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To fully understand how the human brain works, knowledge of its structure at high resolution is needed. Presented here is a computationally intensive reconstruction of the ultrastructure of a cubic millimeter of human temporal cortex that was surgically removed to gain access to an underlying epileptic focus. It contains about 57,000 cells, about 230 millimeters of blood vessels, and about 150 million synapses and comprises 1.4 petabytes. Our analysis showed that glia outnumber neurons 2:1, oligodendrocytes were the most common cell, deep layer excitatory neurons could be classified on the basis of dendritic orientation, and among thousands of weak connections to each neuron, there exist rare powerful axonal inputs of up to 50 synapses. Further studies using this resource may bring valuable insights into the mysteries of the human brain.
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Córtex Cerebral , Humanos , Axônios/fisiologia , Axônios/ultraestrutura , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/ultraestrutura , Dendritos/fisiologia , Neurônios/ultraestrutura , Oligodendroglia/ultraestrutura , Sinapses/fisiologia , Sinapses/ultraestrutura , Lobo Temporal/ultraestrutura , MicroscopiaAssuntos
Diafragma , Enteropatias , Humanos , Intestino Delgado , Anti-Inflamatórios não Esteroides , Íleo , ÚlceraRESUMO
Primary cilia act as antenna receivers of environmental signals and enable effective neuronal or glial responses. Disruption of their function is associated with circuit disorders. To understand the signals these cilia receive, we comprehensively mapped cilia's contacts within the human cortical connectome using serial-section EM reconstruction of a 1 mm3 cortical volume, spanning the entire cortical thickness. We mapped the "contactome" of cilia emerging from neurons and astrocytes in every cortical layer. Depending on the layer and cell type, cilia make distinct patterns of contact. Primary cilia display cell-type- and layer-specific variations in size, shape, and microtubule axoneme core, which may affect their signaling competencies. Neuronal cilia are intrinsic components of a subset of cortical synapses and thus a part of the connectome. This diversity in the structure, contactome, and connectome of primary cilia endows each neuron or glial cell with a unique barcode of access to the surrounding neural circuitry.
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Cílios , Conectoma , Humanos , Neurônios/fisiologia , Córtex Cerebral , Neuroglia/fisiologiaRESUMO
OBJECTIVES: Chronic constipation occurs frequently in children with autism spectrum disorder (ASD). The primary objective was to determine whether chronic constipation is associated with a higher rate of abnormal colonic motor activity in ASD children than in non-ASD children. A secondary goal was to determine if clinical variables could identify children with ASD at risk for possessing abnormal colonic motility. METHODS: A retrospective, propensity-matched, case-control study compared colonic manometry (CM) of an ASD cohort and non-ASD controls with chronic constipation. Clinical variables were evaluated as potential predictors for abnormal colonic motility. RESULTS: Fifty-six patients with ASD and 123 controls without the diagnosis of ASD who underwent CM were included. Propensity score resulted in 35 matched cohorts of ASD and controls. The rate of abnormal CM findings between ASD and matched controls (24% vs 20%, P = 0.78) did not differ significantly. A prediction model of abnormal CM that included ASD diagnosis, duration of constipation, and soiling achieved a sensitivity of 0.94 and specificity of 0.65. The risk for abnormal colonic motility increased 11% for every 1-year increase in duration of constipation. Odds for abnormal motility were 30 times higher in ASD children with soiling than controls with soiling (P < 0.0001). CONCLUSIONS: Chronic constipation does not appear to be associated with a higher rate of abnormal colonic motility in children with ASD. Clinical information of disease duration and presence of soiling due to constipation show promise in identifying patients with ASD at a greater risk for abnormal colonic motility.
