Tissue-specific roles of mitochondrial unfolded protein response during obesity.

Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPRmt), a quality control pathway that occurs in a nuclear DNA-mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPRmt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPRmt signaling during obesity, bringing an overview of UPRmt across different metabolic tissues.

Corrigendum: Home-based exercise program in the indeterminate form of Chagas disease (PEDI-CHAGAS study): a study protocol for a randomized clinical trial.

[This corrects the article DOI: 10.3389/fmed.2022.1087188.].

Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase.

OBJECTIVE: The mitochondrial unfolded protein response (UPRmt) is an adaptive cellular response to stress to ensure mitochondrial proteostasis and function. Here we explore the capacity of physical exercise to induce UPRmt in the skeletal muscle. METHODS: Therefore, we combined mouse models of exercise (swimming and treadmill running), pharmacological intervention, and bioinformatics analyses. RESULTS: Firstly, RNA sequencing and Western blotting analysis revealed that an acute aerobic session stimulated several mitostress-related genes and protein content in muscle, including the UPRmt markers. Conversely, using a large panel of isogenic strains of BXD mice, we identified that BXD73a and 73b strains displayed low levels of several UPRmt-related genes in the skeletal muscle, and this genotypic feature was accompanied by body weight gain, lower locomotor activity, and aerobic capacity. Finally, we identified that c-Jun N-terminal kinase (JNK) activation was critical in exercise-induced UPRmt in the skeletal muscle since pharmacological JNK pathway inhibition blunted exercise-induced UPRmt markers in mice muscle. CONCLUSION: Our findings provide new insights into how exercise triggers mitostress signals toward the oxidative capacity in the skeletal muscle.

A clindamycin acetylated derivative with reduced antibacterial activity inhibits articular hyperalgesia and edema by attenuating neutrophil recruitment, NF-κB activation and tumor necrosis factor-α production.

We recently demonstrated that clindamycin exhibits activities in acute and chronic models of pain and inflammation. In the present study, we investigated the effects of clindamycin and a clindamycin acetylated derivative (CAD) in models of acute joint inflammation and in a microbiological assay. Joint inflammation was induced in mice by intraarticular (i.a.) injection of zymosan or lipopolysaccharide (LPS). Clindamycin or CAD were administered via the intraperitoneal route 1 h before zymosan or LPS. Paw withdrawal threshold, joint diameter, histological changes, neutrophil recruitment, tumor necrosis factor-α (TNF-α) production and phosphorylation of the IκBα and NF-κB/p65 were evaluated. In vitro assays were used to measure the antibacterial activity of clindamycin and CAD and also their effects on zymosan-induced TNF-α production by RAW264.7 macrophages. Clindamycin exhibited activity against Staphylococcus aureus and Salmonella Typhimurium ATCC® strains at much lower concentrations than CAD. Intraarticular injection of zymosan or LPS induced articular hyperalgesia, edema and neutrophil infiltration in the joints. Zymosan also induced histological changes, NF-κB activation and TNF-α production. Responses induced by zymosan and LPS were inhibited by clindamycin (200 and 400 mg/kg) or CAD (436 mg/kg). Both clindamycin and CAD inhibited in vitro TNF-α production by macrophages. In summary, we provided additional insights of the clindamycin immunomodulatory effects, whose mechanism was associated with NF-κB inhibition and reduced TNF-α production. Such effects were extended to a clindamycin derivative with reduced antibacterial activity, indicating that clindamycin derivatives should be investigated as candidates to drugs that could be useful in the management of inflammatory and painful conditions.

