RESUMO
Longitudinal dissociation of the aggregated specialized cardiomyocytes within the non-branching portion of atrioventricular conduction axis has proved a controversial topic for both morphologists and electrophysiologists. We have now used morphological methods, including three-dimensional assessment, to revisit, in human, canine, and bovine hearts, the presence or absence of interconnections between the aggregated cardiomyocytes making up the non-branching bundle. We analyzed three datasets from human and canine hearts, and two from bovine hearts, using longitudinal and orthogonal serial histological sections. In addition, we assessed three hearts using translucent India ink injected specimens, permitting assessment of the three-dimensional arrangement of the cardiomyocytes. Using the longitudinal sections, we found numerous oblique interconnections between the groups of specialized cardiomyocytes. When assessing orthogonal sections, we noted marked variation in the grouping of the cardiomyocytes. We interpreted this finding as evidence of bifurcation and convergence of the groups seen in the longitudinal sections. The three-dimensional assessment of the bovine material confirmed the presence of the numerous interconnections. The presence of multiple connections between the cardiomyocytes in the non-branching bundle rules out the potential for longitudinal dissociation.
Assuntos
Nó Atrioventricular , Sistema de Condução Cardíaco , Animais , Cães , Bovinos , Humanos , Sistema de Condução Cardíaco/anatomia & histologia , Nó Atrioventricular/patologia , Fascículo Atrioventricular/patologiaRESUMO
The cerebrovascular system provides crucial functions that maintain metabolic and homeostatic states of the brain. Despite its integral role of supporting cerebral viability, the topological organization of these networks remains largely uncharacterized. This void in our knowledge surmises entirely from current technological limitations that prevent the capturing of data through the entire depth of the brain. We report high-resolution reconstruction and analysis of the complete vascular network of the entire brain at the capillary level in adult female and male mice using a vascular corrosion cast procedure. Vascular network analysis of the whole brain revealed sex-related differences of vessel hierarchy. In addition, region-specific network analysis demonstrated different patterns of angioarchitecture between brain subregions and sex. Furthermore, our group is the first to provide a three-dimensional analysis of the angioarchitecture and network organization in a single reconstructed tomographic data set that encompasses all hierarchy of vessels in the brain of the adult mouse.
Assuntos
Encéfalo/irrigação sanguínea , Imageamento Tridimensional/métodos , Neuroimagem/métodos , Microtomografia por Raio-X/métodos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Evidence of executive dysfunction in autism spectrum disorders (ASD) across development remains mixed and establishing its role is critical for guiding diagnosis and intervention. The primary objectives of this meta-analysis is to analyse executive function (EF) performance in ASD, the fractionation across EF subdomains, the clinical utility of EF measures and the influence of multiple moderators (for example, age, gender, diagnosis, measure characteristics). The Embase, Medline and PsychINFO databases were searched to identify peer-reviewed studies published since the inclusion of Autism in DSM-III (1980) up to end of June 2016 that compared EF in ASD with neurotypical controls. A random-effects model was used and moderators were tested using subgroup analysis. The primary outcome measure was Hedges' g effect size for EF and moderator factors. Clinical sensitivity was determined by the overlap percentage statistic (OL%). Results were reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 235 studies comprising 14 081 participants were included (N, ASD=6816, Control=7265). A moderate overall effect size for reduced EF (Hedges' g=0.48, 95% confidence interval (CI) 0.43-0.53) was found with similar effect sizes across each domain. The majority of moderator comparisons were not significant although the overall effect of executive dysfunction has gradually reduced since the introduction of ASD. Only a small number of EF measures achieved clinical sensitivity. This study confirms a broad executive dysfunction in ASD that is relatively stable across development. The fractionation of executive dysfunction into individual subdomains was not supported, nor was diagnostic sensitivity. Development of feasible EF measures focussing on clinical sensitivity for diagnosis and treatment studies should be a priority.
Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Função Executiva/fisiologia , Adolescente , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Criança , Feminino , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: While CVD risk has decreased in the general population during the last decade, the situation in patients with schizophrenia (SCZ) and bipolar disorder (BD) is unknown. METHODS: We compared CVD risk factors in patients with SCZ and BD recruited from 2002-2005 (2005 sample, N = 270) with patients recruited from 2006-2017 (2017 sample, N = 1011) from the same catchment area in Norway. The 2017 sample was also compared with healthy controls (N = 922) and the general population (N range = 1285-4587, Statistics Norway) from the same area and period. RESULTS: Patients with SCZ and BD in the 2017 sample had significantly higher level of most CVD risk factors compared to healthy controls and the general population. There was no significant difference in the prevalence of CVD risk factors in SCZ between the 2005 and 2017 samples except a small increase in glucose in the 2017 sample. There were small-to-moderate reductions in hypertension, obesity, total cholesterol, low-density lipoprotein, systolic and diastolic blood pressure in the BD 2017 sample compared to the 2005 sample. CONCLUSION: Despite major advances in health promotion during the past decade, there has been no reduction in the level of CVD risk factors in patients with SCZ and modest improvement in BD.
Assuntos
Transtorno Bipolar/epidemiologia , Doenças Cardiovasculares/epidemiologia , Esquizofrenia/epidemiologia , Adulto , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Fatores de Risco , Adulto JovemRESUMO
Accumulating research demonstrates the potential of intranasal delivery of psychopharmacological agents to treat a range of psychiatric disorders and symptoms. It is believed that intranasal administration offers both direct and indirect pathways to deliver psychopharmacological agents to the central nervous system. This administration route provides a unique opportunity to repurpose both old drugs for new uses and improve currently approved drugs that are indicated for other administration routes. Despite this promise, however, the physiology of intranasal delivery and related assumptions behind the bypassing of the blood brain barrier is seldom considered in detail in clinical trials and translational research. In this review, we describe the current state of the art in intranasal psychopharmacological agent delivery research and current challenges using this administration route, and discuss important aspects of nose-to-brain delivery that may improve the efficacy of these new therapies in future research. We also highlight current gaps in the literature and suggest how research can directly examine the assumptions of nose-to-brain delivery of psychopharmacological agents in humans.
Assuntos
Transtornos Mentais/tratamento farmacológico , Psicotrópicos/administração & dosagem , Administração Intranasal , Animais , Humanos , Transtornos Mentais/metabolismo , Psicotrópicos/efeitos adversos , Psicotrópicos/farmacocinéticaRESUMO
The role of non-diagnostic features in the pathophysiology of autism spectrum disorders (ASDs) is unclear. Increasing evidence suggests immune system alterations in ASD may be implicated in the severity of behavioral impairment and other developmental outcomes. The primary objective of this meta-analysis was to investigate if there is a characteristic abnormal cytokine profile in ASD compared with healthy controls (HCs). We identified relevant studies following a search of MEDLINE, EMBASE, PsycINFO, Web of Knowledge and Scopus. A meta-analysis was performed on studies comparing plasma and serum concentrations of cytokines in unmedicated participants with ASD and HCs. Results were reported according to PRISMA statement. Seventeen studies with a total sample size of 743 participants with ASD and 592 HC were included in the analysis. Nineteen cytokines were assessed. Concentrations of interleukin (IL)-1beta (P<0.001), IL-6 (P=0.03), IL-8 (P=0.04), interferon-gamma (P=0.02), eotaxin (P=0.01) and monocyte chemotactic protein-1 (P<0.05) were significantly higher in the participants with ASD compared with the HC group, while concentrations of transforming growth factor-ß1 were significantly lower (P<0.001). There were no significant differences between ASD participants and controls for the other 12 cytokines analyzed. The findings of our meta-analysis identified significantly altered concentrations of cytokines in ASD compared to HCs, strengthening evidence of an abnormal cytokine profile in ASD where inflammatory signals dominate.
