Evaluation of the dietary inflammatory index in children and adolescents with type 1 diabetes mellitus and its relationship with nutritional status and metabolic control.

OBJECTIVES: The aim of this study was to evaluate the association of the dietary inflammatory index (DII) with the nutritional status and metabolic control of children and adolescents with type 1 diabetes mellitus. METHODS: This was a cross-sectional study that examined data of children and adolescents ages 7 to 16 y diagnosed with type 1 diabetes mellitus. Dietary intake was assessed using a 24-h dietary recall, from which the DII was calculated. The outcomes were body mass index, lipid profiles (low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol), and glycated hemoglobin. The DII was evaluated in tertiles and in a continuous way. Multiple linear regression was adopted in the analysis, with P < 0.05 considered significant. RESULTS: Overall, 120 children and adolescents with a mean age of 11.7 (± 2.8) y were included, 53.3% (n = 64) of whom were girls. Excess weight was present in 31.7% participants (n = 38). The average DII was +0.25, ranging from -1.11 to +2.67. Higher values of selenium (P = 0.011), zinc (P = 0.001), fiber (P < 0.001), and other micronutrients were observed in the first tertile of the DII (diet with more antiinflammatory potential). The DII appeared as a predictor of body mass index (P = 0.002; ß = 0.23; 95% confidence interval [CI], 0.39-1.75) and non-high-density lipoprotein cholesterol (P = 0.034; ß = 0.19; 95% CI, -13.5 to 0.55). There was a tendency for DII to be associated with glycemic control (P = 0.09; ß = 0.19; 95% CI, -0.04 to 0.51). CONCLUSIONS: The inflammatory potential of the diet was associated with increased body mass index and aspects related to metabolic control in children and adolescents with type 1 diabetes mellitus.

Cancer Impacts Prognosis on Mortality in Patients with Acute Heart Failure: Analysis of the EPICTER Study.

INTRODUCTION: Heart failure (HF) and cancer are currently the leading causes of death worldwide, with an increasing incidence with age. Little is known about the treatment received and the prognosis of patients with acute HF and a prior cancer diagnosis. OBJECTIVE: to determine the clinical characteristics, palliative treatment received, and prognostic impact of patients with acute HF and a history of solid tumor. METHODS: The EPICTER study ("Epidemiological survey of advanced heart failure") is a cross-sectional, multicenter project that consecutively collected patients admitted for acute HF in 74 Spanish hospitals. Patients were classified into two groups according to whether they met criteria for acute HF with and without solid cancer, and the groups were subsequently compared. A multivariable logistic regression analysis was conducted, using the forward stepwise method. A Kaplan-Meier survival analysis was performed to evaluate the impact of solid tumor on prognosis in patients with acute HF. RESULTS: A total of 3127 patients were included, of which 394 patients (13%) had a prior diagnosis of some type of solid cancer. Patients with a history of cancer presented a greater frequency of weight loss at admission: 18% vs. 12% (p = 0.030). In the cancer group, functional impairment was noted more frequently: 43% vs. 35%, p = 0.039). Patients with a history of solid cancer more frequently presented with acute HF with preserved ejection fraction (65% vs. 58%, p = 0.048) than reduced or mildly reduced. In-hospital and 6-month follow-up mortality was 31% (110/357) in patients with solid cancer vs. 26% (637/2466), p = 0.046. CONCLUSION: Our investigation demonstrates that in-hospital mortality and mortality during 6-month follow-up in patients with acute HF were higher in those subjects with a history of concomitant solid tumor cancer diagnosis.

Determinants of ultra-processed food consumption in Brazilian children and adolescents with type 1 diabetes mellitus: a cross-sectional study.