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Transtorno do Espectro Autista , Humanos , Criança , Estudos Retrospectivos , Estudos de Casos e Controles , Transtorno do Espectro Autista/complicações , Motilidade Gastrointestinal , Constipação Intestinal/complicações , Constipação Intestinal/diagnóstico , Colo , Manometria/métodosRESUMO
The first phase of the Human Connectome Project pioneered advances in MRI technology for mapping the macroscopic structural connections of the living human brain through the engineering of a whole-body human MRI scanner equipped with maximum gradient strength of 300 mT/m, the highest ever achieved for human imaging. While this instrument has made important contributions to the understanding of macroscale connectional topology, it has also demonstrated the potential of dedicated high-gradient performance scanners to provide unparalleled in vivo assessment of neural tissue microstructure. Building on the initial groundwork laid by the original Connectome scanner, we have now embarked on an international, multi-site effort to build the next-generation human 3T Connectome scanner (Connectome 2.0) optimized for the study of neural tissue microstructure and connectional anatomy across multiple length scales. In order to maximize the resolution of this in vivo microscope for studies of the living human brain, we will push the diffusion resolution limit to unprecedented levels by (1) nearly doubling the current maximum gradient strength from 300 mT/m to 500 mT/m and tripling the maximum slew rate from 200 T/m/s to 600 T/m/s through the design of a one-of-a-kind head gradient coil optimized to minimize peripheral nerve stimulation; (2) developing high-sensitivity multi-channel radiofrequency receive coils for in vivo and ex vivo human brain imaging; (3) incorporating dynamic field monitoring to minimize image distortions and artifacts; (4) developing new pulse sequences to integrate the strongest diffusion encoding and highest spatial resolution ever achieved in the living human brain; and (5) calibrating the measurements obtained from this next-generation instrument through systematic validation of diffusion microstructural metrics in high-fidelity phantoms and ex vivo brain tissue at progressively finer scales with accompanying diffusion simulations in histology-based micro-geometries. We envision creating the ultimate diffusion MRI instrument capable of capturing the complex multi-scale organization of the living human brain - from the microscopic scale needed to probe cellular geometry, heterogeneity and plasticity, to the mesoscopic scale for quantifying the distinctions in cortical structure and connectivity that define cyto- and myeloarchitectonic boundaries, to improvements in estimates of macroscopic connectivity.
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Conectoma/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Masculino , Neuroimagem/métodos , Imagens de FantasmasRESUMO
Introduction: Pediatric convulsive status epilepticus (CSE) which is refractory to first-line benzodiazepines is a significant clinical challenge, especially within resource-limited countries. Parenteral phenobarbital is widely used in Africa as second-line agent for pediatric CSE, however evidence to support its use is limited. Purpose: This study aimed to compare the use of parenteral phenobarbital against parenteral phenytoin as a second-line agent in the management of pediatric CSE. Methodology: An open-labeled single-center randomized parallel clinical trial was undertaken which included all children (between ages of 1 month and 15 years) who presented with CSE. Children were allocated to receive either parenteral phenobarbital or parenteral phenytoin if they did not respond to first-line benzodiazepines. An intention-to-treat analysis was performed with the investigators blinded to the treatment arms. The primary outcome measure was the success of terminating CSE. Secondary outcomes included the need for admission to the pediatric intensive care unit (PICU) and breakthrough seizures during the admission. In addition, local epidemiological data was collected on the burden of pediatric CSE. Results: Between 2015 and 2018, 193 episodes of CSE from 111 children were enrolled in the study of which 144 met the study requirements. Forty-two percent had a prior history of epilepsy mostly from structural brain pathology (53%). The most common presentation was generalized CSE (65%) caused by acute injuries or infections of the central nervous system (59%), with 19% of children having febrile status epilepticus. Thirty-five percent of children required second-line management. More patients who received parenteral phenobarbital were at a significantly reduced risk of failing second-line treatment compared to those who received parenteral phenytoin (RR = 0.3, p = 0.0003). Phenobarbital also terminated refractory CSE faster (p < 0.0001). Furthermore, patients who received parenteral phenobarbital were less likely to need admission to the PICU. There was no difference between the two groups in the number of breakthrough seizures that occurred during admission. Conclusion: Overall this study supports anecdotal evidence that phenobarbital is a safe and effective second-line treatment for the management of pediatric CSE. These results advocate for parenteral phenobarbital to remain available to health care providers managing pediatric CSE in resource-limited settings. Attachments: CONSORT 2010 checklist Trial registration: NCT03650270 Full trial protocol available: https://clinicaltrials.gov/ct2/show/NCT03650270?recrs=e&type=Intr&cond=Status+Epilepticus&age=0&rank=1.
