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1.
Hypertension ; 80(12): 2559-2571, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37767691

RESUMO

BACKGROUND: Children from pregnancies affected by preeclampsia have an increased risk of cognitive and behavioral alterations via unknown pathophysiology. We tested the hypothesis that preeclampsia generated reduced brain cortex angiogenesis in the offspring. METHODS: The preeclampsia-like syndrome (PELS) mouse model was generated by administering the nitric oxide inhibitor NG-nitroarginine methyl ester hydrochloride. Confirmatory experiments were done using 2 additional PELS models. While in vitro analysis used mice and human brain endothelial cells exposed to serum of postnatal day 5 pups or umbilical plasma from preeclamptic pregnancies, respectively. RESULTS: We report significant reduction in the area occupied by blood vessels in the motor and somatosensory brain cortex of offspring (postnatal day 5) from PELS compared with uncomplicated control offspring. These data were confirmed using 2 additional PELS models. Furthermore, circulating levels of critical proangiogenic factors, VEGF (vascular endothelial growth factor), and PlGF (placental growth factor) were lower in postnatal day 5 PELS. Also we found lower VEGF receptor 2 (KDR [kinase insert domain-containing receptor]) levels in mice and human endothelial cells exposed to the serum of postnatal day 5 PELS or fetal plasma of preeclamptic pregnancies, respectively. These changes were associated with lower in vitro angiogenic capacity, diminished cell migration, larger F-actin filaments, lower number of filopodia, and lower protein levels of F-actin polymerization regulators in brain endothelial cells exposed to serum or fetal plasma of offspring from preeclampsia. CONCLUSIONS: Offspring from preeclampsia exhibited diminished brain cortex angiogenesis, associated with lower circulating VEGF/PlGF/KDR protein levels, impaired brain endothelial migration, and dysfunctional assembly of F-actin filaments. These alterations may predispose to structural and functional alterations in long-term brain development.


Assuntos
Pré-Eclâmpsia , Proteínas da Gravidez , Gravidez , Criança , Feminino , Humanos , Animais , Camundongos , Fator de Crescimento Placentário/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas da Gravidez/metabolismo , Células Endoteliais/metabolismo , Encéfalo/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular
2.
Int J Mol Sci ; 23(24)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36555863

RESUMO

Amyotrophic lateral sclerosis (ALS) is a disease that progressively annihilates spinal cord motor neurons, causing severe motor decline and death. The disease is divided into familial and sporadic ALS. Mutations in the TAR DNA binding protein 43 (TDP-43) have been involved in the pathological emergence and progression of ALS, although the molecular mechanisms eliciting the disease are unknown. Transposable elements (TEs) and DNA sequences capable of transposing within the genome become dysregulated and transcribed in the presence of TDP-43 mutations. We performed RNA-Seq in human motor neurons (iMNs) derived from induced pluripotent stem cells (iPSCs) from TDP-43 wild-type-iMNs-TDP-43WT-and mutant-iMNs-TDP-43M337V-genotypes at 7 and 14 DIV, and, with state-of-the-art bioinformatic tools, analyzed whether TDP-43M337V alters both gene expression and TE activity. Our results show that TDP-43M337V induced global changes in the gene expression and TEs levels at all in vitro stages studied. Interestingly, many genetic pathways overlapped with that of the TEs activity, suggesting that TEs control the expression of several genes. TEs correlated with genes that played key roles in the extracellular matrix and RNA processing: all the regulatory pathways affected in ALS. Thus, the loss of TE regulation is present in TDP-43 mutations and is a critical determinant of the disease in human motor neurons. Overall, our results support the evidence that indicates TEs are critical regulatory sequences contributing to ALS neurodegeneration.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Elementos de DNA Transponíveis/genética , Neurônios Motores/metabolismo , Mutação , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo
3.
Int J Mol Sci ; 24(1)2022 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-36613689

RESUMO

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Doenças Musculares , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Elementos de DNA Transponíveis , Rosuvastatina Cálcica/efeitos adversos , Sinvastatina/efeitos adversos , Sinvastatina/metabolismo , Fibras Musculares Esqueléticas , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Doenças Musculares/tratamento farmacológico , Colesterol/metabolismo , Músculo Esquelético/metabolismo
4.
Neuropsychopharmacology ; 47(2): 497-506, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34689167

RESUMO

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.


