Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease.

Mitochondrial dysfunction has been described in many neurodegenerative disorders; however, there is less information regarding mitochondrial deficits in Machado-Joseph disease (MJD), a polyglutamine (polyQ) disorder caused by CAG repeat expansion in the ATXN3 gene. In the present study, we characterized the changes in mitochondrial function and biogenesis markers in two MJD models, CMVMJD135 (MJD135) transgenic mice at a fully established phenotype stage and tetracycline-regulated PC6-3 Q108 cell line expressing mutant ataxin-3 (mATXN3). We detected mATXN3 in the mitochondrial fractions of PC6-3 Q108 cells, suggesting the interaction of expanded ATXN3 with the organelle. Interestingly, in both the cerebella of the MJD135 mouse model and in PC6-3 Q108 cells, we found decreased mitochondrial respiration, ATP production and mitochondrial membrane potential, strongly suggesting mitochondrial dysfunction in MJD. Also, in PC6-3 Q108 cells, an additional enhanced glycolytic flux was observed. Supporting the functional deficits observed in MJD mitochondria, MJD135 mouse cerebellum and PC6-3 Q108 cells showed reduced cytochrome c mRNA and protein levels. Overall, our findings show compromised mitochondrial function associated with decreased cytochrome c levels in both cell and animal models of MJD.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure. STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. RESULTS: The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer's disease.

Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER-mitochondria cross-talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl-H3 in AD human cortex, and increased HDAC2-3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aß1-42 oligomers (AßO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER-Ca2+ retention and mitochondrial Ca2+ accumulation, mitochondrial depolarization and impaired ER-mitochondria cross-talk, as observed in 3xTg-AD mouse hippocampal neurons and AßO-exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial-associated ER membranes (MAM) in cells exposed to AßO upon Tac treatment, along with reduction in ER-mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER-mitochondria Ca2+ transfer and mitochondrial Ca2+ retention, while knockdown of HDAC3 decreased ER-Ca2+ accumulation in AßO-treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM-related proteins, and reduced Aß levels. These data demonstrate that Tac normalizes Ca2+ signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac-mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER-mitochondria communication as a promising target for innovative therapeutics in AD.

Mitochondrial and Redox Changes in Periodontitis and Type 2 Diabetes Human Blood Mononuclear Cells.

Periodontitis (PDT) and type 2 diabetes (T2D) have demonstrated a bidirectional relationship and imbalanced oxidative stress linked to mitochondrial dysfunction. Therefore, we investigated mitochondrial and redox (de)regulation in peripheral blood mononuclear cells (PBMCs) in comorbid T2D-PDT, compared to PDT, T2D patients, and control individuals. PBMCs were analyzed for mitochondrial respiration, reactive oxygen species, antioxidant proteins, and expression of Nrf2-target genes. PDT and T2D-PDT patients exhibited altered periodontal clinical markers, while T2D and T2D-PDT patients displayed increased blood HbA1c. Decreased oxygen consumption and ATP production were observed in the PDT patient's PBMCs. PDT and T2D-PDT PBMCs also evidenced increased H2O2 levels and reduced catalase levels (also detected in T2D patients), whereas a compromised glutathione cycle was observed in T2D-PDT patients. PBMCs from both T2D or T2D-PDT patients showed increased Nrf2 protein levels, enhanced GCL activity and GCL-catalytic subunit protein levels, and maintained GCLc, GST, and HO-1 mRNA levels. In contrast, the expressions of Nrf2-target genes were significantly diminished in the PDT patient's PBMCs. Decreased SOD1 and GST mRNA levels were also observed in CD3+CD8+-lymphocytes derived from PDT and T2D-PDT patients. In conclusion, PBMCs from T2D-PDT patients showed major redox changes, while mononuclear cells from PDT patients showed mitochondrial deregulation and reduced expression of Nrf2-target genes.

Sexual Dysfunctions in Parkinson's Disease and Their Influence on Partnership-Data of the PRISM Study.