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PURPOSE: The effects of antiseizure medications (ASMs) on bone metabolism is inconsistent. Most studies are in high income settings and none from sub-Saharan Africa. METHODS: A hospital based cross-sectional study in a paediatric epilepsy service with a comparison group assessed vitamin D metabolism. RESULTS: Seventy-five children with epilepsy and 75 comparison group were recruited. Median age for children with epilepsy was 9 years (range 1-17 years) and controls 3 years (range 1-12 years). Vitamin D deficiency occurred in 11(16.2%) children with epilepsy versus 6 (8.8%) control group (p = 0.29). Vitamin D insufficiency occurred in 30 (44.1%) children with epilepsy compared to 27(39.7%) control group. Children on ASMs had lower mean vitamin D levels than the control group (p = 0.02). Children on enzyme-inducing ASMs had lower mean vitamin D levels (p = 0.08), vitaminD2 (p = 0.0018), vitaminD3 (p = 0.004), serum phosphate levels (p = 0.000), and higher mean parathyroid hormone levels (p = 0.03) compared to controls. There was no difference in dietary intake and ancestry, although the dietary content of both groups was low in vitamin D products. CONCLUSIONS: Low vitamin D levels were common in children from both groups, but statistically lower for the children on ASMs. Children on enzyme-inducing ASMs need screening for vitamin D deficiency. The literature supports extending this for all children on ASMs. This is the first study to report that children on enzyme-inducing ASMs have lower levels of Vitamin D2 and D3 levels, probably as result of increased destruction of vitamin D. Improved vitamin D intake for children in vulnerable settings is important.
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Remodelação Óssea , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Vitamina D/metabolismo , Adolescente , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Dieta , Epilepsia/complicações , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , África do Sul/epidemiologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/metabolismoRESUMO
We outline an approach to achieve wound closure in the event of a failed elliptical excision on the leg. The various steps are shown, and a clinical example is presented.
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Procedimentos Cirúrgicos Dermatológicos/métodos , Perna (Membro)/cirurgia , Terapia de Salvação/métodos , HumanosRESUMO
DNA-RNA hybrids arise in all cell types, and are removed by multiple enzymes, including the trimeric ribonuclease, RNase H2. Mutations in human RNase H2 result in Aicardi-Goutières syndrome (AGS), an inflammatory brain disorder notable for being a Mendelian mimic of congenital viral infection. Previous studies have shown that several AGS-associated mutations of the RNase H2B subunit do not affect trimer stability or catalytic activity and are clustered on the surface of the complex, leading us to speculate that these mutations might impair important interactions of RNase H2 with so far unidentified proteins. In this study, we show that AGS mutations in this cluster impair the interaction of RNase H2 with several members of the CoREST chromatin-silencing complex that include the histone deacetylase HDAC2 and the demethylase KDM1A, the transcriptional regulators RCOR1 and GTFII-I as well as ZMYM3, an MYM-type zinc finger protein. We also show that the interaction is mediated by the zinc finger protein ZMYM3, suggesting that ZMYM3 acts as a novel type of scaffold protein coordinating interactions between deacetylase, demethylase and RNase H type enzymes, raising the question of whether coordination between histone modifications and the degradation of RNA-DNA hybrids may be required to prevent inflammation in humans.