OBJECTIVES: To analyze the determinants of UPP consumption among children and adolescents with type 1 diabetes mellitus. METHODS: Cross-sectional study at a reference hospital for the treatment of diabetes in Rio de Janeiro, Brazil. The sociodemographic, anthropometric, dietary, and clinical factors associated with the percentage of total energy intake (TEI) consumed in the form of UPP were investigated. Food consumption was assessed by 24 h recall and the foods were classified according to the degree of processing as described in the NOVA classification, after which the TEI of each food group was calculated. Multiple linear regression was adopted in the analysis, and associations with p<0.05 were considered significant. RESULTS: The study included 120 children and adolescents with a mean age of 11.74 ± 2.88 years, 53.3% female. Body mass index z-score was 0.65 (± 0.89) and 31.7% (n=38) were overweight. The average total energy consumption was 1,756.38 kcal (± 518.38). The mean percentage of TEI from UPP was 24.2% ± 17.9, meaning that 425.59 kcal (± 380.15) of all calories ingested came from such foods. The independent variables associated with the percentage of ultra-processed foods (UPP) in TEI were: per capita household income up to one the minimum wage (ß: -22.03; CI 95% -35.24 to -8.82); and parents/guardians schooling of the up to nine years in formal education (ß: 19.86; CI 95% 8.27-31.45). CONCLUSIONS: Lower household income and fewer years in formal education seem to determine a preference for UPP over fresh and minimally processed foods.

Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology.

SPLICE-q: a Python tool for genome-wide quantification of splicing efficiency.

BACKGROUND: Introns are generally removed from primary transcripts to form mature RNA molecules in a post-transcriptional process called splicing. An efficient splicing of primary transcripts is an essential step in gene expression and its misregulation is related to numerous human diseases. Thus, to better understand the dynamics of this process and the perturbations that might be caused by aberrant transcript processing it is important to quantify splicing efficiency. RESULTS: Here, we introduce SPLICE-q, a fast and user-friendly Python tool for genome-wide SPLICing Efficiency quantification. It supports studies focusing on the implications of splicing efficiency in transcript processing dynamics. SPLICE-q uses aligned reads from strand-specific RNA-seq to quantify splicing efficiency for each intron individually and allows the user to select different levels of restrictiveness concerning the introns' overlap with other genomic elements such as exons of other genes. We applied SPLICE-q to globally assess the dynamics of intron excision in yeast and human nascent RNA-seq. We also show its application using total RNA-seq from a patient-matched prostate cancer sample. CONCLUSIONS: Our analyses illustrate that SPLICE-q is suitable to detect a progressive increase of splicing efficiency throughout a time course of nascent RNA-seq and it might be useful when it comes to understanding cancer progression beyond mere gene expression levels. SPLICE-q is available at: https://github.com/vrmelo/SPLICE-q.

AIDS in the meeting of the Tapajós and Amazon rivers: deaths in the period 2010-2018 in Santarém, Pará, Brazil / AIDS no encontro dos rios Tapajós e Amazonas: óbitos no período de 2010-2018 em Santarém, Pará, Brasil

INTRODUCTION: The city of Santarém, the regional healthcare center in the western Pará State, lacks studies on the epidemic of the human immunodeficiency virus (HIV), in particular, on the causes of death. OBJECTIVE: To characterize the sociodemographic and clinical profile related to the evolution of HIV infection to death. METHODS: The sample consisted of 94 medical records of patients from a reference center in the city of Santarém-PA, who died between 2010-2018. Data were collected on the sociodemographic profile, immunological and clinical characteristics of the patients. Data were analyzed using descriptive and inferential statistics, adopting p<0.05. RESULTS: Most deaths were male (67%), aged between 15-29 years (39%) and diagnosed between 30-44 years (41%), single (54%), mixed race (91.5%), from Santarém (77%) and with sexual intercourse being the main type of exposure (95.7%). Most patients were not being treated at the moment of death (56.4%), the main cause of death was respiratory failure (5%), in which, these individuals had, at the moment of death, TCD4+ lymphocytes <200 cell/mm3 (26%) and detectable viral load (29%). CONCLUSION: The lifetime from diagnosis to death was 48.45±50,30 months, and immunosuppression in the diagnosis was positively associated with the shortest survival time. However, sex was not associated with the immunological profile, age at the time of diagnosis, and death. There was only a tendency for women towards immunosuppression and detectable viral load.

