Lack of NAD(P)+ transhydrogenase activity in patients with primary adrenal insufficiency due to NNT variants.

BACKGROUND: Pathogenic variants in the nicotinamide nucleotide transhydrogenase gene (NNT) are a rare cause of primary adrenal insufficiency (PAI), as well as functional impairment of the gonads. OBJECTIVE: Despite the description of different homozygous and compound heterozygous NNT variants in PAI patients, the extent to which the function and expression of the mature protein are compromised remains to be clarified. DESIGN: The activity and expression of mitochondrial NAD(P)+ transhydrogenase (NNT) were analyzed in blood samples obtained from patients diagnosed with PAI due to genetically confirmed variants of the NNT gene (n = 5), heterozygous carriers as their parents (n = 8), and healthy controls (n = 26). METHODS: NNT activity was assessed by a reverse reaction assay standardized for digitonin-permeabilized peripheral blood mononuclear cells (PBMCs). The enzymatic assay was validated in PBMC samples from a mouse model of NNT absence. Additionally, the PBMC samples were evaluated for NNT expression by western blotting and reverse transcription quantitative polymerase chain reaction and for mitochondrial oxygen consumption. RESULTS: NNT activity was undetectable (<4% of that of healthy controls) in PBMC samples from patients, independent of the pathogenic genetic variant. In patients' parents, NNT activity was approximately half that of the healthy controls. Mature NNT protein expression was lower in patients than in the control groups, while mRNA levels varied widely among genotypes. Moreover, pathogenic NNT variants did not impair mitochondrial bioenergetic function in PBMCs. CONCLUSIONS: The manifestation of PAI in NNT-mutated patients is associated with a complete lack of NNT activity. Evaluation of NNT activity can be useful to characterize disease-causing NNT variants.

Construcción y validación de un cuestionario para evaluar burnout académico en estudiantes de ciencias de la salud / Construction and validation of a questionnaire to assess academic burnout in health science students / Construção e validação de um questionário para avaliar o burnout acadêmico em estudantes da área da saúde

Objetivo: el burnout (BA) académico puede presentarse en el contexto universitario, se caracteriza por un estado de agotamiento vital que afecta la salud física y mental de los estudiantes, lo que genera una disminución en el rendimiento académico. Este problema aparece con mayor frecuencia en programas universitarios con altas exigencias académicas. El objetivo de este trabajo fue construir y evaluar la estructura factorial de un cuestionario de BA académico en estudiantes que cursaban los programas de medicina, enfermería y psicología. Metodología: los participantes fueron 710 estudiantes de ciencias de la salud (hombres 40.8 % y mujeres 59.2 %), de 16 a 33 años (M = 20.42 años, DT = 3 años). Se evaluó la validez de constructo mediante análisis factorial exploratorio (AFE) y análisis factorial confirmatorio (AFC); además, se calculó la consistencia interna por medio del estadístico alfa de Cronbach. Resultados: el cuestionario burnout académico (CBA-24) quedó conformado por 24 reactivos y una estructura factorial de cuatro dimensiones (agotamiento emocional, cinismo hacia el estudio, cinismo hacia las personas y realización personal). Con la prueba se evaluó el nivel de malestar emocional ante las demandas del entorno académico. Los índices de ajuste alcanzaron valores altos en el modelo propuesto, por lo tanto, el modelo de cuatro factores alcanzó los criterios para considerar que el ajuste es adecuado en todos los índices y mostró una estructura multidimensional. Dichos índices se agruparon de acuerdo con la taxonomía propuesta. Conclusiones: el cuestionario permitió identificar de manera ecológica el constructo de BA ajustado a las demandas de los contextos universitarios.