Assuntos
Depressão , Estudo de Associação Genômica Ampla , Encéfalo , Pré-Escolar , Depressão/genética , Humanos , Lactente , Acontecimentos que Mudam a Vida , Fatores de Risco
5.
Int J Mol Sci ; 22(24)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34948421

RESUMO

Spatial transcriptomics (ST) is transforming the way we can study gene expression and its regulation through position-specific resolution within tissues. However, as in bulk RNA-Seq, transposable elements (TEs) are not being studied due to their highly repetitive nature. In recent years, TEs have been recognized as important regulators of gene expression, and thus, TE expression analysis in a spatially resolved manner could further help to understand their role in gene regulation within tissues. We present SpatialTE, a tool to analyze TE expression from ST datasets and show its application in somatic and diseased tissues. The results indicate that TEs have spatially regulated expression patterns and that their expression profiles are spatially altered in ALS disease, indicating that TEs might perform differential regulatory functions within tissue organs. We have made SpatialTE publicly available as open-source software under an MIT license.


Assuntos
Esclerose Lateral Amiotrófica/genética , Biologia Computacional/métodos , Elementos de DNA Transponíveis , Software , Transcriptoma , Animais , Encéfalo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Rim , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Medula Espinal , Superóxido Dismutase-1/genética
6.
PLoS One ; 16(10): e0258291, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34614020

RESUMO

Transposable Elements (TEs) are ubiquitous genetic elements with the ability to move within a genome. TEs contribute to a large fraction of the repetitive elements of a genome, and because of their nature, they are not routinely analyzed in RNA-Seq gene expression studies. Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease, and a well-accepted model for its study is the mouse harboring the human SOD1G93A mutant. In this model, landmark stages of the disease can be recapitulated at specific time points, making possible to understand changes in gene expression across time. While there are several works reporting TE activity in ALS models, they have not explored their activity through the disease progression. Moreover, they have done it at the expense of losing their locus of expression. Depending on their genomic location, TEs can regulate genes in cis and in trans, making locus-specific analysis of TEs of importance in order to understand their role in modulating gene expression. Particularly, the locus-specific role of TEs in ALS has not been fully elucidated. In this work, we analyzed publicly available RNA-Seq datasets of the SOD1G93A mouse model, to understand the locus-specific role of TEs. We show that TEs become up-regulated at the early stages of the disease, and via statistical associations, we speculate that they can regulate several genes, which in turn might be contributing to the genetic dysfunction observed in ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Elementos de DNA Transponíveis/genética , Progressão da Doença , Loci Gênicos , Superóxido Dismutase/genética , Animais , Simulação por Computador , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos Transgênicos , Mapas de Interação de Proteínas/genética , RNA-Seq , Reprodutibilidade dos Testes , Software
7.
Mob DNA ; 12(1): 23, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686213

RESUMO

The submandibular gland (SG) is a relatively simple organ formed by three cell types: acinar, myoepithelial, and an intricate network of duct-forming epithelial cells, that together fulfills several physiological functions from assisting food digestion to acting as an immune barrier against pathogens. Successful SG organogenesis is the product of highly controlled and orchestrated genetic and transcriptional programs. Mounting evidence links Transposable Elements (TEs), originally thought to be selfish genetic elements, to different aspects of gene regulation in mammalian development and disease. To our knowledge, the role of TEs during murine SG organogenesis has not been studied. Using novel bioinformatic tools and publicly available RNA-Seq datasets, our results indicate that a significant number of genic and intergenic TEs are differentially expressed during the SG development. Furthermore, changes in expression of specific TEs correlated with that of genes involved in cellular division and differentiation, critical aspects for SG maturation. Altogether, we propose that TEs modulate gene networks that operate during SG development.