INTRODUÇÃO: A cidade de Santarém, o polo assistencial da região oeste do Pará, carece de estudos sobre a epidemia do vírus da imunodeficiência humana (HIV), especialmente, sobre as causas de óbitos. OBJETIVO: Caracterizar o perfil sociodemográfico e clínico relacionado à evolução da infecção pelo HIV até a morte. MÉTODO: A amostra foi de 94 prontuários de pacientes de um centro de referência do município de Santarém-PA, que evoluíram a óbito entre os anos de 2010-2018. Foram levantados os dados sobre o perfil sociodemográfico, características imunológicas e clínicas dos pacientes. Os dados foram analisados por estatística descritiva e inferencial, adotando-se p<0,05. RESULTADOS: A maioria dos óbitos foi de indivíduos do sexo masculino (67%), com faixa etária do diagnóstico entre 15-29 anos (39%) e de falecimento entre 30-44 anos (41%), solteiros (54%), pardos (91,5%), procedentes de Santarém (77%) e com a relação sexual sendo o principal tipo de exposição (95,7%). A maioria dos pacientes não estava em tratamento no momento do óbito (56,4%), a principal causa de morte foi por insuficiência respiratória (5%), no qual, esses indivíduos apresentavam, no momento da morte, linfócitos TCD4+ <200 cél/mm3 (26%) e carga viral detectável (29%). CONCLUSÃO: O tempo de vida do diagnóstico ao óbito foi de 48,45±50,30 meses e a presença de imunossupressão no diagnóstico associou-se positivamente com o menor tempo de sobrevida. Contudo, o sexo não apresentou associação com o perfil imunológico, a idade no momento do diagnóstico e do óbito, apenas notou-se uma tendência das mulheres para a imunossupressão e carga viral detectável.

Association between social isolation, level of physical activity and sedentary behavior in pandemic times / Associação de isolamento social, nível de atividade física e comportamento sedentário em tempos pandêmicos / Asociación entre el aislamiento social, el nivel de actividad física y la conducta sedentaria en tiempos de pandemia

Objective: To analyze the association between social isolation (SI), physical activity level (PAL) and sedentary behavior in the university community in pandemic times. Methods: A cross-sectional epidemiological study was carried out from May 7 to June 4, 2020, with 194 participants linked to the Federal University of Jataí Universidade Federal de Jataí ­ UFJ), in Goiás, Brazil. Data were collected using a form created on Google Forms® and sent to the email addresses of the academic community of UFJ to assess socioeconomic characteristics, lifestyle, body composition, physical activity level, and sedentary behavior, taking into account the periods prior to and during SI. Data were analyzed using descriptive and inferential statistics, with p<0.05 considered significant. Results: The study participants were predominantly women (n=141; 72.6%), 18-27 years old (n=100; 71%), single(n=96; 68%), students (n=110; 78%), and had no pre-existing diseases (n=94; 67%). Increases in the body mass and body massindex (BMI) (p<0.05) were observed during SI, and physical activity downtime increased for all participants, regardless of sex(p<0.05). Conclusion: SI recommended by health managers due to the pandemic caused by COVID-19 was responsible for inducing an increase in body mass and BMI accompanied by an increase in screen time during the week, as well as a decrease in the PAL of individuals belonging to the community of university students of UFJ. Descriptors: Coronavirus Infections; Sedentary Behavior; Motor Activity.

Objetivo: Analisar a associação de isolamento social (IS), nível de atividade física (NAF) e comportamento sedentário na comunidade universitária em tempos pandêmicos. Métodos: Estudo epidemiológico transversal realizado no período de 7 de maio a 4 de junho de 2020 com 194 participantes vinculados à Universidade Federal de Jataí (UFJ), Goiás, Brasil. Para coleta de dados, foi enviado ao e-mail da comunidade acadêmica da UFJ um formulário criado no Google Forms® para avaliar as características socioeconômicas, os hábitos de vida, a composição corporal, o nível de atividade física e o comportamento sedentário, levando em consideração o período anterior e durante o IS. Os dados foram analisados por estatística descritiva e inferencial, com p<0,05. Resultados: Os participantes do estudo foram, predominantemente, mulheres (n=141; 72,6%), na faixa etária de 18-27 anos (n=100; 71%), solteiras (n=96; 68%), discentes (n=110; 78%), com ausência de doenças pré-existentes(n=94; 67%). Durante o IS ocorreu aumento da massa corporal e do índice de massa corporal (IMC) dos indivíduos (p<0,05). Além disso, o tempo de inatividade física aumentou para todos os indivíduos, independente do sexo (p<0,05). Conclusão: O IS proporcionado pelos gestores de saúde em decorrência da pandemia ocasionada pela COVID-19 foi responsável por induzir um aumento da massa corporal e do IMC, acompanhado pela elevação do tempo de tela durante a semana e a diminuição do NAF dos indivíduos pertencentes à comunidade universitária da UFJ.

