in Brazil, 2000–2011: Epidemiology of a neglected neurologic cause of death

Neurocysticercosis (NCC) is an important cause of severe neurological disease mainly in low- and middle-income countries, but data on NCC mortality from endemic areas are scarce. Here we analysed the epidemiological patterns of NCC-related mortality in Brazil. We included all deaths recorded in Brazil between 2000 and 2011, in which NCC was mentioned on death certificates, either as underlying or as associated cause of death. NCC was identified in 1829/12,491,280 deaths (0.015%), 1130 (61.8%) as underlying cause, and 699 (38.2%) as associated cause. Overall age-adjusted mortality rate for the period was 0.97 deaths/1,000,000 inhabitants (95% confidence interval [CI]: 0.83-1.12). The highest NCC-related mortality rates were found in males, elderly, white race/colour and residents in endemic states/regions. Age-adjusted mortality rates at national level decreased significantly over time (annual percent change [APC]: -4.7; 95% CI: -6.0 to -3.3), with a decrease in the Southeast, South and Central-West regions, and a non-significant increasing trend in the North and Northeast regions. We identified spatial and spatiotemporal high-risk mortality clusters located mainly in NCC-endemic areas. Conditions related to the nervous system were the most commonly associated causes of death when NCC was mentioned as an underlying cause, and HIV/AIDS was the main underlying cause when NCC was an associated cause. NCC is a neglected and preventable cause of severe neurologic disease and death with high public health impact in Brazil. There is a clear need to strengthen nationwide epidemiological surveillance and control for the taeniasis/cysticercosis complex.

Zika virus shedding in human milk during lactation: an unlikely source of infection?

Zika virus (ZIKV) transmission through non-mosquito-dependent routes has become increasingly important since reports of sexual transmission. Breastfeeding is a potential means of ZIKV transmission, but data on this remain limited. The cases of four mothers with laboratory-proven infections are reported. No disease evolved in three of the breastfed babies despite detectable maternal viremia and viruria, the presence of viral RNA shedding, and the isolation of infective particles in one milk sample. Fever and rash in one infant of a ZIKV-infected mother proved to be related to chikungunya virus infection. The results suggest that the presence of infective particles in breast milk may not be sufficient for the efficient perinatal transmission of ZIKV.

Schistosomiasis: Clinical management of liver disease

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A Luminex-based single DNA fragment amplification assay as a practical tool for detecting and serotyping dengue virus.

Dengue is a mosquito-borne viral infection that can evolve from subclinical to severe forms of disease. Early recognition during initial primary and secondary infections correlates with a reduced case-fatality rate in susceptible groups. The aim of this study was to standardize a DNA hybridization assay based on the Luminex technology for detecting and serotyping dengue virus (DENV). Reference DENVs representing the four different serotypes were used as controls to standardize the test. For validation, 16 DENV isolates obtained from a reference laboratory were analyzed in a double-blind manner to validate the test. Sixty blood samples from patients suspected of having dengue fever were used to evaluate the methodology after the validation step, and the results were compared with the reference semi-nested RT-PCR. Additionally, five human samples of each Zika and Chikungunya confirmed patients were used for specificity analysis. The Luminex-based assay correctly identified all 16 DENV isolates. In the evaluation step, the results of the RT-PCR/Luminex assay showed a concordance of 86.7% with those of the semi-nested RT-PCR. None of other virus infection samples was amplified. This is the first description of a hybridization assay that can discriminate the four DENV serotypes using probes against a single DENV sequence. The results indicated that the RT-PCR/Luminex DENV assay designed and evaluated in this study is a valuable additional tool for the early and rapid detection and serotyping of DENV, which could, in the future, be applied to new targets such as the Zika and Chikungunya viruses.

Transient elastography evaluation of hepatic and spleen stiffness in patients with hepatosplenic schistosomiasis.