Toxina botulínica no tratamento da neuralgia pós herpética: um desafio terapêutico / Botulinum toxin in the treatment of postherpetic neuralgia: a therapeutic challenge

A neuralgia pós-herpética (NPH) é a principal complicação do herpes zoster. Caracteriza-se por dor que persiste por mais de três meses após o episódio de reativação do vírus varicela zoster, com impacto importante na qualidade de vida. A terapia de primeira linha da NPH consiste nos antidepressivos tricíclicos, inibidores de recaptação de serotonina e noradrenalina, além dos anticonvulsionantes pregabalina e gabapentina. Nos casos refratários, o uso subcutâneo da toxina botulínica A (TXB-A), é uma possibilidade terapêutica. A TXB-A, além de inibir a exocitose da acetilcolina na fenda sináptica da junção neuromuscular, também diminui a liberação de outros mediadores como glutamato, substância P e peptídeo relacionado à calcitonina, responsáveis pela ativação de nociceptores. Neste estudo, foram analisados os prontuários de seis pacientes com NPH, tratados com TXB-A concomitantemente à terapia padrão, no ambulatório de Dermatologia Geral do Hospital do Servidor Público Municipal de São Paulo, com o objetivo de avaliar se houve melhora da dor, através da comparação dos valores da escala visual de dor (EVA). Palavras-chave: Neuralgia pós herpética. Toxinas Botulínicas Tipo A. Herpes zoster.

Investigation of breast pathologies in medical students and their families

Introduction: Breast diseases include benign and malignant pathologies. However, during the differential diagnosis, it is important to distinguish benign pathology, precursor lesions of breast cancer, and malignant breast neoplasm. We believe that research among medical students on the prevalence of breast pathologies in this population and their families is important in addition to identifying patients at high familial risk for breast and/or ovarian cancer and awakening the interest of other medical students in this topic. The objective of this study was to analyze the prevalence of benign and malignant breast pathologies among medical students and their families. Methods: This is a quantitative analytical cross-sectional study. Female medical students over 18 years old were included in the study. Data collection was carried out using an online questionnaire. It was approved by the Research Ethics Committee under CAAE Protocol No. 51338121.0.0000.5515, and each participant consented through the free and informed consent form (TCLE). Results: A total of 303 medical students responded to the questionnaire and were included in the study. Around 13.5% of participants reported having had some breast pathology, 76.2% of which were cases of breast lumps. The average age of participants was 22.9 years (ranging between 18 and 53 years). The average age of family members at diagnosis (a sample of 69 women) was 57.1 years (ranging between 29 and 84 years). There was an association between the prevalence of breast pathologies and a family history of breast cancer (OR=1.712 [0.818; 3.585]). Conclusion: From the results, it appears that 13.5% of the participants had already been diagnosed with breast pathology, and 20.8% of these reported a family history of breast cancer. In this way, we can affirm the contribution of the study in the evaluation of screening criteria for breast and neoplasms and thus increase the detection rate and carry out early therapy. (AU)

Corrigendum: Impact of COVID-19 in-hospital mortality in chagas disease patients.

[This corrects the article DOI: 10.3389/fmed.2022.880796.].

Cost-effectiveness of an exercise-based cardiovascular rehabilitation program in patients with chronic Chagas cardiomyopathy in Brazil: An analysis from the PEACH study.

OBJECTIVES: The present study aimed to perform a cost-effectiveness analysis of an exercise-based cardiovascular rehabilitation (CR) program in patients with chronic Chagas cardiomyopathy (CCC). METHODS: Cost-effectiveness analysis alongside a randomised clinical trial evaluating the effects of a 6-month exercise-based CR program. The intervention group underwent 3 weekly exercise sessions. The variation of peak oxygen consumption (VO2peak ) was used as a measurement of clinical outcome. Cost information from all healthcare expenses (examinations, healthcare visits, medication and hospitalisation) were obtained from the medical records in Brazilian reais (R$) and transformed into dollars using the purchasing power parity ($PPP). The longitudinal costs variation was evaluated through linear mixed models, represented by ß coefficient, adjusted for the baseline values of the dependent variable. The cost-effectiveness evaluation was determined through an incremental cost-effectiveness ratio using the HEABS package (Stata 15.0). RESULTS: The intervention group presented higher costs with healthcare visits (ß = +3317.3; p < 0.001), hospitalisation (ß = +2810.4; p = 0.02) and total cost (ß = +6407.9; p < 0.001) after 3 months of follow-up. Costs related to healthcare visits (ß = +2455.8; p < 0.001) and total cost (ß = +4711.4; p < 0.001) remained higher in the intervention group after 6 months. The CR program showed an incremental cost-effectiveness ratio (ICER) of $PPP 1874.3 for each increase of 1.0 ml kg-1  min-1 of VO2peak . CONCLUSIONS: The CR program can be considered a cost-effective alternative and should be included as an intervention strategy in the care of patients with CCC.