Objetivo: Analizar la asociación entre el aislamiento social (AS), el nivel de actividad física (NAF) y la conducta sedentaria de la comunidad universitaria en tiempos de pandemia. Métodos: Estudio epidemiológico transversal realizado entre el 07 de mayo y el 4 de junio de 2020 con 194 participantes de la Universidad Federal de Jataí (UFJ), Goiás, Brazil. La recogida de datos se dio a través de un formulario del Google Forms® que ha sido enviado para el correo electrónico de la comunidad académica de la UFJ para la obtención de las características socioeconómicas, el estilo de vida, la composición corporal, el nivel de actividad física y la conducta sedentaria en el periodo antes y durante el AS. Se ha utilizado la estadística descriptiva e inferencial para el análisis de datos con p<0,05. Resultados: Los participantes del estudio eran predominantemente mujeres (n=141; 72.6%), entre 18 y 27 años de edad (n=100; 71%), solteras (n=96; 68%), estudiantes (n=110; 78%) sin enfermedades anteriores (n=94; 67%). Durante el AS ha sido observado el aumento en la masa corporal y en el Índice de Masa Corporal (IMC) (p<0.05) y la inactividad física ha aumentado para todos los participantes, independientemente del sexo (p<0.05). Conclusión: El AS proporcionado por los gestores de salud debido a la pandemia de la COVID-19 ha sido responsable por inducir el aumento en la masa corporal yen el IMC asociado con el aumento del tiempo de tela durante la semana así como la disminución del NAF de los individuos de la comunidad de estudiantes universitarios de la UFJ.

Acessos cirúrgicos combinados para tratamento de fraturas em assoalho orbital e lâmina papirácea: relato de caso / Combined surgical accesses for treatment of fractures in the orbital floor and lamina papyracea: case repor

A região orbitária é bastante suscetível a traumas, visto que apresenta uma posição exposta, além de ser composta por ossos frágeis. Quando indicada, é preciso intervenção cirúrgica para preservar a função visual e harmonia facial do paciente. Os acessos transconjuntival e transcaruncular são descritos na literatura como formas seguras, rápidas, funcionais e esteticamente benéficas para a abordagem ao assoalho orbitário e lâmina papirácea. Sobre os materiais biocompatíveis utilizados, a placa de titânio é inabsorvível e permite fixação interna rígida, moldada às curvaturas naturais dos ossos, com baixo risco de infecção. As folhas de polietileno poroso são polímeros inertes e não absorvíveis que facilitam o crescimento de tecido e reduzem as chances de rejeição. Nesse relato de caso, evidencia-se paciente masculino, 28 anos, vítima de traumatismo facial após prática esportiva que apresentou fratura de assoalho e parede medial orbitária direita, com indicação de reconstrução orbitária com acessos transconjuntival e transcaruncular para fixação de placa de titânio em assoalho da órbita direita e de folhas de polietileno poroso em lâmina papirácea à direita, respectivamente (AU)

The orbital region is quite susceptible to trauma, since it has an exposed position, besides being com-posed of fragile bones. When indicated, surgical intervention is required to preserve the patient's visual function and facial harmony. Transconjunctival and transcaruncular accesses are described in the literatu-re as safe, fast, functional and with esthetic benefits for the approach to the orbital floor and papyraceous lamina. Among the biocompatible materials used, the titanium plate does not undergo resorption and allows rigid internal fixation, being shaped to the natural curvatures of the bones, with low risk of infec-tion. Porous polyethylene sheets are inert and nonabsorbable polymers that facilitate tissue growth an reduce the chances of rejection. In this case report, a 28-year-old male patient, a victim of facial trauma after sports practice presented a fracture of the floor and the right orbital medial wall, and orbital recons-truction was indicated with transconjunctival and transcaruncular accesses for fixation of titanium plate in the floor of the right orbit and porous polyethylene sheets in papyracea leaf on the right, respectively (AU)

A Service-Oriented Platform for Approximate Bayesian Computation in Population Genetics.