Assuntos
Transtorno do Espectro Autista/metabolismo , Citocinas/metabolismo , Bases de Dados Bibliográficas/estatística & dados numéricos , HumanosRESUMO
OBJECTIVE: Despite current diagnostic systems distinguishing schizophrenia (SZ) and bipolar disorder (BD) as separate diseases, emerging evidence suggests they share a number of clinical and epidemiological features, such as increased cardiovascular disease (CVD) risk. It is not well understood if poor cardiac autonomic nervous system regulation, which can be indexed non-invasively by the calculation of heart rate variability (HRV), contributes to these common CVD risk factors in both diseases. METHOD: We calculated HRV in 47 patients with SZ, 33 patients with BD and 212 healthy controls. Measures of symptom severity were also collected from the patient groups. RESULTS: Heart rate variability was significantly reduced in both these disorders in comparison with the healthy participants; however, there were no HRV differences between disorders. Importantly, these reductions were independent of the medication, age or body mass index effects. There was also preliminary evidence that patients with reduced HRV had increased overall and negative psychosis symptom severity regardless of SZ or BD diagnosis. CONCLUSION: We suggest that HRV may provide a possible biomarker of CVD risk and symptom severity in severe mental illness. Thus, our results highlight the importance of cardiometabolic screening across SZ and bipolar spectrum disorders.
Assuntos
Transtorno Bipolar/fisiopatologia , Doenças Cardiovasculares/psicologia , Frequência Cardíaca/fisiologia , Coração/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Atrial structures are important in the current era of cardiac interventions using percutaneous transcatheter procedures. Understanding their locations and component parts helps to reduce risks of procedural-related damage. The general arrangement of the myofibers that make up the atrial walls is reviewed to provide a morphologic basis for atrial conduction and potential substrates of arrhythmias. The right atrium, dominated by its appendage, is characterized by having an extensive array of pectinate muscles. These extend almost perpendicularly from the terminal crest. The left atrium has relatively smooth walls and a small tubular-shaped appendage. The myofibers show changes in orientations when traced through the thickness of the walls. Extensions of atrial myocardium onto the pulmonary veins and the superior caval vein are common. Apart from Bachmann's bundle, there are other muscular bridges of variable numbers and sizes that provide interatrial connections, connections between the left atrium and the coronary sinus, and connections between the muscular sleeves of the right pulmonary veins and the right atrium. The purpose of this review is to summarize the three-dimensional arrangement of gross atrial structures, the myoarchitecture and variations in muscular interatrial connections. These are important features in intra- and interatrial conduction.
Assuntos
Arritmias Cardíacas/patologia , Átrios do Coração/anatomia & histologia , Sistema de Condução Cardíaco/anatomia & histologia , Complicações Intraoperatórias/prevenção & controle , Miócitos Cardíacos/citologia , Arritmias Cardíacas/fisiopatologia , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/patologia , Sistema de Condução Cardíaco/fisiopatologia , HumanosRESUMO
Heart rate variability (HRV) is a widely used measure that reflects autonomic (parasympathetic) control of the heart. HRV has been linked with attentional performance, but it is unclear to what extent resting HRV is associated with both attention and attentional maintenance. In order to address this, we calculated HRV in seventy-four young and healthy volunteers (43 men, age: 21.6⯱â¯2.4), who completed the D2 Test of Attention (D2), which was used to calculate an index of Concentration Performance (CP) and a measure of attention maintenance, the coefficient of variation (CV). After accounting for the effects of sex and age on HRV, there was no significant association between HRV and CP (pâ¯=â¯.2), but a significant relationship between HRV and CV (pâ¯=â¯.03). Overall, our study demonstrates that attention maintenance, but not attentional performance, is associated with higher resting state HRV which suggests that attentional performance from D2 subtest-to-subtest may reflect HRV's facilitation of behaviour flexibility.