8.
Sci Rep ; 10(1): 17625, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077756

RESUMO

Although cells of mushroom-producing fungi typically contain paired haploid nuclei (n + n), most Armillaria gallica vegetative cells are uninucleate. As vegetative nuclei are produced by fusions of paired haploid nuclei, they are thought to be diploid (2n). Here we report finding haploid vegetative nuclei in A. gallica at multiple sites in southeastern Massachusetts, USA. Sequencing multiple clones of a single-copy gene isolated from single hyphal filaments revealed nuclear heterogeneity both among and within hyphae. Cytoplasmic bridges connected hyphae in field-collected and cultured samples, and we propose nuclear migration through bridges maintains this nuclear heterogeneity. Growth studies demonstrate among- and within-hypha phenotypic variation for growth in response to gallic acid, a plant-produced antifungal compound. The existence of both genetic and phenotypic variation within vegetative hyphae suggests that fungal individuals have the potential to evolve within a single generation in response to environmental variation over time and space.


Assuntos
Armillaria/genética , Evolução Biológica , Hifas/genética , Esporos Fúngicos/genética , Núcleo Celular/genética , Citoplasma/genética , Diploide
9.
Animals (Basel) ; 10(7)2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32708533

RESUMO

The objective of this study was to determine the effect of mineral supplementation on the serum concentration of calcium, phosphorus, and magnesium in pre- and postpartum Blackbelly sheep throughout three successive lambing periods under free grazing conditions in the Ecuadorian Amazon Region. The field work was carried out between January 2015 and February 2018 using 20 Blackbelly sheep belonging to the Centre for Research, Postgraduate Studies and Conservation of Amazon Biodiversity, Ecuador. The flock was randomly divided into two groups: Group 1 (G1) was fed with forage plus a supplementation (Pecutrin® Mineral supplement plus vitamins A, D3, and E. Bayer HealthCare) and Group 2 (G2) was fed only with forage without mineral supplementation. Three blood samples from the coccygeal vein were taken from each sheep 30 days before lambing, 30 days after, and 60 days after lambing. Concerning the average of calcium, significant differences were found at different times inside each group and also between them (p < 0.0001 in both cases). As for the phosphorus, significant differences were found between the means of the groups for all times from 30 days after the second lambing season (p < 0.05). It was observed that the groups differed significantly in terms on the average of magnesium (considering a significance level of 0.05) 30 days before the first lambing and at all times measured from the 30 days after the second lambing (p < 0.005). In this study, we showed that Blackbelly sheep raised under free grazing conditions in the Ecuadorian Amazon Region had very low serum calcium values, and supplementation was unable to improve them. Meanwhile, phosphorus and magnesium levels were below the required values, but after supplementation, they exceeded the minimum threshold. Mineral supplementation in the rearing of sheep in grazing systems is necessary during the entire production cycle, but it must be done taking into account the soil-plant-animal relationship specifically for the Amazonian Region systems.

10.
J Chem Inf Model ; 60(8): 3935-3943, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32687361

RESUMO

Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges in achieving an accurate structural and dynamical description of many biological assemblies, particularly to coarse-grained (CG) models. Although the reduced computational cost of CG methods often makes them the technique of choice for the study of large biomolecular systems, the parameterization of metal ions is still very crude or not available for the vast majority of CG force fields. Here, we show that incorporating statistical data retrieved from the Protein Data Bank (PDB) to set specific Lennard-Jones interactions can produce structurally accurate CG molecular dynamics simulations using the SIRAH force field. We provide a set of interaction parameters for calcium, magnesium, and zinc ions, which cover more than 80% of the metal-bound structures reported in the PDB. Simulations performed on several proteins and DNA systems show that it is possible to preclude the use of topological constraints by modifying specific Lennard-Jones interactions.


Assuntos
Simulação de Dinâmica Molecular , Proteínas , Cátions Bivalentes , DNA , Bases de Dados de Proteínas
12.
Acta Neuropathol Commun ; 7(1): 147, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31514753

RESUMO

The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.