Undifferentiated Embryonal Sarcoma of the Liver Involving All Major Hepatic Veins Treated by Left Extended Trisectionectomy.

Introduction: Over the past few years, liver surgery has been in constant evolution and gained many improvements that helped surgeons push limits further. A complex procedure such as left extended trisectionectomy, as described by Makuuchi in 1987, may be performed in selected cases. Aim: Describe a case of successful resection of a huge bilobar liver sarcoma involving all hepatic veins from a young female patient, in which the blood outflow was preserved through an inferior right hepatic vein, leaving only segment 6 as liver remnant. Case Report. A 19-year-old female with a 3-month history of abdominal pain, vomiting, and weight loss was referred for our evaluation. CT scan and MRI revealed a heterogeneous and bulky expansive hepatic lesion, sparing only segment 6, with an estimated volume of 530 cm3, corresponding to a 1.2 FLR/BW ratio. The tumor involved the three major hepatic veins, but an inferior right hepatic vein was present, draining the spared segment 6. She was submitted to a left trisectionectomy extended to the caudate lobe and segment 7, including resection of all hepatic veins and lymphadenectomy of the hepatic pedicle. She was discharged on the 7th postoperative day without complications. The histopathological and immunohistochemical analysis demonstrated an undifferentiated embryonal sarcoma of the liver. Conclusion: Inferior right hepatic vein-preserving left extended trisectionectomy is a safe and feasible procedure that should be performed by a hepatobiliary team experienced in major complex hepatectomies.

What can the Allium cepa test say about pesticide safety? A review.

The increasing use of pesticides has caused global concerns about the toxic effects and adverse consequences of pesticides on humans and the environment. Among the ways to understand the impact of pesticides, the Allium cepa bioassay stands out. This test is suitable to evaluate different toxic, cytotoxic, genotoxic, and mutagenic outcomes. In this context, the present review aimed to summarize the history of using the A. cepa bioassay to investigate pesticide damages. Data on the experimental conditions were also discussed. The reviewed studies showed the toxicity profile of 113 active ingredients primarily tested in the laboratory, using water for exposure. The most used biomarkers were the mitotic index, chromosomal aberrations, and nuclear abnormalities. All active ingredients caused some toxicity levels in A. cepa, showing the efficiency and sensibility of this bioindicator and the adverse effect of pesticides on humans and the environment. Furthermore, it was evident that pesticides have great potential to damage the mitotic spindle and DNA because almost all active ingredients tested induced chromosomal aberrations and nuclear abnormalities. The current review showed that the A. cepa bioassay is an effective and appropriate model to evaluate pesticide toxicity, and it might indicate research gaps and recommendations for further studies.

Toxic Potential of Cerrado Plants on Different Organisms.

Cerrado has many compounds that have been used as biopesticides, herbicides, medicines, and others due to their highly toxic potential. Thus, this review aims to present information about the toxicity of Cerrado plants. For this purpose, a review was performed using PubMed, Science Direct, and Web Of Science databases. After applying exclusion criteria, 187 articles published in the last 20 years were selected and analyzed. Detailed information about the extract preparation, part of the plant used, dose/concentration tested, model system, and employed assay was provided for different toxic activities described in the literature, namely cytotoxic, genotoxic, mutagenic, antibacterial, antifungal, antiviral, insecticidal, antiparasitic, and molluscicidal activities. In addition, the steps to execute research on plant toxicity and the more common methods employed were discussed. This review synthesized and organized the available research on the toxic effects of Cerrado plants, which could contribute to the future design of new environmentally safe products.