Objective: Academic burnout (AB) can occur in the university context and is characterized by a state of vital exhaustion that affects the physical and mental health of students, leading to a decrease in academic performance. This problem is more commonly observed in college programs with high academic demands. The aim of this study was to construct and evaluate the factorial structure of a questionnaire for assessing AB in students enrolled in medicine, nursing, and psychology programs. Methodology: The participants consisted of 710 health science students (40.8% male and 59.2% female) aged between 16 and 33 years (M = 20.42 years, SD = 3 years). Construct validity was assessed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Additionally, internal consistency was calculated using Cronbach's alpha statistic. Results: The academic burnout questionnaire (ABQ-24) consisted of 24 items and a four-factor factorial structure (emotional exhaustion, cynicism towards studying, cynicism towards people, and personal accomplishment). The questionnaire assessed the level of emotional distress experienced in response to academic demands. The fit indices achieved high values in the proposed structure, indicating that the four-factor model met the criteria for adequate fit across all indices and exhibited a multidimensional structure. These indices were grouped according to the proposed taxonomy. Conclusions: The questionnaire provided an ecologically valid means of identifying the construct of AB, adapted to the demands of university contexts.

Objetivo: o burnoutacadêmico (BA) pode ocorrer no contexto universitário, é caracteri-zado por um estado de esgotamento vital que afeta a saúdefísica e mentaldos alunos, o que gera uma diminuição no desempenho acadêmico. Esse problema aparece com mais frequência em programas universitários com altas demandas acadêmicas. O objetivo deste trabalho foi construir e avaliar a estrutura fatorial de um questionário acadêmico de graduação em estudantes de medicina, enfermagem e psicologia. Metodologia: Os participantes foram 710 estudantes de ciências da saúde (40,8% ho-mens e 59,2 % mulheres), de 16 a 33 anos (M = 20,42 anos, DT = 3 anos). A validade de construto foi avaliada por meio de análise fatorial exploratória (EFA) e análise fatorial confirmatória (AFC); além disso, a consistência interna foi calculada usando a estatística alfa de Cronbach. Resultados: o questionário de burnoutacadêmico (CBA-24) foi composto por 24 itens e uma estrutura fatorial de quatro dimensões (exaustão emocional, cinismo em relação ao estudo, cinismo em relação às pessoas e realização pessoal). Com o teste, avaliou-se o nível de desconforto emocional diante das demandas do ambiente acadêmico. Os índices de ajuste atingiram valores altos no modelo proposto, portanto, o modelo de quatro fatores atendeu aos critérios para considerar que o ajuste é adequado em todos os índices e apresentou uma estrutura multidimensional. Esses índices foram agrupados de acordo com a taxonomia proposta.Conclusões:o questionário permitiu identificar de forma ecológica o construto BA ajustado às demandas dos contextos universitários

Low Correlation between Gait and Quality of Life in Advanced Knee Osteoarthritis.

Advanced knee osteoarthritis patients' gait usually undergoes alterations leading to decreased mobility and lower functional performance, which can result in a worsening of their quality of life (QoL). While several authors have reported a moderate correlation between gait parameters and QoL assessed by generic questionnaires, the literature is scarce. This study aimed to explore the relationship between gait and QoL parameters assessed by a generic and a disease-specific questionnaire in patients with advanced knee osteoarthritis. In this single-centre, prospective, observational study, 129 patients with advanced knee osteoarthritis scheduled for elective total knee replacement were selected. The patients' gait was evaluated by means of a validated wireless device while they walked 30 m at a comfortable speed. Patient function was also analysed using the Knee Society Score (KSS). QoL was measured with the EQ-5D and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaires. Patients showed a mean walking speed of 0.95 ± 0.19 m/s, a mean cadence of 105.6 ± 9.9 steps/min, and a mean stride length of 1.25 ± 0.17 m on both legs. They presented poor knee status (KSS < 60) and poor QoL, with an EQ-5D of 0.44 ± 0.24 and a total KOOS of 29.77 ± 13.99. Positive low correlations (r <0.5, p <0.5) were found only between the speed, propulsion and stride length of both legs, and the overall and ADLs subscale scores of the total KOOS questionnaire. In conclusion, several gait parameters have a significant low correlation with the QoL of patients with advanced knee osteoarthritis, as assessed by an osteoarthritis-specific questionnaire.