Assuntos
Neurônios Motores/fisiologia , Junção Neuromuscular/fisiologia , Receptores de Fator de Crescimento Neural/fisiologia , Vesículas Sinápticas/fisiologia , Animais , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Neurônios Motores/ultraestrutura , Junção Neuromuscular/ultraestrutura , Receptores de Fator de Crescimento Neural/genética , Vesículas Sinápticas/ultraestrutura
13.
J Mol Med (Berl) ; 97(8): 1085-1097, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31129757

RESUMO

Our data proposes that glucose is transferred directly to the cerebrospinal fluid (CSF) of the hypothalamic ventricular cavity through a rapid "fast-track-type mechanism" that would efficiently stimulate the glucosensing areas. This mechanism would occur at the level of the median eminence (ME), a periventricular hypothalamic zone with no blood-brain barrier. This "fast-track" mechanism would involve specific glial cells of the ME known as ß2 tanycytes that could function as "inverted enterocytes," expressing low-affinity glucose transporters GLUT2 and GLUT6 in order to rapidly transfer glucose to the CSF. Due to the large size of tanycytes, the presence of a high concentration of mitochondria and the expression of low-affinity glucose transporters, it would be expected that these cells accumulate glucose in the endoplasmic reticulum (ER) by sequestering glucose-6-phosphate (G-6-P), in a similar way to that recently demonstrated in astrocytes. Glucose could diffuse through the cells by micrometric distances to be released in the apical region of ß2 tanycytes, towards the CSF. Through this mechanism, levels of glucose would increase inside the hypothalamus, stimulating glucosensing mechanisms quickly and efficiently. KEY MESSAGES: • Glucose diffuses through the median eminence cells (ß2 tanycytes), towards the hypothalamic CSF. • Glucose is transferred through a rapid "fast-track-type mechanism" via GLUT2 and GLUT6. • Through this mechanism, hypothalamic glucose levels increase, stimulating glucosensing.


Assuntos
Barreira Hematoencefálica/metabolismo , Glucose/metabolismo , Hipotálamo/metabolismo , Mitocôndrias/metabolismo , Animais , Transporte Biológico Ativo/fisiologia , Regulação da Expressão Gênica/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley
14.
Arch Gerontol Geriatr ; 80: 70-75, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30390427

RESUMO

OBJECTIVE: To determine the prevalence and to characterize frailty in elderly subjects in four urban provincial capitals and two rural communes from Maule Region in Chile. DESIGN: Cross-sectional study. PARTICIPANTS: 1205 participants aged 65 and older. METHODS: The dataset was obtained from the PIEI-ES Study. Frailty syndrome was determined according to the criteria proposed by Fried. Data collection included questionnaires. RESULTS: The study sample included 1205 individuals, of which 68% were females. Mean age was 73 years. The overall prevalence of frailty was 24.6%. Increase prevalence of frailty was observed in people 80 years old and older, both in women and men. Using adjusted logistic regression, advanced frailty state was more likely to occur in subjects with cognitive impairment. CONCLUSION: This study provides evidence that frailty may be related with cognitive functioning, educational level and nutritional status in older adults.


Assuntos
Fragilidade/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Chile/epidemiologia , Disfunção Cognitiva/complicações , Estudos Transversais , Feminino , Idoso Fragilizado/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Prevalência , População Rural
15.
Rev. Fac. Cienc. Méd. Univ. Cuenca ; 36(2): 37-45, Noviembre 2018. tab
Artigo em Espanhol | LILACS | ID: biblio-998639

RESUMO

La exposición a sustancias psicoactivas puede predisponer al individuo a padecer alteraciones de orden cognitivo. La atención y la memoria son las funciones que comúnmente se afectan. Objetivo:El presente estudio evaluó los niveles de atención y memoria en pacientes con trastorno por consumo de sustancia en tres centros especializados. Método:Estudio exploratorio-descriptivo con 60 participantes. La evaluación neuropsicológica se realizó con la batería Neuropsi para atención y memoria. El análisis se realizó mediante estadística descriptiva con frecuencias y porcentajes. Resultados: Se observó que la población investigada presentó un mayor deterioro en el área de memoria con un 70% y en la atención 33.3% de déficit. La memoria de trabajo se encuentra conservada en la mayoría de participantes. Conclusiones:Los resultados indican que el deterioro cognitivo en los niveles de atención y memoria están presentes en sujetos con trastorno por consumo de sustancias, siendo la memoria la función más afectada.