Thoracic epidural analgesia and immediate extubation for less than 10 kg infants undergoing living donor liver transplantation: A report of two successful cases.

BACKGROUND: Perioperative pain management in small infants weighing <10 kg undergoing liver transplantation is challenging. The use of TEA in this setting has not been reported, as well as its potential role to facilitate IE, ie, in the OR. METHODS: We describe here the use of TEA in two small infants who had IE after a LDLT procedure. RESULTS: TEA was successfully performed and IE was achieved in both cases. Postoperative analgesia assessment in the OR was satisfactory according to the FLACC pain scale, with scores of 2 and 3 for each patient, respectively. There were no major complications in the postoperative period, and the two children were discharged home uneventfully. CONCLUSIONS: The use of TEA and its influence on IE rate and other perioperative outcomes should be more explored in small infants undergoing LDLT.

Home-based exercise program in the indeterminate form of Chagas disease (PEDI-CHAGAS study): A study protocol for a randomized clinical trial.

Background: Chagas disease (CD) is a neglected endemic disease with worldwide impact due to migration. Approximately 50-70% of individuals in the chronic phase of CD present the indeterminate form, characterized by parasitological and/or serological evidence of Trypanosoma cruzi infection, but without clinical signs and symptoms. Subclinical abnormalities have been reported in indeterminate form of CD, including pro-inflammatory states and alterations in cardiac function, biomarkers and autonomic modulation. Moreover, individuals with CD are usually impacted on their personal and professional life, making social insertion difficult and impacting their mental health and quality of life (QoL). Physical exercise has been acknowledged as an important strategy to prevent and control numerous chronic-degenerative diseases, but unexplored in individuals with the indeterminate form of CD. The PEDI-CHAGAS study (which stands for "Home-Based Exercise Program in the Indeterminate Form of Chagas Disease" in Portuguese) aims to evaluate the effects of a home-based exercise program on physical and mental health outcomes in individuals with indeterminate form of CD. Methods and design: The PEDI-CHAGAS is a two-arm (exercise and control) phase 3 superiority randomized clinical trial including patients with indeterminate form of CD. The exclusion criteria are <18 years old, evidence of non-Chagasic cardiomyopathy, musculoskeletal or cognitive limitations that preclude the realization of exercise protocol, clinical contraindication for regular exercise, and regular physical exercise (≥1 × per week). Participants will be assessed at baseline, and after three and 6 months of follow-up. The primary outcome will be QoL. Secondary outcomes will include blood pressure, physical fitness components, nutritional status, fatigability, autonomic modulation, cardiac morphology and function, low back pain, depression and anxiety, stress, sleep quality, medication use and adherence, and biochemical, inflammatory and cardiac biomarkers. Participants in the intervention group will undergo a home-based exercise program whilst those in the control group will receive only general information regarding the benefits of physical activity. Both groups will receive the same general nutritional counseling consisting of general orientations about healthy diets. Conclusion: The findings from the present study may support public health intervention strategies to improve physical and mental health parameters to be implemented more effectively in this population. Clinical trial registration: [https://ensaiosclinicos.gov.br/rg/RBR-10yxgcr9/], identifier [U1111-1263-0153].

Rhinophototherapy, an alternative treatment of allergic rhinitis: Systematic review and meta-analysis / Rinofototerapia, uma alternativa para o tratamento de rinite alérgica: revisão sistemática e metanálise