Approximate Bayesian computation (ABC) is a useful technique developed for solving Bayesian inference without explicitly requiring a likelihood function. In population genetics, it is widely used to extract part of the information about the evolutionary history of genetic data. The ABC compares the summary statistics computed on simulated and observed data sets. Typically, a forward-in-time approach is used to simulate the genetic material of a population starting from an initial ancestral population and following the evolution of the individuals by advancing generation by generation under various demographic and genetic forces. This approach is computationally expensive and requires a large number of computations making the use of high-performance computing crucial for decreasing the overall response times. In this work, we propose a fully distributed web service-oriented platform for ABC that is based on forward-in-time simulations. Our proposal is based on a client-server approach. The client enables users to define simulation scenarios. The server enables efficient and scalable population simulations and can be deployed on a distributed cluster of processors or even in the cloud. It is composed of four services: a workload generator, a simulation controller, a simulation results analyzer, and a result builder. The server performs multithread simulations by executing a simulation kernel encapsulated in a proposed libgdrift library. We present and evaluate three different libgdrift library approaches whose algorithms aim to reduce execution times and memory consumption.

Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign tumor growths in multiple organs and neurological symptoms induced by mTOR hyperfunction. Because the molecular pathology is highly complex and the etiology poorly understood, we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology and suggest new targets for treatment. METHODS: We investigate the disease phenotype of TSC by neural differentiation of a human stem cell model that had been deleted for TSC2 by genome editing. Comprehensive genomic analysis was performed by RNA sequencing and ribosome profiling to obtain a detailed genome-wide description of alterations on both the transcriptional and translational level. The molecular effect of mTOR inhibitors used in the clinic was monitored and comparison to published data from patient biopsies and mouse models highlights key pathogenic processes. RESULTS: TSC2-deficient neural stem cells showed severely reduced neuronal maturation and characteristics of astrogliosis instead. Transcriptome analysis indicated an active inflammatory response and increased metabolic activity, whereas at the level of translation ribosomal transcripts showed a 5'UTR motif-mediated increase in ribosome occupancy. Further, we observed enhanced protein synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but transcriptional dysfunction persisted. CONCLUSIONS: Our results extend the understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies.

Overweight among children and adolescent with type I diabetes mellitus: prevalence and associated factors.

OBJECTIVES: Describe the overweight frequency (overweight and obesity) and identify the factors associated with this in children and adolescents with type 1 diabetes mellitus (T1DM) treated at a University Children's Hospital in Rio de Janeiro. METHODS: This is an analytical cross-sectional study, which included patients diagnosed with T1DM who had complete anthropometric data (weight and height) and excluded those using drugs with effect on weight gain, genetic syndromes, celiac disease, hypothyroidism, renal failure and other chronic diseases, and pregnant women. The data collection was referring to the last consultation, and with respect to laboratory tests, the most recent data was collected. The dependent variable was the overweight, defined as Z score ≥1. The independent variables were gender, age, insulin dose, duration of disease, lipid profile, glycated hemoglobin, type of prescribed food planning, and place of residence. A logistic regression model was built for each outcome studied, considering significant associations those with p < 0.05. RESULTS: The study included 195 patients with a mean age of 10.6 (±3.8) years, and 49.7 % (n = 97) aged less than 10 years. The overweight frequency was 40 % (n = 78). The age ≥10 years (OR 0.41; 95 % CI 0.20-0.86; p = 0.019) and the dose of insulin/kg ideal weight (OR 3.38; 95 % CI 1:55-7:39; p = 0.002) were considered the variables associated with overweight. CONCLUSIONS: There was a high prevalence of overweight, which explains strategies for promoting healthy eating habits and changing lifestyle with a focus on children and adolescents with diabetes.

mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis.

Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2(+/-) and TSC2(-/-) neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis.

Serial interactome capture of the human cell nucleus.

Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present 'serial RNA interactome capture' (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)-RNA-protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA-RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs.

The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage.

Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo.

Role of adult hippocampal neurogenesis in cognition in physiology and disease: pharmacological targets and biomarkers.

Adult hippocampal neurogenesis is a remarkable form of brain structural plasticity by which new functional neurons are generated from adult neural stem cells/precursors. Although the precise role of this process remains elusive, adult hippocampal neurogenesis is important for learning and memory and it is affected in disease conditions associated with cognitive impairment, depression, and anxiety. Immature neurons in the adult brain exhibit an enhanced structural and synaptic plasticity during their maturation representing a unique population of neurons to mediate specific hippocampal function. Compelling preclinical evidence suggests that hippocampal neurogenesis is modulated by a broad range of physiological stimuli which are relevant in cognitive and emotional states. Moreover, multiple pharmacological interventions targeting cognition modulate adult hippocampal neurogenesis. In addition, recent genetic approaches have shown that promoting neurogenesis can positively modulate cognition associated with both physiology and disease. Thus the discovery of signaling pathways that enhance adult neurogenesis may lead to therapeutic strategies for improving memory loss due to aging or disease. This chapter endeavors to review the literature in the field, with particular focus on (1) the role of hippocampal neurogenesis in cognition in physiology and disease; (2) extrinsic and intrinsic signals that modulate hippocampal neurogenesis with a focus on pharmacological targets; and (3) efforts toward novel strategies pharmacologically targeting neurogenesis and identification of biomarkers of human neurogenesis.