Calidad de vida relacionada con edad e ingreso económico en adultos mayores diabéticos. Chillán, Chile, 2019

Fundamento padecer diabetes puede influenciar la percepción del propio individuo y cambiar su rutina diaria, afectando así su calidad de vida; partiendo de ello, la profundización en el tema reviste gran importancia Objetivo determinar la relación entre calidad de vida, edad e ingreso económico en adultos mayores con diabetes mellitus tipo 2. Métodos se realizó un estudio descriptivo, de corte transversal, en 33 adultos mayores con diabetes mellitus tipo 2, seleccionados mediante un muestreo no probabilístico por conveniencia, en la comunidad de las Mariposas (Chillán, Chile), en el año 2019. Para el análisis de la calidad de vida fue aplicado el instrumento Diabetes 39. Se utilizaron las pruebas estadísticas de Kolmogorov-Smirnov y Rho de Spearman. Resultados existió predominio del sexo femenino, así como de personas casadas. La edad tuvo un valor medio de 71,45 años. Con respecto al ingreso económico, un 66,7 % de los participantes refirió imposibilidad para costear los gastos del mes. Entre las dimensiones de la calidad de vida analizadas, las más afectadas fueron: severidad de la diabetes (media de 55,05), energía/movilidad (media de 44,1), y calidad de vida (media de 43,9). La edad y el ingreso económico no mostraron una correlación significativa con ninguna de las dimensiones estudiadas. Conclusiones la calidad de vida de los adultos mayores con diabetes mellitus tipo 2 se ve afectada, sin que exista una relación significativa con la edad e ingresos económicos.

Background suffering from diabetes can influence the perception of the individual himself and change his daily routine, thus affecting his quality of life; Based on this, the deepening of the subject is of great importance Objective to determine the relationship between quality of life, age and income in older adults with type 2 diabetes mellitus. Methods a descriptive, cross-sectional study was carried out in 33 older adults with type 2 diabetes mellitus, selected by non-probabilistic convenience sampling, in the Las Mariposas community (Chillán, Chile), in 2019. The Diabetes 39 instrument was applied for quality of life analysis. The Kolmogorov-Smirnov and Spearman's Rho statistical tests were used. Results the female sex was the predominant, as well as married people. Age had a mean value of 71.45 years. In the economic income, 66.7% of the participants reported the impossibility of paying the expenses of the month. Among the life's quality dimensions analyzed, the most affected were: diabetes severity (mean 55.05), energy/mobility (mean 44.1), and quality of life (mean 43.9). Age and income did not show a significant correlation with any of the dimensions studied. Conclusions the older adults' quality of life with type 2 diabetes mellitus is affected, without a significant relationship with age and economic income.

Neither Chia Flour nor Whey Protein Supplementation Further Improves Body Composition or Strength Gains after a Resistance Training Program in Young Subjects with a Habitual High Daily Protein Intake.

The aim of this study was to compare the potential additional effect of chia flour, whey protein, and a placebo juice to resistance training on fat-free mass (FFM) and strength gains in untrained young men. Eighteen healthy, untrained young men underwent an 8-week whole-body resistance training program, comprising three sessions per week. Subjects were randomized into three groups that after each training session consumed: (1) 30 g whey protein concentrate containing 23 g protein (WG), (2) 50 g chia flour containing 20 g protein (CG), or (3) a placebo not containing protein (PG). Strength tests (lower- and upper-limb one repetition maximum (1 RM) tests) and body composition analyses (dual-energy X-ray absorptiometry; DXA) were performed before (PRE) and after (POST) the intervention. Resistance training increased FFM and the 1 RM for each of the strength tests similarly in the three groups. FFM increased by 2.3% in WG (p = 0.04), by 3.6% in CG (p = 0.004), and by 3.0% in PG (p = 0.002)., and 1 RM increased in the different strength tests in the three groups (p < 0.05) with no difference between PG, CG, and WG. In conclusion, neither chia flour nor whey protein supplementation elicited an enhanced effect on FFM and strength gains after an 8-week resistance training program in healthy, untrained young men consuming a habitual high protein mixed diet (>1.2 g/kg/day).

