Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

Abstract

Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy.

Methods

We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY.

Results

We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction.

Conclusion

Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

     

The Effect of Taurine on Hepatic Steatosis Induced by Thioacetamide in Zebrafish (<Emphasis Type="Italic">Danio rerio</Emphasis>)

Background  

Nonalcoholic fatty liver disease is one of the most prevalent forms of chronic liver disease in the Western world. Taurine is a conditionally essential amino acid in humans that may be a promising therapy for treating this disease.     

Altered aquaporins in the brains of mice submitted to intermittent hypoxia model of sleep apnea

Rostral fluid displacement has been proposed as a pathophysiologic mechanism of both central and obstructive sleep apnea. Aquaporins are membrane proteins that regulate water transport across the cell membrane and are involved in brain edema formation and resolution. The present study investigated the effect of intermittent hypoxia (IH), a model of sleep apnea, on brain aquaporins.     

Real-time polymerase chain reaction detection of methicillin-resistant Staphylococcus aureus: impact on nosocomial transmission and costs.

OBJECTIVES: To assess the impact of real-time polymerase chain reaction (PCR) detection of methicillin-resistant Staphylococcus aureus (MRSA) on nosocomial transmission and costs. DESIGN: Monthly MRSA detection rates were measured from April 1, 2000, through December 31, 2005. Time series analysis was used to identify changes in MRSA detection rates, and decision analysis was used to compare the costs of detection by PCR and by culture.Setting. A 1,200-bed, tertiary care hospital in Canada. PATIENTS: Admitted patients at high risk for MRSA colonization. MRSA detection using culture-based screening was compared with a commercial PCR assay. RESULTS: The mean monthly incidence of nosocomial MRSA colonization or infection was 0.37 cases per 1,000 patient-days. The time-series model indicated an insignificant decrease of 0.14 cases per 1,000 patient-days per month (95% confidence interval, -0.18 to 0.46) after the introduction of PCR detection (P=.39). The mean interval from a reported positive result until contact precautions were initiated decreased from 3.8 to 1.6 days (P<.001). However, the cost of MRSA control increased from Can$605,034 to Can$771,609. Of 290 PCR-positive patients, 120 (41.4%) were placed under contact precautions unnecessarily because of low specificity of the PCR assay used in the study; these patients contributed 37% of the increased cost. The modeling study predicted that the cost per patient would be higher with detection by PCR (Can$96) than by culture (Can$67). CONCLUSION: Detection of MRSA by the PCR assay evaluated in this study was more costly than detection by culture for reducing MRSA transmission in our hospital. The cost benefit of screening by PCR varies according to incidences of MRSA colonization and infection, the predictive values of the assay used, and rates of compliance with infection control measures.     

Rosmarinic acid as a protective agent against genotoxicity of ethanol in mice

The aim of the present work was to study the protective effects of rosmarinic acid against ethanol-induced DNA damage in mice. The antigenotoxic capacity of rosmarinic acid (100 mg/kg) was tested using pre-, co- and post-treatment with ethanol (5 g/kg). Peripheral blood (1 and 24 h) and brain cells (24 h) were evaluated using the comet assay and bone marrow was analyzed using the micronucleus assay (24 h). The results were compared to data of TBARS, enzymes with antioxidant activity, and DCFH-DA test. Peripheral blood and brain cells show that mean damage index (DI) and damage frequency (DF) values of ethanol with pre-treatment with rosmarinic acid group were significantly lower than in the ethanol group. In brain cells all different treatments with ethanol and rosmarinic acid showed significant decrease in DI and DF mean values when compared to ethanol group and negative control. No significant differences were observed in micronucleus frequency, activity of antioxidant enzymes and TBARS between groups. The DCFH-DA test show a reduction of 18% of fluorescence intensity when compare with ethanol group. The results show that rosmarinic acid could decrease the levels of DNA damage induced by ethanol, for both tissues and treatment periods.     