Background Hepatosplenic schistosomiasis (HES) has not been evaluated by transient elastography so far and its correlation with ultrasound variables remains to be defined. Aims The aim of this study was to describe the parameters of liver and spleen stiffness in HES assessed by transient elastography in comparison with cirrhotics and controls evaluating its correlation with ultrasonographic data. Patients and methods HES, hepatitis C virus-cirrhotic, and control patients were included in this sectional study. Liver and spleen stiffness were compared among the three groups. The ultrasonographic parameters were compared with transient elastography in HES patients. Results Thirty HES, 30 hepatitis C virus-cirrhotic patients, and 17 controls were included. Those with HES presented liver stiffness that was significantly higher than the controls and lower than the cirrhotics: 9.7 (3.6–75.0) versus 3.7 (2.8–5.4) versus 27.0 (14.7–61.5) kPa (P<0.001). Spleen stiffness values were comparable between hepatosplenic and cirrhotics: 66.4 (25.7–75.0) versus 69.1 (18.0–75.0) kPa (P=0.78) and were significantly higher than the controls 16.5 kPa (6.3–34.3) (P<0.001). In patients with HES, high spleen stiffness was associated with right liver lobe diameter (P=0.015), splenic artery resistance index (P=0.002), portal vein diameter (P=0.021), portal vein area (P=0.008), portal vein congestion index (P=0.035), splenic vein diameter (P=0.013), and spleen diameter (P=0.021). Conclusion Liver stiffness may be a useful tool to differentiate portal hypertension related to cirrhosis from that of HES. High spleen stiffness is a potential surrogate marker of portal hypertension in this population.

Fatal Human Case of Zika and Chikungunya Virus Co-Infection with Prolonged Viremia and Viruria

Zika virus (ZIKV) infection usually presents as a mild and self-limited illness, but it may be associated with severe outcomes. We describe a case of a 30-year-old man with systemic erythematous lupus and common variable immunodeficiency who became infected with both Zika (ZIKV) and Chikungunya (CHIKV) virus during the 2016 outbreak in Rio de Janeiro, Brazil. The patient presented with intense wrist and right ankle arthritis, and ZIKV RNA and virus particles were detected in synovial tissue, blood and urine, and CHIKV RNA in serum sample, at the time of the diagnosis. During the follow up, ZIKV RNA persisted for 275 days post symptoms onset. The patient evolved with severe arthralgia/arthritis and progressive deterioration of renal function. Fatal outcome occurred after 310 days post ZIKV and CHIKV co-infection onset. The results show the development of severe disease and fatal outcome of ZIKV infection in an immunosuppressed adult. The data suggests a correlation between immunodeficiency and prolonged ZIKV RNA shedding in both blood and urine with progressive disease. The results also indicate a possible role for arbovirus co-infections as risk factors for severe and fatal outcomes from ZIKV infection.

Schistosomiasis – Updating Technologies and Diagnostic Approaches in Surveillance Strategies and Clinical Management

Schistosoma infection is a poverty-related parasitic infection, being the second most important neglected tropical disease in the world after malaria. Schistosomiasis is caused by five distinct Schistosoma species distributed in tropical and subtropical areas. But, imported cases can also be seen in non endemic areas. Human popula‐ tions acquire infection after exposure to contaminated water collections. Schistosoma infection falls on a large spectrum of clinical manifestations that ranges from absence of signs and symptoms to severe forms of disease. Although morbidity and mortality have been reduced along the years after use of mass drug administration (MDA) in endemic areas, large populations are still at risk of disability-related outcomes on dai‐ ly basis. Recently, a great deal of debate has been done over two main issues in schis‐ tosomiasis management in endemic and non-endemic areas: how to accurately diagnosis Schistosoma infections pre and post-therapy in addition to assess morbidity level. Adoption of promising new diagnostic tools and development of new markers of disease progression might change the current scenario by improving schistosomia‐ sis clinical management in both community and institutional settings.