BACKGROUND: Sexual dysfunctions (SD) are common but underreported in Parkinson's disease (PD) and have negative impacts on the quality of life (QoL) and partnership. METHODS: We analyzed the data set from the PRISM study for demographics of SD and their influence on quality of life and partnership. RESULTS: 449/861 (52.1%) PD patients reported SD, with male patients being affected more often and having a longer course of disease. The most common SD in men was erectile dysfunction (ED) (n = 152), while women's most frequent complaints were orgasm dysfunction (n = 84) and reduced libido (n = 81). Hypersexual SDs were reported significantly more often by men. Spousal caregivers of patients reporting inability to relax and enjoy sex and reduced libido indicated a negative influence on the relationship in general. Negative effects on the sexual relationship were reported significantly more often for patients with ED, difficulties with sexual arousal, inability to relax and enjoy sex, and reduced libido. Hypersexual dysfunctions showed no effect on the relationship. CONCLUSION: SD is a common but underreported problem in the treatment of patients with PD. Due to the negative influence on the relationship and QoL of patients and caregivers, SD should be assessed routinely.

Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aß) oligomers (AßO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AßO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AßO. Naturally-derived compounds have been proposed as potential modifiers of Aß-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AßO. We examined the protective effect of boldine (1-10 µM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AßO (24-48 h). We found that boldine interacts with Aß in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AßO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AßO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AßO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aß and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aß in vivo.

The challenge of long-term follow-up of survivors of childhood acute leukemia after hematopoietic stem cell transplantation in resource-limited countries: A single-center report from Brazil.

With the number of long-term HSCT survivors steadily increasing, attention needs to be focused on the late complications and quality of life. We therefore analyzed the outcome of 101 pediatric patients (<18 years old at the time of HSCT) transplanted for acute leukemia between 1981 and 2015 at Complexo Hospital de Clínicas, Federal University of Paraná, Brazil, and who survived at least two years after HSCT. The median follow-up was 5.9 years (2.0-29.0); median age at follow-up was 17.5 years (2.98-39.0). The 5-year cumulative incidence of relapse was 27.5% (95% CI 18.6%-36.4%). Two-year cumulative incidence of chronic GVHD was 21.8% (95% CI 13.7%-29.8%). Of the 101 patients, 72 patients (71.3%) presented with late effects. Those surviving longer after HSCT experienced more complications. Patients who received TBI-based regimen developed more late effects (P = .013) and more endocrinological complications (P = .024). Endocrinological complications were the most common late sequelae found in this study. For childhood survivors, quality of life was not influenced by age (at HSCT or at last visit), time from HSCT, gender, donor, or GVHD. For survivors that no longer were children, only age at last visit impacted financial domain measures, irrespective of gender, donor, or GVHD. The current study confirms the high burden late complications after pediatric HSCT have on the survivors and underlines the importance of extended follow-up.

Safety culture: perception of health professionals in a mental hospital.

OBJECTIVE: To evaluate the culture of patient safety in a mental health service. METHOD: Cross-sectional study conducted with health professionals in a mental hospital, by applying the Safety Attitudes Questionnaire (SAQ). Descriptive and inferential analyses were performed. RESULTS: One-hundred and three professionals participated in the study, with female predominance (64.1%) and time of performance equal to or greater than 21 years (32.4%). The nursing professionals of technical level and with statutory work regime were the most participative, 54.4% and 52% respectively. The total score was 69 points. The domain that reached the highest score was Job satisfaction (80 points) and the lowest was Working conditions (57 points). The statutory professionals and those with longer professional experience obtained better scores in the perception of safety culture. CONCLUSION: The result of safety culture was below the recommended, indicating the need for strengthening this construct in mental health hospitals.

Safety culture: perception of health professionals in a mental hospital / Cultura de seguridad: la percepción de los profesionales de salud en un hospital mental / Cultura de segurança: percepção dos profissionais de saúde em um hospital mental

ABSTRACT Objective: To evaluate the culture of patient safety in a mental health service. Method: Cross-sectional study conducted with health professionals in a mental hospital, by applying the Safety Attitudes Questionnaire (SAQ). Descriptive and inferential analyses were performed. Results: One-hundred and three professionals participated in the study, with female predominance (64.1%) and time of performance equal to or greater than 21 years (32.4%). The nursing professionals of technical level and with statutory work regime were the most participative, 54.4% and 52% respectively. The total score was 69 points. The domain that reached the highest score was Job satisfaction (80 points) and the lowest was Working conditions (57 points). The statutory professionals and those with longer professional experience obtained better scores in the perception of safety culture. Conclusion: The result of safety culture was below the recommended, indicating the need for strengthening this construct in mental health hospitals.