Assuntos
Atenção/fisiologia , Sistema Nervoso Autônomo/fisiologia , Frequência Cardíaca/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Autosomal dominant Alzheimer disease (AD) is caused by rare mutations in one of three specific genes. This is in contrast to idiopathic, late-onset AD (LOAD), which has a more polygenetic risk profile and represents more than 95% of cases. Previously, we have demonstrated that increased expression of microRNA (miRNA)-34a (miR-34a) in AD brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Here we report the generation of a heterozygous, conditional miR-34a overexpression mouse (miR-34a+/-(TetR-TetO-miR-34a) Transgenic Mice). Doxycycline-treated mice of either sex exhibited profound behavioral impairment compared to untreated groups with only 1-2â¯months of over-expression of miR-34a. Cognitive impairment of individual mice in T- and Y-maze tasks correlated with elevated miR-34a expression in many parts of the brain including the hippocampus and prefrontal cortex, regions which are known to be involved in this task and implicated in LOAD dysfunction. Immunocytochemistry of brain sections from mice show high amyloid ß and phosphorylated tau-specific staining in the hippocampus and cortex. Analysis of protein samples from these mice revealed that miR-34a targets specific genes involved in memory formation, amyloid precursor protein (APP) metabolism and phosphorylation-dephosphorylation of tau. Thus, our results suggest that the polygenetic dysfunction caused by miR-34a may occur in LOAD and disclose miR-34a as a potential therapeutic target. SIGNIFICANCE STATEMENT: Late-onset Alzheimer disease (LOAD) is associated with multiple gene alleles, a polygenetic profile of risk factors that is difficult to model in animals. Our approach to modeling LOAD was to produce a conditional over-expressing, miR-34a mouse using doxycycline-induction to activate expression. We observed that miR-34a over-expression results in a rapid cognitive impairment, associated with accumulation of intracellular Aß and tau hyperphosphorylation in multiple brain regions. Targets for miR-34a, including ADAM10, NMDAR 2B, and SIRT1 RNAs, were profoundly reduced by miR-34a over-expression. Collectively, these results indicate that a rapid, profound cognitive decline and Alzheimer's disease neuropathology can be induced with miR-34a over-expression, suggesting that this animal model may represent a polygenetic risk factor model for LOAD.
Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , MicroRNAs/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/metabolismo , Plasticidade Neuronal , Fosforilação , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
The Drosophila latheo (lat) gene was identified in a behavioral screen for olfactory memory mutants. The original hypomorphic latP1 mutant (Boynton and Tully, 1992) shows a structural defect in adult brain. Homozygous lethal lat mutants lack imaginal discs, show little cell proliferation in the CNS of third instar larvae, and die as early pupae. latP1 was cloned, and all of the above mentioned defects of hypomorphic or homozygous lethal lat mutants were rescued with a lat+ transgene. lat encodes a novel protein with homology to a subunit of the origin recognition complex (ORC). Human and Drosophila LAT both associate with ORC2 and are related to yeast ORC3, suggesting that LAT functions in DNA replication during cell proliferation.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila , Drosophila/genética , Memória/fisiologia , Mutação/genética , Neurônios/patologia , Condutos Olfatórios/fisiopatologia , Sequência de Aminoácidos/genética , Animais , Animais Geneticamente Modificados , Encéfalo/anormalidades , Encéfalo/patologia , Encéfalo/fisiopatologia , Divisão Celular/fisiologia , Sistema Nervoso Central/patologia , Anormalidades Congênitas/genética , Drosophila/crescimento & desenvolvimento , Transtornos da Memória/genética , Dados de Sequência Molecular , Mutação/fisiologia , Complexo de Reconhecimento de Origem , Pupa/fisiologia , Homologia de Sequência de Aminoácidos , Transcrição Gênica/genética , Transgenes/fisiologiaRESUMO
OBJECTIVE: Serum levels of procollagen type IIA N-terminal propeptide (sPIIANP) and type-II collagen helical peptide (sHELIXII) biomarkers were evaluated for variation diurnally and with physical activity and food in participants with osteoarthritis (OA) of the knee. METHODS: Forty participants with OA of at least one knee were admitted overnight to the General Clinical Research Center for serial serum sampling. Samples were obtained on the evening (6-8 pm) of Day 1 (T3, n=40); prior to rising (8 am) from bed (T0, n=40); 1 h after rising (9 am) without food consumption (T1a, n=20); 1-2 h after rising (9-10 am) with food consumption (T1, n=40); and additionally at noon, 4 h after rising (T2, n=20). sPIIANP and sHELIXII were measured by enzyme-linked immunosorbent assay. Results were analyzed using non-parametric Freidman's test with Dunn's post-hoc multiple comparison test. RESULTS: Normalized mean concentrations for sPIIANP and sHELIXII increased significantly from T0 to T1 (P<0.05). CONCLUSIONS: This is the first study to demonstrate diurnal variation of these collagen-II biomarkers in individuals with knee OA. These results suggest that serum sampling for these markers should be standardized for purposes of clinical trials.
Assuntos
Cartilagem Articular/patologia , Colágeno Tipo II/metabolismo , Osteoartrite do Joelho/patologia , Fragmentos de Peptídeos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/metabolismo , Ritmo Circadiano , Estudos de Coortes , Colágeno Tipo II/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/sangue , Fragmentos de Peptídeos/sangue , Estatística como AssuntoRESUMO
The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η2=0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.