Clinical profile of oral mucosa lesions in elderly patients: a 20-year retrospective study / Perfil clínico das lesões da mucosa oral em pacientes idosos: um estudo retrospectivo de 20 anos

Background: Life expectancy has considerably increased resulting in population aging. Studies evaluating the outcomes of aging in oral health are scarce. Objective: Evaluate retrospectively the profile of elderly patients from a public Oral Medicine Center during a period of 20 years. Methods:A qualitative and quantitative retrospective observational study was conducted analyzing medical records from an oral medicine service from January 1994 to December 2014. Results were reported as mean ± standard deviation for quantitative variables and percentages for categorical variables. The Chi-square test and T-student test was applied with significance level of 5%. Results: 2,690 medical records were retrieved, comprising of 61% women and 39% men with an average ageof 68.8 ± 6.79 years. Xerostomia was significantly associated, hypoglycemic usage (p<0.0001), anticoagulantusage (p<0.0001), psychotropic usage (p<0.0001) and analgesics and anti-inflammatory usage (p<0.0001). Forcandidiasis, an association with age, xerostomía (p<0.0001), and use of complete dentures was found(p<0.0001). For oral squamous cell carcinoma and oral leukoplakia the tabacco (p<0.0001) and alcohol consumption (p<0.0001) were significant associated. Conclusion:The elderly population was comprised mostly by women that use a large of drugs which wereassociated with xerostomia development. In addition, tabaco and alcohol consumption were associated withoral leukoplakia and OSCC being these two diseases more frequently in men. Dental care services should aimto prevent and treat these complications as way to improve the elderly's quality of life.

Introdução: A expectativa de vida aumentou consideravelmente, resultando no envelhecimento da população. Estudos avaliando os desfechos do envelhecimento na saúde bucal são escassos. Objetivo: Avaliar retrospectivamente o perfil dos pacientes idosos de um Centro de Medicina Oral público durante um período de 20 anos. Materiais e métodos: Estudo observacional retrospectivo qualitativo e quantitativo, analisando os prontuários de um serviço de medicina bucal no período de janeiro de 1994 a dezembro de 2014. Os resultados foram expressos em média ± desvio padrão para variáveis quantitativas e percentuais para variáveis categóricas. Aplicou-se o teste Qui-quadrado e o teste T-student com nível de significância de 5%. Resultados: Foram recuperados 2.690 prontuários, sendo 61% mulheres e 39% homens com idade média de 68,8 ± 6,79 anos. Xerostomia foi significativamente associada, uso de hipoglicemiantes (p<0,0001), uso de anticoagulantes (p<0,0001), uso de psicotrópicos (p<0,0001) e uso de analgésicos e anti-inflamatórios (p<0,0001). Para candidíase, foi encontrada associação com idade, xerostomia (p<0,0001)e uso de prótese total (p<0,0001). Para carcinoma espinocelular oral e leucoplasia oral, o uso de tabaco (p<0,0001) e consumo de álcool (p<0,0001) estiveram associados significativamente. Conclusão: A população idosa foi composta em sua maioria por mulheres que fazem uso de grande quantidade de medicamentos associados ao desenvolvimento de xerostomia. Além disso, o consumo de tabaco e álcool foram associados com leucoplasia oral e OSCC sendo essas duas doenças mais frequentes em homens. Os serviços odontológicos devem ter como objetivo prevenir e tratar essas complicações como forma de melhorar a qualidade de vida dos idosos.

JMJD3 intrinsically disordered region links the 3D-genome structure to TGFß-dependent transcription activation.

Enhancers are key regulatory elements that govern gene expression programs in response to developmental signals. However, how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter remains unclear. To address this question, we exploited our previously characterized TGFß-response model, the neural stem cells, focusing on a ~374 kb locus where enhancers abound. Our 4C-seq experiments reveal that the TGFß pathway drives the assembly of an enhancer-cluster and precise gene activation. We discover that the TGFß pathway coactivator JMJD3 is essential to maintain these structures. Using live-cell imaging techniques, we demonstrate that an intrinsically disordered region contained in JMJD3 is involved in the formation of phase-separated biomolecular condensates, which are found in the enhancer-cluster. Overall, in this work we uncover novel functions for the coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin and the TGFß-driven response during mammalian neurogenesis.