The exposure to psychoactive substances may predispose the individual to suffer alterations cognitive order. Attention and memory are the functions that are commonly affected. Objetive:The present study evaluated the levels of attention and memory in patients with use disorder by substance use in three specialized centers. Method:It is an exploratory-descriptive study with a 60 participants. The neuropsychological evaluation was performed with the Neuropsi battery for attention and memory. The analysis was carried out using descriptive statistics with frequencies and percentages.Results: In this case was observed that the researched population showed a greater deterioration in the area of memory with a 70% of alteration, while in the attention was evidenced 33.3% of deficit. Working memory is preserved in most of the population. Conclusions:The results indicate that cognitive deterioration in attention and memory levels are present in subjects with substance use disorder being the memory the most affected function. There was not a considerable relationship between the time of consumption and cognitive damage.


Assuntos
Humanos , Atenção , Transtornos Relacionados ao Uso de Substâncias , Memória , Disfunção Cognitiva , Memória de Curto Prazo , Neuropsicologia
16.
Sci Rep ; 8(1): 14491, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262876

RESUMO

A challenging aspect of neuroscience revolves around mapping the synaptic connections within neural circuits (connectomics) over scales spanning several orders of magnitude (nanometers to meters). Despite significant improvements in serial section electron microscopy (SSEM) technologies, several major roadblocks have impaired its general applicability to mammalian neural circuits. In the present study, we introduce a new approach that circumvents some of these roadblocks by adapting a genetically-encoded ascorbate peroxidase (APEX2) as a fusion protein to a membrane-targeted fluorescent reporter (CAAX-Venus), and introduce it in single pyramidal neurons in vivo using extremely sparse in utero cortical electroporation. This approach allows us to perform Correlated Light-SSEM (CoLSSEM), a variant of Correlated Light-EM (CLEM), on individual neurons, reconstructing their dendritic and axonal arborization in a targeted way via combination of high-resolution confocal microscopy, and subsequent imaging of its ultrastructural features and synaptic connections with ATUM-SEM (automated tape-collecting ultramicrotome - scanning electron microscopy) technology. Our method significantly will improve the feasibility of large-scale reconstructions of neurons within a circuit, and permits the description of some ultrastructural features of identified neurons with their functional and/or structural connectivity, one of the main goal of connectomics.


Assuntos
Conectoma/métodos , Imageamento Tridimensional/métodos , Microscopia Eletrônica de Varredura/métodos , Células Piramidais/ultraestrutura , Animais , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Endonucleases/genética , Endonucleases/metabolismo , Feminino , Camundongos , Camundongos Transgênicos , Enzimas Multifuncionais , Células Piramidais/metabolismo
17.
Clin Gerontol ; 41(2): 130-135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28960164