Assuntos
Administração Intranasal/instrumentação , Transtorno do Espectro Autista/tratamento farmacológico , Cognição/efeitos dos fármacos , Ocitócicos/farmacocinética , Ocitocina/farmacocinética , Administração Intranasal/métodos , Adolescente , Adulto , Transtorno do Espectro Autista/psicologia , Cognição/fisiologia , Estudos Cross-Over , Emoções/efeitos dos fármacos , Emoções/fisiologia , Expressão Facial , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Ocitócicos/administração & dosagem , Ocitócicos/farmacologia , Ocitocina/administração & dosagem , Ocitocina/sangue , Ocitocina/farmacologia , Comportamento Social , Adulto JovemRESUMO
A new flexible sensor for in vitro experiments was developed to measure the surface potential, Phi, and its gradient, E (electric near field), at given sites of the heart. During depolarisation, E describes a vector loop from which direction and magnitude of local conduction velocity theta can be computed. Four recording silver electrodes (14 microm x 14 microm) separated by 50 microm, conducting leads, and solderable pads were patterned on a 50 microm thick polyimide film. The conductive structures, except the electrodes, were isolated with polyimide, and electrodes were chlorided. Spacer pillars mounted on the tip fulfil two functions: they keep the electrodes 70 microm from the tissue allowing non-contact recording of Phi and prevent lateral slipping. The low mass (9.1 mg) and flexibility (6.33 N/m) of the sensor let it easily follow the movement of the beating heart without notable displacement. We examined the electrodes on criteria like rms-noise of Phi, signal-to-noise ratio of Phi and E, maximum peak-slope recording dPhi/dt, and deviation of local activation time (LAT) from a common signal and obtained values of 24-28 microV, 46 and 41 dB, 497-561 V/s and no differences, respectively. With appropriate data acquisition (sampling rate 100 kHz, 24-bit), we were able to record Phi and to monitor E and theta on-line from beat-to-beat even at heart rates of 600 beats/min. Moreover, this technique can discriminate between uncoupled cardiac activations (as occur in fibrotic tissue) separated by less than 1 mm and 1 ms.
Assuntos
Mapeamento Potencial de Superfície Corporal/instrumentação , Eletrodos Implantados , Sistema de Condução Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Microeletrodos , Transdutores , Animais , Mapeamento Potencial de Superfície Corporal/métodos , Campos Eletromagnéticos , Desenho de Equipamento , Análise de Falha de Equipamento , Cobaias , Técnicas In Vitro , CamundongosRESUMO
The number of publications investigating heart rate variability (HRV) in psychiatry and the behavioral sciences has increased markedly in the last decade. In addition to the significant debates surrounding ideal methods to collect and interpret measures of HRV, standardized reporting of methodology in this field is lacking. Commonly cited recommendations were designed well before recent calls to improve research communication and reproducibility across disciplines. In an effort to standardize reporting, we propose the Guidelines for Reporting Articles on Psychiatry and Heart rate variability (GRAPH), a checklist with four domains: participant selection, interbeat interval collection, data preparation and HRV calculation. This paper provides an overview of these four domains and why their standardized reporting is necessary to suitably evaluate HRV research in psychiatry and related disciplines. Adherence to these communication guidelines will help expedite the translation of HRV research into a potential psychiatric biomarker by improving interpretation, reproducibility and future meta-analyses.