Periodontal treatment of patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a rare condition in which fragile vascular walls lead to increased risks of bleeding, cerebral abscesses, arteriovenous malformations, anemia, and thrombosis. To date, no protocol has been established for optimizing the clinical outcomes of periodontal treatment in patients with this condition. The aim of this case report is to describe a safe clinical approach to periodontal treatment in a patient with HHT. A 39-year-old woman had a history of multiple macules on the oral mucosa, and a diagnosis of HHT was made based on the Curaçao diagnostic criteria (epistaxis, telangiectases, visceral lesions, and family history). Evaluation of the patient's periodontal clinical parameters and radiographs led to a diagnosis of generalized periodontitis, stage IV, grade C. The patient underwent nonsurgical periodontal therapy consisting of supragingival and subgingival scaling and root planing under a careful and specific protocol that included antibiotic prophylaxis before each session. Two months after therapy, the periodontal reevaluation showed improvement in the clinical parameters at most sites. Sites with remaining periodontal pockets were re-treated according to the same protocol, including the antibiotic prophylaxis. The patient was enrolled in a periodontal maintenance program, and her HHT was routinely monitored by her physician. Periodontal treatment may promote secondary complications in patients with HHT if appropriate systemic care is not provided, and the periodontal treatment plan should be designed individually for each patient. Establishing the correct HHT diagnosis and coordinating care with the patient's physician are essential to safe, effective treatment.

Aggravation of hepatic lipidosis in red-footed tortoise Chelonoidis carbonaria with age is associated with alterations in liver mitochondria.

The occurrence of hepatic lipidosis is commonly reported in different reptilian species, especially in animals under captivity. Liver accumulation of fat is associated with disorders, better described in mammals as non-alcoholic fatty liver diseases (NAFLD), ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH), and to more severe lesions of cirrhosis and hepatocellular carcinoma. Mitochondria play a central role in NAFLD pathogenesis, therefore in this study we characterized livers of ad libitum fed captive red-footed tortoise Chelonoidis carbonaria through histological and mitochondrial function evaluations of juvenile and adult individuals. Livers from adult tortoises exhibited higher levels of lipids, melanomacrophages centers and melanin than juveniles. The observed high score levels of histopathological alterations in adult tortoises, such as microvesicular steatosis, inflammation and fibrosis, indicated the progression to a NASH condition. Mitochondrial oxygen consumption at different respiratory states and with different substrates was 30 to 58% lower in adult when compared to juvenile tortoises. Despite citrate synthase activity was also lower in adults, cardiolipin content was similar to juveniles, indicating that mitochondrial mass was unaffected by age. Mitochondrial Ca2+ retention capacity was reduced by 70% in adult tortoises. Overall, we found that aggravation of NAFLD in ad libitum fed captive tortoises is associated with compromised mitochondrial function, indicating a critical role of the organelle in liver disease progression in reptiles.

A dataset describing glycolytic inhibitors overcoming the underestimation of maximal mitochondrial oxygen consumption rate in oligomycin-treated cells.

Determination of oxygen consumption is one of the most valuable methodologies to evaluate mitochondrial (dys)function. Previous studies demonstrated that a widely used protocol, consisting of adding the ATP synthase inhibitor oligomycin before mitochondrial respiratory uncoupling by sequential addition of a protonophore (e.g., carbonyl cyanide 3-chlorophenyl hydrazone [CCCP]), may lead to underestimation of maximal oxygen consumption rate (OCRmax) and spare respiratory capacity (SRC) parameters in highly glycolytic tumor cell lines. In this dataset, we report the effects of the glycolytic inhibitors 2-deoxy-D-glucose, iodoacetic acid, and lonidamine on overcoming the underestimation of OCRmax and SRC in oligomycin-treated cells. We propose a protocol in which 2-deoxy-D-glucose is added after oligomycin and just before the sequential addition of CCCP to avoid underestimation of OCRmax and SRC parameters in A549, C2C12, and T98G cells. The oxygen consumption rates were determined in intact suspended cell lines using a high-resolution oxygraph device. The data can be used in several fields of research that require characterization of mitochondrial respiratory parameters in intact cells.

Dichloroacetate reactivates pyruvate-supported peroxide removal by liver mitochondria and prevents NAFLD aggravation in NAD(P)+ transhydrogenase-null mice consuming a high-fat diet.