Characterization of a human pluripotent stem cell-derived model of neuronal development using multiplexed targeted proteomics.

PURPOSE: Human pluripotent stem cell (hPSC)-derived cellular models have great potential to enable drug discovery and improve translation of preclinical insights to the clinic. We have developed a hPSC-derived neural precursor cell model for studying early events in human brain development. We present protein-level characterization of this model, using a multiplexed SRM approach, to establish reproducibility and physiological relevance; essential prerequisites for utilization of the neuronal development model in phenotypic screening-based drug discovery. EXPERIMENTAL DESIGN: Profiles of 246 proteins across three key stages of in vitro neuron differentiation were analyzed by SRM. Three independently hPSC-derived isogenic neural stem cell (NSC) lines were analyzed across five to nine independent neuronal differentiations. RESULTS: One hundred seventy-five proteins were reliably quantified revealing a time-dependent pattern of protein regulation that reflected protein dynamics during in vivo brain development and that was conserved across replicate differentiations and multiple cell lines. CONCLUSIONS AND CLINICAL RELEVANCE: SRM-based protein profiling enabled establishment of the reproducibility and physiological relevance of the hPSC-derived neuronal model. Combined with the successful quantification of proteins relevant to neurodevelopmental diseases, this validates the platform for use as a model to enable neuroscience drug discovery.

Anesthetic complications in a rehabilitation hospital: is the incidence related to the pre-anesthetic visit? / Complicação anestésica em hospital de reabilitação. A incidência tem relação com a consulta pré-anestésica? / Complicación anestésica en un hospital de rehabilitación. ¿La incidencia tiene relación con la consulta preanestésica?

Introduction: Approximately 234 million surgeries are done annually worldwide. There is a growing concern for the safety of the anesthetic act, and the pre-anesthetic consultation emerges as an important and widely recommended activity, used as a preventive measure for the emergence of a complication. Objectives: To describe the complications related to anesthesia, to identify the factors that contribute to its appearance and to reflect on ways to improve clinical practice. Methods: 700 patients, 175 cases and 525 controls, were evaluated over a period of 21 months. The data obtained through the pre-anesthetic consultation were evaluated descriptively and then tested with conditional univariate and multivariate logistic regression analysis. Results: 175 cases of anesthesia-related complications (2.74%) out of 6365 anesthetic acts were evaluated. Hypotension was the most common complication (40 patients, 22.8%), followed by vomiting (24 patients, 13.7%) and arrhythmia (24 patients, 13.7%). Among the complications, 55% were due to patient conditions, 26% accidental, 10% predictable and 9% iatrogenic. The complications were classified as mild in 106 (61%), moderate in 63 (36%) and severe in six (3%) patients. Conclusion: Patients with more impaired physical status (American Society of Anaesthesiology 3 and 4), with airway disease, tumor or parenchymal disease, diabetes or disorder of lipid metabolism, thyroid disease, former smokers and very prolonged anesthetic acts present a higher risk of anesthesia-related complications. Therefore, they should be actively investigated in the pre-anesthetic evaluation consultation. .