RESUMO

OBJECTIVES: To examine relationships between cognitive expectancies about sleep and hypnotics and use of medications commonly used for insomnia (hypnotics). METHODS: We analyzed baseline data from older veterans who met diagnostic criteria for insomnia and were enrolled in a trial comparing CBTI delivered by a supervised, sleep educator to an attention control condition (N = 159; 97% male, mean age 72 years). We classified individuals as hypnotic users (N = 23) vs. non-users (N = 135) based upon medication diaries. Associations between hypnotic status and Dysfunctional Beliefs and Attitudes about Sleep-16 (DBAS) total score (0-10, higher = worse) and two DBAS medication item scores (Item 1: "…better off taking a sleeping pill rather than having a poor night's sleep;" Item 2: "Medication… probably the only solution to sleeplessness"; 0-10, higher = worse) were examined in logistic regression models. RESULTS: Higher scores on the DBAS medication items (both odds ratios = 1.3; p-values < .001) were significantly associated with hypnotic use. DBAS-16 total score was not associated with hypnotic use. CONCLUSION: Cognitive expectancy (dysfunctional beliefs) about hypnotics was associated with hypnotic use in older adults with chronic insomnia disorder. CLINICAL IMPLICATIONS: Strategies that specifically target dysfunctional beliefs about hypnotics are needed and may impact hypnotic use in older adults.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Hipnóticos e Sedativos/uso terapêutico , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/terapia , Idoso , Terapia Cognitivo-Comportamental , Estudos Transversais , Feminino , Humanos , Masculino , Distúrbios do Início e da Manutenção do Sono/psicologia , Veteranos/psicologia
18.
Proc Natl Acad Sci U S A ; 114(39): E8294-E8303, 2017 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-28904095

RESUMO

Mutations in autophagy genes can cause familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of autophagy in ALS pathogenesis is poorly understood, in part due to the lack of cell type-specific manipulations of this pathway in animal models. Using a mouse model of ALS expressing mutant superoxide dismutase 1 (SOD1G93A), we show that motor neurons form large autophagosomes containing ubiquitinated aggregates early in disease progression. To investigate whether this response is protective or detrimental, we generated mice in which the critical autophagy gene Atg7 was specifically disrupted in motor neurons (Atg7 cKO). Atg7 cKO mice were viable but exhibited structural and functional defects at a subset of vulnerable neuromuscular junctions. By crossing Atg7 cKO mice to the SOD1G93A mouse model, we found that autophagy inhibition accelerated early neuromuscular denervation of the tibialis anterior muscle and the onset of hindlimb tremor. Surprisingly, however, lifespan was extended in Atg7 cKO; SOD1G93A double-mutant mice. Autophagy inhibition did not prevent motor neuron cell death, but it reduced glial inflammation and blocked activation of the stress-related transcription factor c-Jun in spinal interneurons. We conclude that motor neuron autophagy is required to maintain neuromuscular innervation early in disease but eventually acts in a non-cell-autonomous manner to promote disease progression.


Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Autofagia , Neurônios Motores/enzimologia , Superóxido Dismutase-1/metabolismo , Superóxido Dismutase/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Neurônios Motores/patologia , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética
19.
Sleep ; 40(8)2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28482053

RESUMO

Study Objective: To test the effectiveness of a 4-week behavioral Sleep Intervention Program (SIP: sleep compression, modified stimulus control, and sleep hygiene) compared to a 4-week information-only control (IC) among older adults attending a VA Adult Day Health Care (ADHC) program in a double-blind, randomized, clinical trial. Methods: Forty-two individuals (mean age: 77 years, 93% male) enrolled in a VA ADHC program were randomized to receive SIP or IC. All completed in-person sleep and health assessments at baseline, post-treatment and 4-months follow-up that included 3 days/nights of wrist actigraphy, the Pittsburgh Sleep Quality Index (PSQI), and the Insomnia Severity Index (ISI). Mixed repeated measures analysis was used to compare sleep outcomes at post-treatment and 4-months follow-up, with baseline values as covariates. Results: SIP participants (n = 21) showed significant improvement on actigraphy sleep efficiency (p = .007), number of nighttime awakenings (p = .016), and minutes awake at night (p = .001) at post-treatment, compared to IC participants (n = 21). Benefits were slightly attenuated but remained significant at 4-month follow-up (all p's < .05). There were no differences in total sleep time between groups. There was significant improvement on PSQI factor 3 (daily disturbances) at 4-month follow-up (p = .016), but no differences were observed between SIP and IC on other PSQI components or ISI scores at post-treatment or 4-month follow-up. Conclusions: A short behavioral sleep intervention may have important benefits in improving objectively measured sleep in older adults participating in ADHC. Future studies are needed to study implementation of this intervention into routine clinical care within ADHC.