The mechanisms by which a high-fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunction and redox imbalance. The functional loss of the enzyme NAD(P)+ transhydrogenase, a main source of mitochondrial NADPH, results in impaired mitochondrial peroxide removal, pyruvate dehydrogenase inhibition by phosphorylation, and progression of NAFLD in HFD-fed mice. The present study aimed to investigate whether pharmacological reactivation of pyruvate dehydrogenase by dichloroacetate attenuates the mitochondrial redox dysfunction and the development of NAFLD in NAD(P)+ transhydrogenase-null (Nnt-/-) mice fed an HFD (60% of total calories from fat). For this purpose, Nnt-/- mice and their congenic controls (Nnt+/+) were fed chow or an HFD for 20 weeks and received sodium dichloroacetate or NaCl in the final 12 weeks via drinking water. The results showed that HFD reduced the ability of isolated liver mitochondria from Nnt-/- mice to remove peroxide, which was prevented by the dichloroacetate treatment. HFD-fed mice of both Nnt genotypes exhibited increased body and liver mass, as well as a higher content of hepatic triglycerides, but dichloroacetate treatment attenuated these abnormalities only in Nnt-/- mice. Notably, dichloroacetate treatment decreased liver pyruvate dehydrogenase phosphorylation levels and prevented the aggravation of NAFLD in HFD-fed Nnt-/- mice. Conversely, dichloroacetate treatment elicited moderate hepatocyte ballooning in chow-fed mice, suggesting potentially toxic effects. We conclude that the protection against HFD-induced NAFLD by dichloroacetate is associated with its role in reactivating pyruvate dehydrogenase and reestablishing the pyruvate-supported liver mitochondrial capacity to handle peroxide in Nnt-/- mice.

Enhanced resistance to Ca2+-induced mitochondrial permeability transition in the long-lived red-footed tortoise Chelonoidis carbonaria.

The interaction between supraphysiological cytosolic Ca2+ levels and mitochondrial redox imbalance mediates the mitochondrial permeability transition (MPT). The MPT is involved in cell death, diseases and aging. This study compared the liver mitochondrial Ca2+ retention capacity and oxygen consumption in the long-lived red-footed tortoise (Chelonoidis carbonaria) with those in the rat as a reference standard. Mitochondrial Ca2+ retention capacity, a quantitative measure of MPT sensitivity, was remarkably higher in tortoises than in rats. This difference was minimized in the presence of the MPT inhibitors ADP and cyclosporine A. However, the Ca2+ retention capacities of tortoise and rat liver mitochondria were similar when both MPT inhibitors were present simultaneously. NADH-linked phosphorylating respiration rates of tortoise liver mitochondria represented only 30% of the maximal electron transport system capacity, indicating a limitation imposed by the phosphorylation system. These results suggested underlying differences in putative MPT structural components [e.g. ATP synthase, adenine nucleotide translocase (ANT) and cyclophilin D] between tortoises and rats. Indeed, in tortoise mitochondria, titrations of inhibitors of the oxidative phosphorylation components revealed a higher limitation of ANT. Furthermore, cyclophilin D activity was approximately 70% lower in tortoises than in rats. Investigation of critical properties of mitochondrial redox control that affect MPT demonstrated that tortoise and rat liver mitochondria exhibited similar rates of H2O2 release and glutathione redox status. Overall, our findings suggest that constraints imposed by ANT and cyclophilin D, putative components or regulators of the MPT pore, are associated with the enhanced resistance to Ca2+-induced MPT in tortoises.

Feeding effects on liver mitochondrial bioenergetics of Boa constrictor (Serpentes: Boidae).

Snakes are interesting examples of taxa that can overcome energy metabolism challenges, as many species can endure long periods without feeding, and their eventual meals are of reasonably large sizes, thus exhibiting dual extreme adaptations. Consequently, metabolic rate increases considerably to attend to the energetic demand of digestion, absorption and protein synthesis. These animals should be adapted to transition from these two opposite states of energy fairly quickly, and therefore we investigated mitochondrial function plasticity in these states. Herein, we compared liver mitochondrial bioenergetics of the boid snake Boa constrictor during fasting and after meal intake. We fasted the snakes for 60 days, and then we fed a subgroup with 30% of their body size and evaluated their maximum postprandial response. We measured liver respiration rates from permeabilized tissue and isolated mitochondria. From isolated mitochondria, we also measured Ca2+ retention capacity and redox status. Mitochondrial respiration rates were maximized after feeding, reaching an approximately 60% increase from fasting levels when energized with complex I-linked substrates. Interestingly, fasting and fed snakes exhibited similar respiratory control ratios and citrate synthase activity. Furthermore, we found no differences in Ca2+ retention capacity, indicating no increase in susceptibility to mitochondrial permeability transition, and no changes in mitochondrial redox state, although fed animals exhibited increases in the release of H2O2. Thus, we conclude that liver mitochondria from B. constrictor snakes increase respiration rates during the postprandial period and quickly improve the bioenergetic capacity without compromising redox balance.