Envenomation by Micrurus coral snakes in the Brazilian Amazon region: report of two cases

Two cases of proven coral snake bites were reported in Belém, Pará State, Brazil. The first case was a severe one caused by Micrurus surinamensis. The patient required mechanical ventilation due to acute respiratory failure. The second case showed just mild signs of envenomation caused by Micrurus filiformis. Both patients received specific Micrurus antivenom and were discharged without further complications. Coral snake bites are scarcely reported in the Amazon region and there is a broad spectrum of clinical manifestations, varying from extremely mild to those which may rapidly lead to death if the patient is not treated as soon as possible.     

Impact of hospital infections on patients outcomes undergoing cardiac surgery at Santa Casa de Misericórdia de Marília

Objective

this study aimed to determine the incidence of nosocomial infections, the risk factors and the impact of these infections on mortality among patients undergoing to cardiac surgery.

Methods

Retrospective cohort study of 2060 consecutive patients from 2006 to 2012 at the Santa Casa de Misericórdia de Marília.

Results

351 nosocomial infections were diagnosed (17%), 227 non-surgical infections and 124 surgical wound infections. Major infections were mediastinitis (2.0%), urinary tract infection (2.8%), pneumonia (2.3%), and bloodstream infection (1.7%). The in-hospital mortality was 6.4%. Independent variables associated with non-surgical infections were age > 60 years (OR 1.59, 95% CI 1.09 to 2.31), ICU stay > 2 days (OR 5, 49, 95% CI 2.98 to 10, 09), mechanical ventilation > 2 days (OR11, 93, 95% CI 6.1 to 23.08), use of urinary catheter > 3 days (OR 4.85 95% CI 2.95 -7.99). Non-surgical nosocomial infections were more frequent in patients with surgical wound infection (32.3% versus 7.2%, OR 6.1, 95% CI 4.03 to 9.24). Independent variables associated with mortality were age greater than 60 years (OR 2.0; 95% CI 1.4 to3.0), use of vasoactive drugs (OR 3.4, 95% CI 1.9 to 6, 0), insulin use (OR 1.8; 95% CI 1.2 to 2.8), surgical reintervention (OR 4.4; 95% CI 2.1 to 9.0) pneumonia (OR 4.3; 95% CI 2.1 to 8.9) and bloodstream infection (OR = 4.7, 95% CI 2.0 to 11.2).

Conclusion

Non-surgical hospital infections are common in patients undergoing cardiac surgery; they increase the chance of surgical wound infection and mortality.     

Reliability of Vertical Jump Performance evaluated with contact mat in elderly women

The aim of this study was to evaluate the reliability of the vertical jump (VJ) using a contact mat in elderly women. Thirty‐one physically active women aged 69·5 ± 5·6 years participated in this study. Jump performance was evaluated with a contact mat. The first testing session (s1) consisted of four countermovement jumps interspersed with 40 s rest intervals. After a period of 5–7 days, volunteers performed the second session (s2) utilizing the same procedures. The intersession statistical analysis was calculated considering the two highest jumps, one obtained in each section. The intra‐session analysis utilized all eight jumps, all four from each section, and the differences between means were calculated by repeated measures ANOVA. Reliability was tested using the intra‐class correlation coefficient (ICC) and agreement by the Bland–Altman method. The intra‐ and inter‐subject variation percentage was calculated by the coefficient of variation (CV). Results: The intersession results displayed a high ICC (0·91; P<0·001) and a good agreement verified by the Bland–Altman method. There was a significant difference in the intra‐session analysis only in s2 between the jumps 2 and 4. Both in s1 and s2, the ICC was high (0·96; P<0·001; 0·95; P<0·001), and the within session reliability CV was low (10·14% and 9·07%). Conclusion: In physically active elderly women, VJ evaluation using a contact mat is a reliable method and could be used to estimate jump height. Additionally, the results of this study could serve as reference values in similar samples evaluated with the same procedures.