introdução: Cerca de 234 milhões de cirurgias são feitas anualmente no mundo. É cada vez maior o interesse pela segurança do ato anestésico e a consulta pré-anestésica surge como atividade importante e amplamente recomendada, usada como medida preventiva para o surgimento de uma complicação. Objetivos: Descrever as complicações relacionadas à anestesia, identificar os fatores que contribuem para o seu surgimento e refletir sobre formas de melhoria na prática clínica. Métodos: foram avaliados 700 pacientes, 175 casos e 525 controles, em um período de 21 meses. Os dados obtidos por meio da consulta pré-anestésica foram avaliados descritivamente e em seguida testados com regressão logística condicional univariada e multivariada. Resultados: Foram avaliados 175 casos de complicação relacionada à anestesia (2,74%) dentre 6.365 atos anestésicos. A hipotensão foi a complicação mais comum (40 casos, 22,8%), seguida do vômito (24%, 13,7%) e arritmia (24%, 13,7%). Das complicações, 55% foram devidas às condições do paciente, 26% acidentais, 10% previsíveis e 9% iatrogênicas. As complicações foram classificadas como leves em 106 pacientes (61%), moderadas em 63 (36%) e graves em seis (3%). Conclusão: Pacientes com estado físico mais debilitado (ASA 3 e 4), com doença de vias aéreas, tumor ou doença parenquimatosa, com diabetes ou transtorno do metabolismo lipídico, com doença de tireoide, ex-fumantes e as anestesias muito prolongadas apresentam maior risco de complicações relacionadas à anestesia e, por isso, devem ser investigados ativamente na consulta de avaliação pré-anestésica. .

Introducción: Cerca de 234 millones de cirugías se hacen anualmente en todo el mundo. Cada vez crece más el interés por la seguridad de la anestesia, y la consulta preanestésica surge como una actividad importante y ampliamente recomendada, usada como medida preventiva para el surgimiento de una complicación. Objetivos: Describir las complicaciones relacionadas con la anestesia, identificar los factores que contribuyen a su aparición y reflexionar sobre las formas de mejorar la práctica clínica. Métodos: Se evaluaron 700 pacientes, 175 casos y 525 controles, en un período de 21 meses. Los datos que se obtuvieron por medio de la consulta preanestésica se calcularon descriptivamente y enseguida fueron testados con la regresión logística condicional univariada y multivariada. Resultados: Fueron evaluados 175 casos de complicación relacionada con la anestesia (2,74%) entre 6.365 anestesias practicadas. La hipotensión fue la complicación más común (40 casos; 22,8%), seguida del vómito (24%; 13,7%) y de la arritmia (24%; 13,7%). De las complicaciones, un 55% de debieron a las condiciones del paciente, un 26% accidentales, un 10% previsibles y un 9% iatrogénicas. Las complicaciones fueron clasificadas como leves en 106 pacientes (61%), moderadas en 63 (36%) y graves en 6 (3%). Conclusión: Los pacientes con estado físico más debilitado (ASA 3 y 4), con enfermedad de vías aéreas, tumor o enfermedad parenquimatosa, con diabetes o trastorno del metabolismo lipídico, con enfermedad de la tiroides, exfumadores y las anestesias muy prolongadas presentan un mayor riesgo de complicaciones relacionadas con la anestesia y por eso deben ser investigados activamente en la consulta de evaluación preanestésica. .

[Anesthetic complications in a rehabilitation hospital: is the incidence related to the pre-anesthetic visit?]. / Complicação anestésica em hospital de reabilitação. A incidência tem relação com a consulta pré-anestésica?

INTRODUCTION: Approximately 234 million surgeries are done annually worldwide. There is a growing concern for the safety of the anesthetic act, and the pre-anesthetic consultation emerges as an important and widely recommended activity, used as a preventive measure for the emergence of a complication. OBJECTIVES: To describe the complications related to anesthesia, to identify the factors that contribute to its appearance and to reflect on ways to improve clinical practice. METHODS: 700 patients, 175 cases and 525 controls, were evaluated over a period of 21 months. The data obtained through the pre-anesthetic consultation were evaluated descriptively and then tested with conditional univariate and multivariate logistic regression analysis. RESULTS: 175 cases of anesthesia-related complications (2.74%) out of 6365 anesthetic acts were evaluated. Hypotension was the most common complication (40 patients, 22.8%), followed by vomiting (24 patients, 13.7%) and arrhythmia (24 patients, 13.7%). Among the complications, 55% were due to patient conditions, 26% accidental, 10% predictable and 9% iatrogenic. The complications were classified as mild in 106 (61%), moderate in 63 (36%) and severe in six (3%) patients. CONCLUSION: Patients with more impaired physical status (American Society of Anaesthesiology 3 and 4), with airway disease, tumor or parenchymal disease, diabetes or disorder of lipid metabolism, thyroid disease, former smokers and very prolonged anesthetic acts present a higher risk of anesthesia-related complications. Therefore, they should be actively investigated in the pre-anesthetic evaluation consultation.

Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency.

Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function.

Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance.

Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.