The histone demethylase PHF8 regulates astrocyte differentiation and function.

Epigenetic factors have been shown to play a crucial role in X-linked intellectual disability (XLID). Here, we investigate the contribution of the XLID-associated histone demethylase PHF8 to astrocyte differentiation and function. Using genome-wide analyses and biochemical assays in mouse astrocytic cultures, we reveal a regulatory crosstalk between PHF8 and the Notch signaling pathway that balances the expression of the master astrocytic gene Nfia. Moreover, PHF8 regulates key synaptic genes in astrocytes by maintaining low levels of H4K20me3. Accordingly, astrocytic-PHF8 depletion has a striking effect on neuronal synapse formation and maturation in vitro. These data reveal that PHF8 is crucial in astrocyte development to maintain chromatin homeostasis and limit heterochromatin formation at synaptogenic genes. Our studies provide insights into the involvement of epigenetics in intellectual disability.

Labio-facial Necrotizing Fasciitis in a Young Patient.

ABSTRACT: Necrotizing fasciitis (NF) is an infection of the deeper tissues that results in progressive destruction of muscle fascia and overlying subcutaneous fat. It has a fast and destructive course. Moreover, it is related to immunosuppression and could be fatal. The aim of this study is to report a clinical case of a young patient, without immunosuppression, who developed NF evolution due to an erroneous diagnosis of abscess at the beginning of the disease. Patient was submitted to broad-spectrum antibiotic therapy and aggressive surgical treatment. Adequate treatment led to a satisfactory evolution in a short period of time. Early recognition and adequate treatment are essential for a favorable prognosis.

Análisis de las consecuencias cognitivas y afectivas de la violencia de género en relación con el tipo de maltrato / Analysis of the cognitive and affective consequences of gender violence in relation to the type of abuse

La violencia de género evidencia la desigualdad, la subordinación y las relaciones de poder de los hombres sobre las mujeres, que podrían generar déficits neuropsicológicos y síntomas psicopatológicos. Con el objetivo de analizar estas consecuencias se realizó una investigación en la que participaron 34 mujeres (17 víctimas de violencia de género, con edades entre los 25 y los 60 años). Las herramientas de evaluación utilizadas se han dividido en 2: por un lado, pruebas neuropsicológicas para medir la velocidad de procesamiento, la atención y la memoria: TMT A, TMT B, letras y números, cubos de Corsi, HVLT y d2; por otro lado, pruebas psicopatológicas para medir la ansiedad, la depresión, el abuso y el estrés postraumático: STAI, BDI-II, ISA y EGEP-5. Los resultados mostraron que el abuso está relacionado con mayores déficits neuropsicológicos y numerosos síntomas psicopatológicos. Además, los niveles altos de estrés se relacionaron con una peor memoria de trabajo. Por otro lado, no se encontraron diferencias significativas en relación con el tipo de abuso en los síntomas psicopatológicos, pero sí en algunas variables neuropsicológicas como la memoria a largo plazo y la memoria visual de trabajo. Los datos obtenidos apuntan a la necesidad de centrar la atención en la causa de estas diferencias que podrían estar relacionadas con el abuso físico y psicológico, así como en los efectos que estos déficits cognitivos y el incremento en los niveles de ansiedad y depresión tienen sobre la calidad de vida de las mujeres maltratadas