Abstract Introduction: Allergic rhinitis is a chronic inflammatory disease of the nasal mucosa, mediated by immunoglobulin E, affecting 1 in 6 individuals. The treatment aims at attaining symptomatic control with minimal side effects, a requirement for new alternative therapies, including phototherapy, as it has an immunosuppressive and immunomodulatory effect. Objective: To identify the effectiveness of phototherapy in the treatment of allergic rhinitis through a meta-analysis. Methods: We searched Web of Science, Scielo, PubMed, SCOPUS, PEDro, and LILACS databases, using the terms: ''intranasal irradiation'', ''phototherapy'' and ''allergic rhinitis''. The R software Metafor package was used for the meta-analysis and the effect size was calculated for each symptom individually. Results: All symptoms decreased considerably after phototherapy: rhinorrhea (ES• = -1.35; p < 0.0001; I2 = 91.84%), sneezing (ES• = -1.24; p < 0.0001; I2 = 91.43%), nasal pruritus (ES• = -1.10; p < 0.0001; I2 = 91.43%); nasal obstruction (ES• = -1.11; p < 0.0001; I2 = 91.88%). The effects were more significant in perennial allergic rhinitis than in the seasonal type. Conclusion: Considering the effect size and the statistical significance attained in our study, rhinophototherapy showed to be an effective treatment for reducing the nasal symptom scores triggered by AR.

Resumo Introdução: A rinite alérgica é uma doença inflamatória crônica da mucosa nasal, imunomediada por imunoglobulina E, que afeta 1/6 dos indivíduos. O tratamento visa o controle dos sintomas com efeitos colaterais mínimos, uma prerrogativa para novas terapias alternativas, como a fototerapia, por apresentar efeitos imunossupressor e imunomodulador. Objetivo: Identificar, mediante uma metanálise, a eficácia da fototerapia no tratamento da rinite alérgica. Método: Usamos as bases de dados: Web of Science, Scielo, PubMed, SCOPUS, PEDro e LILACS, com os termos de busca: intranasal irradiation, phototherapy, allergic rhinitis. Para a metanálise foi usado o pacote metafor do software R, o tamanho do efeito foi calculado para cada sintoma separadamente. Resultados: Todos os sintomas apresentaram diminuição significante após a fototerapia: coriza (ES =-1,35; p < 0,0001; I2 = 91,84%), espirros (ES =-1,24; p < 0,0001; I2 = 91,43%), prurido nasal (ES =-1,10; p < 0,0001; I2 = 91,43%); obstrução nasal (ES =-1,11; p < 0,0001; I2 = 91,88%), com efeitos mais expressivos na rinite alérgica perene do que na rinite alérgica sazonal. Conclusão: Considerando-se a magnitude do efeito e a significância estatística alcançadas em nosso estudo, a rinofototerapia demonstrou-se um tratamento eficaz para a redução dos escores dos sintomas nasais desencadeados pela rinite alérgica.

Effects of Selenium treatment on cardiac function in Chagas heart disease: Results from the STCC randomized Trial.

BACKGROUND: Chagas disease (caused by Trypanosoma cruzi infection) evolves to chronic chagasic cardiomyopathy (CCC) affecting 1.8 million people worldwide. This is the first randomized, placebo-controlled, double-blinded, clinical trial designed to estimate efficacy and safety of selenium (Se) treatment in CCC. METHODS: 66 patients with CCC stages B1 (left ventricular ejection fraction [LVEF] > 45% and no heart failure; n = 54) or B2 (LVEF < 45% and no heart failure; n = 12) were randomly assigned to receive 100 mcg/day sodium selenite (Se, n = 32) or placebo (Pla, n = 34) for one year (study period: May 2014-September 2018). LVEF changes over time and adverse effects were investigated. Trial registration number: NCT00875173 (clinicaltrials.gov). FINDINGS: No significant differences between the two groups were observed for the primary outcome: mean LVEF after 6 (ß= +1.1 p = 0.51 for Se vs Pla) and 12 months (ß= +2.1; p = 0.23). In a subgroup analysis, statistically significant longitudinal changes were observed for mean LVEF in the stage B2 subgroup (ß= +10.1; p = 0.02 for Se [n = 4] vs Pla [n = 8]). Se treatment was safe for CCC patients, and the few adverse effects observed were similarly distributed across the two groups. INTERPRETATION: Se treatment did not improve cardiac function (evaluated from LVEF) in CCC. However, in the subgroup of patients at B2 stage, a potential beneficial influence of Se was observed. Complementary studies are necessary to explore diverse Se dose and/or associations in different CCC stages (B2 and C), as well as in A and B1 stages with longer follow-up. FUNDING: Brazilian Ministry of Health, Fiocruz, CNPq, FAPERJ.