Assuntos
Lista de Checagem , Frequência Cardíaca , Psiquiatria , Relatório de Pesquisa/normas , Guias como Assunto , Humanos , Seleção de PacientesRESUMO
Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer's disease (AD) impedes identification of a target(s) for disease-modifying therapies. We identified a single microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient's tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFκB, STAT1, c-Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Metabolismo Energético , MicroRNAs/genética , Plasticidade Neuronal , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Glicólise , Humanos , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/metabolismo , Neurônios/metabolismo , Fosforilação Oxidativa , Cultura Primária de CélulasRESUMO
Approximately 5-10% of chronic myeloid leukemia (CML) patients are found to have structural or numerical additional chromosomal abnormality (ACAs) in addition to the characteristic t(9;22)(q34;q11.2) BCR/ABL1 at the time of diagnosis. The prognostic significance of such additional chromosomal abnormalities has been controversial. Translocation t(11;14)(q13;q32) CCND1-IGH is typically associated with mantle cell lymphoma or a subset of plasma cell myeloma and is exceedingly rare in myeloid neoplasm. Here we report a unique case describing a patient found at diagnosis of chronic phase CML to have both the Philadelphia chromosome as well as t(11;14)-a rare cytogenetic combination. The patient was treated with imatinib with appropriate hematologic response but persistent disease by FISH and RT-PCR. She was switched to dasatinib and eventually achieved cytogenetic remission in both translocations, but still with persistent RT-PCR evidence of BCR-ABL1 fusion. As cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6 and is required for the cells to progress through the G1 phase of the cell cycle, overexpression of cyclin D1 will likely promote cells into cell cycle. This may further augment proliferation in addition to upregulated ABL1 kinase activity in the index case. It may also contribute to the resistance to imatinib, as imatinib only targets on BCR-ABL fusion. Therefore, the addition of t(11;14)(q13;q32) may have significant implication in patient management.
Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Ciclina D1/genética , Proteínas de Fusão bcr-abl/genética , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Translocação Genética/genética , Aberrações Cromossômicas , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Pessoa de Meia-Idade , Cromossomo Filadélfia , PrognósticoRESUMO
Fourier transform-infrared spectroscopy has been used for the study of the secondary structure of arrestin from bovine retina rod cells. Spectra have been obtained in H2O and in D2O media. Resolution enhancement of the amide I secondary structure-sensitive overlapped component bands has been achieved by means of Fourier self-deconvolution and Fourier derivation. In order to obtain a quantitative estimation of the proportion of amino acid residues involved in each type of secondary structure, bands at the resolved frequencies have been curve-fitted to the deconvolved amide I contour by means of a least-squares best-fitting iterative program. The analysis of the results suggests that the secondary structure of arrestin comprises 56-63% of extended strands, 12-19% of turns and bends, 15% of alpha-helices and 10% of undefined and irregular segments.
Assuntos
Antígenos/química , Proteínas do Olho/química , Células Fotorreceptoras/química , Amidas/química , Animais , Arrestina , Bovinos , Deutério , Óxido de Deutério , Análise de Fourier , Conformação Proteica , Espectrofotometria Infravermelho/métodos , ÁguaRESUMO
BACKGROUND: Although most ablative procedures undertaken for common atrial flutter target the inferior right atrial isthmus, comparative studies of the morphology of this area are lacking. Our study examines its angiographic anatomy, making correlations with postmortem specimens, to provide a better understanding of the anatomic substrate of this arrhythmia. METHODS AND RESULTS: The gross morphological features and dimensions of the area between the orifice of the inferior caval vein and the attachment of the septal leaflet of the tricuspid valve were determined from angiograms made in 23 patients with documented atrial flutter and 30 control subjects. For comparison, we studied 20 normal heart specimens. When viewed in right anterior oblique projection, 2 morphologically distinct areas were identified. In the specimens, the inferior isthmus measured a mean length of 30+/-4 mm, not significantly different from the dimensions obtained from angiograms of control subjects. The mean length of the isthmus, however, was greater in patients with common atrial flutter than those without (37+/-8 versus 28+/-6 mm). Patients with atrial flutter and structural heart disease had an even longer isthmus than those with flutter alone (39. 6+/-8 versus 33+/-7 mm). Compared with those without flutter, the atrial diameter was also larger in patients with flutter (57.6+/-9 versus 48.5+/-6 mm). Reevaluation carried out at follow-up 10+/-2 months after ablation did not show any reduction in atrial size, although contractility improved. CONCLUSIONS: The inferior isthmus and right atrium in patients with common atrial flutter were significantly larger than those in a control population.
Assuntos
Flutter Atrial/diagnóstico por imagem , Átrios do Coração/anatomia & histologia , Átrios do Coração/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Adulto , Flutter Atrial/patologia , Autopsia , Feminino , Cardiopatias/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , RadiografiaRESUMO
PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categorized was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival. RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman's grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis. CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients' survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.