RESUMEN Objetivo: Evaluar la cultura de seguridad del paciente en un servicio de salud mental. Método: Estudio transversal realizado con los profesionales de la salud en un hospital mental, aplicándose el Safety Attitudes Questionnaire (SAQ). Fueron realizados análisis descriptivos e inferenciales. Resultados: Participaron del estudio 103 profesionales, con predominancia del sexo femenino (el 64,1%) y el tiempo de actuación igual o superior a 21 años (el 32,4%). Los profesionales de enfermería de nivel técnico y con régimen de trabajo estatutario fueron los más participativos, el 54,4% y el 52% respectivamente. El resultado total fue 69 puntos. El dominio que alcanzó el resultado más grande fue el de Satisfacción en el trabajo (80 puntos) y el más pequeño fue el de Condiciones de trabajo (57 puntos). Los profesionales estatutarios y con tiempo más grande de experiencia profesional obtuvieron mejores resultados en la percepción de cultura de seguridad. Conclusión: El resultado de cultura de seguridad fue debajo de lo recomendado, indicando la necesidad de fortalecimiento de ese constructo en los hospitales de salud mental.

RESUMO Objetivo: Avaliar a cultura de segurança do paciente em um serviço de saúde mental. Método: Estudo transversal realizado com profissionais da saúde em um hospital mental, aplicando-se o Safety Attitudes Questionnaire (SAQ). Foram realizadas análises descritivas e inferenciais. Resultados: Participaram do estudo 103 profissionais, com predominância do sexo feminino (64,1%) e tempo de atuação igual ou superior a 21 anos (32,4%). Os profissionais de enfermagem de nível técnico e com regime de trabalho estatutário foram os mais participativos, 54,4% e 52% respectivamente. O escore total foi 69 pontos. O domínio que atingiu maior escore foi Satisfação no trabalho (80 pontos) e o menor foi Condições de trabalho (57 pontos). Os profissionais estatutários e com maior tempo de experiência profissional obtiveram melhores escores na percepção de cultura de segurança. Conclusão: O resultado de cultura de segurança foi abaixo do recomendado, apontando a necessidade de fortalecimento desse construto nos hospitais de saúde mental.

Unrelated hematopoietic stem cell transplantation in the pediatric population: single institution experience

Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution.METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test.RESULTS: This study included 118 patients (46.8%) who received bone marrow and 134 (53.2%) who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value < 0.001). Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value = 0.653). Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value = 0.007). Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value = 0.117). Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value = 0.4666).CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups...

Unrelated hematopoietic stem cell transplantation in the pediatric population: single institution experience.

OBJECTIVE: Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution. METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test. RESULTS: This study included 118 patients (46.8%) who received bone marrow and 134 (53.2%) who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value<0.001). Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value=0.653). Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value=0.007). Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value=0.117). Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value=0.4666). CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups.

[Hybrid approach to structural cardiac disease: three clinical cases]. / Tratamento híbrido de doença estrutural cardiac: a propósito de três casos clínicos.

Structural cardiac diseases can be successfully treated by a multidisciplinary team using a hybrid strategy. We report a small series of complex cases were the team effort of cardiologists, cardiac surgeons and anaesthesiologists allowed a favourable result.

Abuso físico: o perfil do agressor e da criança vitimizada / Physical abuse: the profile of aggressor

Objetivo: Conhecer o perfil da criança vítima de agrsessão física e do agente responsável pela violência contra ela. Método: investigaram-se 225 casos confirmados de abuso físico do SOS Criança, de Curitiba, durante o ano de 1998, aos quais se aplicou um protocolo com quesitos voltados à análise da criança violentada e do agente agressor. Resultados: registraram-se os seguintes modelos: 56 por cento das crianças avaliadas apresentavam-se em idade escolar; 59,6 eram o primeiro filho da família; 84,4 por cento consistiam em filhos naturais e 71,1 por cento das crianças apresentavam satisfatório rendimento escolar. Múltiplas lesões (38,2 por cento) atingiram o corpo das vítimas, e os ferimentos, na maioria das vezes (37,8 por cento), apresentaram-se como hematomas. O principal agente agressor foi a mãe (42,2 por cento), das quais 25,8 por cento alegaram a causa disciplinar para o abuso, utilizaram-se das mãos (32,5 por cento) para efetuar a violência e 72 por cento negam o uso de bebida alcólica. Conclusões: As crianças que mais sofrem agressão física, segundo a amostra estudada, consistem em filhos legiítimos e primogênitos, com faixa etária entre 5 e 11 anos e com nível escolar compatível com a idade. A mãe, com suas próprias mãos, resume-se no principal agente agressor, e deixa geralmente hematomas, em diversos segmentos do corpo da criança, com o princípio de educar, ou seja, a colocação de limites