Assuntos
Terapia Comportamental , Distúrbios do Início e da Manutenção do Sono/terapia , Medicina do Sono/métodos , Sono/fisiologia , Actigrafia , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Resultado do Tratamento
20.
Rev. méd. Hosp. José Carrasco Arteaga ; 9(1): 28-35, MARZO 2017. Tablas, Gáficos
Artigo em Espanhol | LILACS | ID: biblio-1017336

RESUMO

INTRODUCCIÓN: La cirugía bariátrica constituye en la actualidad una alternativa terapéutica eficaz en pacientes con obesidad y comorbilidades. El objetivo fue describir los resultados obtenidos en una serie de pacientes tratados con cirugía bariátrica en el Hospital de Especialidades José Carrasco Arteaga. MÉTODO: Estudio descriptivo, longitudinal y retrospectivo realizado en los pacientes tratados con cirugía bariátrica e ingresados en el departamento de Cirugía del Hospital de Especialidades José Carrasco Arteaga durante el periodo comprendido entre 2009 y 2013. Se estudiaron las medidas antropométricas, niveles de glicemia, perfil lipídico (colesterol, triglicéridos y HDL) y los niveles de tensión arterial previos a la cirugía y 3 controles posteriores (tercer, sexto y duodécimo mes posquirúrgico) para proceder a describir los resultados y compararlos en el tiempo de seguimiento. RESULTADOS: Se estudiaron 71 pacientes con diagnóstico de obesidad mórbida (81.5 % mujeres y 18.5 % varones) con una edad media de 44 ±10 años. El peso medio prequirúrgico fue de 110.16 ±18.6 kg y el IMC de 42.6 ±46 Kg/m2. Al tercer mes, sexto mes y un año después del procedimiento quirúrgico, el IMC promedio fue de 34.54 Kg/m2, 31.64 Kg/m2 y 30.36 Kg/m2 respectivamente. El 90.8 % de los pacientes con dislipidemia, el 100 % de los diabéticos y el 98.5 % de los hipertensos normalizaron sus perfiles correspondientes tras 12 meses. El 7.04 % de los pacientes presentaron complicaciones posquirúrgicas y la mortalidad alcanzó un 5.6 %. CONCLUSIÓN: La cirugía bariátrica constituye un procedimiento útil en la actualidad para el control de la obesidad en sus distintos grados y la reducción de los efectos de las comorbilidades asociadas a ésta como la hipertensión, diabetes y dislipidemia.(au)


BACKGROUND: Bariatric surgery is consideredan effective treatment option in patients with obesity and comorbidities. The aim was to describe the results of bariatric surgery in patients from José Carrasco Arteaga Specialities Hospital. METHODS: A retrospective longitudinal descriptive study was performed in patients treated with bariatric surgery and admitted to Surgery department at José Carrasco Arteaga Specialities Hospital from 2009 to 2013. Anthropometric measures, glucose blood levels, lipid panel (cholesterol, triglycerides and HDL) and blood pressure measures were registered before the surgery and three, six and twelve months after it to describe the results and compare them through follow-up. RESULTS: 71 patients diagnosed with morbid obesity (81.5 % male and 18.5 % female) were studied; their mean age was 45 ±10 years. Average preoperative weight was 110.16 ±18.6 kg and BMI was 42.6 ±4.6 kg/m2. BMI decreased to 34.54kg/m2, 31.64kg/m2 and 30.36kg/m2 after three, six and twelve months respectively. 90.8 % of patients with dyslipidemia, 100 % of diabetics and 98.5 % of hypertensive patients had normal values of their profiles after 12 months. Postoperative complications represented 7.04 % and mortality rate reached 5.6 %. CONCLUSION: Bariatric surgery is a useful procedure to control obesity and the effects associated to its comorbidities such as arterial hypertension, diabetes and dyslipidemia.(au)


Assuntos
Humanos , Masculino , Feminino , Comorbidade , Cirurgia Bariátrica , Obesidade/terapia , Estado Nutricional
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