Temporal changes in the clinical-epidemiological profile of patients with Chagas disease at a referral center in Brazil.

INTRODUCTION: We aimed to describe the sociodemographic, epidemiological, and clinical characteristics of patients with chronic Chagas disease (CD) at an infectious disease referral center. Changes in patient profiles over time were also evaluated. METHODS: This retrospective study included patients with CD from November 1986-December 2019. All patients underwent an evaluation protocol that included sociodemographic profile; epidemiological history; anamnesis; and physical, cardiologic, and digestive examinations. Trend differences for each 5-year period from 1986 to 2019 were tested using a nonparametric trend test for continuous and generalized linear models with binomial distribution for categorical variables. RESULTS: A total of 2,168 patients (52.2% women) were included, with a mean age of 47.8 years old. White patients with low levels of education predominated. The reported transmission mode was vectorial in 90.2% of cases. The majority came from areas with a high prevalence (52.2%) and morbidity (67.8%) of CD. The most common clinical presentation was the indeterminate form (44.9%). The number of patients referred gradually decreased and the age at admission increased during the study period, as did the patients' levels of education. CONCLUSIONS: The clinical profile of CD is characterized by a predominance of the indeterminate form of the disease. Regarding the patients who were followed up at the referral center, there was a progressive increase in the mean age and a concomitant decrease in the number of new patients. This reflects the successful control of vector and transfusion transmission in Brazil as well as the aging population of patients with CD.

Trends in science on glyphosate toxicity: a scientometric study.

As part of the most used herbicides, glyphosate is the most successful ingredient of agrochemical companies. The main objective of this study was to demonstrate research trends related to the glyphosate toxicity and its main effects on human and environmental health. For this purpose, 443 articles published, from 1995 to 2020, on the platform Web of Science™ Thomson Reuters were selected. The main toxicity results related in literature are genotoxicity, cytotoxicity, and endocrine disruption. The environmental effects come mostly from the contamination of groundwater and soils. Several studies have concluded that herbicide concentrations right below the official safety limits induced toxic effects. The results presented a highlighted harmful effect of glyphosate on both human and environmental health. It has been observed that countries where publish the most about the glyphosate toxicity are great investors in large-scale agriculture. It is important to ponder that these countries are in a route of ecosystem exploitation that includes not only fauna and flora, but also human beings. Unfortunately, science does not provide concise data for these pesticide disapproval in the global consumer market. It is necessary to search sustainable global interest alternatives to increase agriculture production based on peoples' food sovereignty.

Prevalence of metabolic syndrome and associated factors among patients with chronic Chagas disease.

The increase in life expectancy and the migration of individuals with Chagas disease (ChD) from rural to urban centers exposes them to the development of chronic-degenerative abnormalities that may increase the prevalence of metabolic syndrome (MetS). The present study aimed to identify the prevalence of MetS and its components in individuals with chronic ChD. This is a cross-sectional study with 361 patients of both sexes, aging >18 years, followed at a national reference center (Rio de Janeiro, Brazil). MetS diagnosis followed the International Diabetes Federation 2005 criteria. The association between the variables was determined through logistic regression models. The mean age was and 60.7±10.8 years. About half (56.2%) were female and the majority self-reported their race as mulatto (59.8%). The percentage of individuals with MetS was 40.4%. The variables independently associated with MetS were age (OR 1.06; 95%CI 1.04-1.09), high education levels (OR 0.36; 95%CI 0.17-0.79) and cardiac form with heart failure (OR 0.34; 95%CI 0.17-0.68). Therefore, a high prevalence of MetS was found in this Brazilian chronic ChD cohort. The identification of the associated factors can facilitate the development of effective approaches for preventing and managing MetS in ChD patients.