Gender violence demonstrates the inequality, subordination and the power in relations of men over women, which could generate neuropsychological deficits and psychopathological symptoms. In order to analyze these consequences, an investigation was carried out with 34 women (17 victims of gender-based violence aged between 25 and 60). The assessment tools used for this research study have been divided into 2: on the one hand, neuropsychological measures composed of: TMT A, TMT B, letters and numbers, Corsi cubes, HVLT and d2 Attention Test. These tools have been used to measure processing speed, attention and memory. On the other hand, psychopathological tests STAI, BDI-II, ISA and EGEP-5 have been used to measure anxiety, depression, abuse and post-traumatic stress respectively. After the data analysis, the results demonstrated that the abuse is related to greater neuropsychological deficits and psychopathological symptoms. In addition, high levels of stress were associated with a worse working memory. Furthermore, no significant differences were found in relation to the type of abuse in psychopathological symptoms, but they appeared in some neuropsychological variables such as long-term memory and working visual memory. The data obtained in this study point out the necessity to focus the attention on the cause of these differences since they could be related to physical and psychological abuse, as well as the effects that these cognitive deficits and the increase in levels of anxiety and depression have on battered women's quality of life

Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration.

Amyotrophic lateral sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as 'severe' and 'mild' from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy number variation and whole exome sequencing analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N = 5) and controls (N = 3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients' iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to the endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to the ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER-mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency.

Effect of a family and interdisciplinary intervention to prevent T2D: randomized clinical trial.

BACKGROUND: Lifestyle changes can reduce the risk of T2D; however, no study has evaluated the effect of a lifestyle intervention involving patients´ family. The aim of this study was to compare the impact of an interdisciplinary family (FI) Vs individual intervention (II) on glucose metabolism, insulin resistance (IR), pancreatic ß-cell function and cardiovascular risk markers in patients with prediabetes, as well as to measure the impact on their families' metabolic risk. METHODS: Randomized Clinical Trial (RCT) to compare the impact of FI and II on IR and pancreatic ß-cell function in subjects with prediabetes. There were 122 subjects with prediabetes (and 101 family members) randomized to FI or II. Data were collected in 2015-2016 and analyzed in 2017-2018. FI group had the support of their family members, who also received personalized diet and exercise recommendations; patients and their family members attended monthly a lifestyle enhancement program. II group received personalized diet and exercise recommendations. The follow-up was for 12 months. Glucose, IR, pancreatic ß-cell function and secondary outcomes (body composition and lipid profile) were assessed at baseline, 6 and 12 months. RESULTS: FI group improved area under the glucose curve (AUC) (from 18,597 ± 2611 to 17,237 ± 2792, p = 0.004) and the Matsuda index (from 3.5 ± 2.3 to 4.7 ± 3.5, p = 0.05) at 12 months. II group improved Disposition Index (from 1.5 ± 0.4 to 1.9 ± 0.73, p < .0001) at 12 months. The improvements achieved in weight and lipids at 6 months, were lost in II group at 12 moths, whereas in FI persisted. Adherence up to 12 months was not different between the study groups (FI 56% Vs II 60%). CONCLUSIONS: FI intervention was more effective by improving glucose AUC, insulin sensitivity and lipid profile, besides that, metabolic risk in family members of the FI group was maintained, while the risk of II group was increased. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov on December 15, 2015 (NTC026365646).

Progressive Shifts in the Gut Microbiome Reflect Prediabetes and Diabetes Development in a Treatment-Naive Mexican Cohort.

Type 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world's population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity. Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity. Associations between gut bacteria and more than 200 clinical variables revealed a defined set of bacterial genera that were consistent biomarkers of T2D prevalence and risk. Specifically, gradual increases in blood glucose levels, beta cell dysfunction, and the accumulation of measured T2D risk factors were correlated with the relative abundances of four bacterial genera. In a cohort of 25 individuals, T2D treatment-predominantly metformin-reliably returned the microbiome to the normoglycemic community state. Deep clinical characterization allowed us to broadly control for confounding variables, indicating that these microbiome patterns were independent of common T2D comorbidities, like obesity or cardiovascular disease. Our work provides the first solid evidence for a direct link between the gut microbiome and T2D in a critically high-risk population. In particular, we show that increased T2D risk is reflected in gradual changes in the gut microbiome. Whether or not these T2D-associated changes in the gut contribute to the etiology of T2D or its comorbidities remains to be seen.