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Doenças Autoimunes do Sistema Nervoso/metabolismo , Proteínas Correpressoras/metabolismo , Histonas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Malformações do Sistema Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Ribonuclease H/metabolismo , Animais , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/patologia , Proteínas Correpressoras/genética , Células HEK293 , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/genética , Humanos , Camundongos , Células-Tronco Embrionárias Murinas , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Mutação , Proteínas do Tecido Nervoso/genética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Proteínas Nucleares/genética , Ribonuclease H/genéticaRESUMO
A national multicenter study identified 17 South African children with vertically acquired HIV-1 infection and HIV-associated vasculopathy. Five of the children (all indigenous African ancestry) had progressive vascular disease, consistent with moyamoya syndrome. Median presentation age 5.8 years (range 2.2-11). The children with moyamoya syndrome presented with abnormal CD4 counts and raised viral loads. Clinical features included motor deficits, neuroregression, and intellectual disability. Neuroimaging supported progressive vascular disease with preceding clinically silent disease course. Neurologic recovery occurred in 1 patient with improved CD4 counts. Four of the 5 children presented during the era when access to antiretroviral therapy was limited, suggesting that with improved management of HIV-1, progressive vasculopathy is less prevalent. However the insidious disease course illustrated indicates that the syndrome can progress "silently," and manifest with misleading phenotypes such as cognitive delay or regression. Sub-Saharan Africa has limited access to neuroimaging and affected children may be underdiagnosed.
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Infecções por HIV/complicações , Doença de Moyamoya/complicações , Encéfalo/diagnóstico por imagem , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/fisiopatologia , Infecções por HIV/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/fisiopatologia , Doença de Moyamoya/terapia , Estudos Retrospectivos , África do Sul , Carga ViralRESUMO
In skip-segment Hirschsprung disease (SS-HSCR), an aganglionic segment of bowel, which extends proximally from the distal rectum, is interrupted by a ganglionated "skip segment." Skip segments are usually located far proximal to the rectum where they do not interfere with initial diagnosis, although the possibility of distal SS-HSCR should be considered during interpretation of intraoperative biopsies or patients with atypical postoperative courses. We report 2 cases of SS-HSCR with skip areas in the distal rectum, 1 of which led to a false-negative diagnosis by suction rectal biopsy. These 2 cases of SS-HSCR, along with others in the literature, highlight the point that ganglionic skip segments can confuse clinicians and lead to inadequate bowel resection, diagnostic delay, or a false-negative diagnosis. The pathogenesis of SS-HSCR is discussed in light of recent discoveries regarding transmesenteric migration of vagal neural crest cells and the role of sacral neural crest cells in hindgut neurodevelopment.
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Gânglios/patologia , Doença de Hirschsprung/patologia , Mucosa Intestinal/inervação , Reto/inervação , Biomarcadores/análise , Biópsia , Calbindina 2/análise , Pré-Escolar , Reações Falso-Negativas , Gânglios/química , Doença de Hirschsprung/genética , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino , Fenótipo , Valor Preditivo dos TestesRESUMO
Hirschsprung disease, which consists of aganglionosis of the rectum and sometimes more proximal bowel, requires surgical removal of the aganglionic bowel and creation of ganglionated neorectum using proximal normally innervated bowel. The border between aganglionic and ganglionic bowel is irregular; the transition zone features variable quantities of ganglion cells and numerous large nerves. We report the histopathology of pull-through bowel segments resected because of poor postoperative outcome from 30 patients (22 boys, 8 girls). The most common indication for reoperation was severe constipation/obstruction. Transition zone (bowel with at least two nerves ≥40 µm diameter per 400× high-power field, and ganglion cells) or aganglionic bowel (bowel with at least two nerves ≥40 µm per high-power field diameter, but without ganglion cells) was found in 19/30 (63%) resections. In colons resected because of familial adenomatous polyposis, rare high-power fields showed two enlarged nerves; the mean age of those patients (135 ± 49.4 months) was significantly higher than that of the patients undergoing redo pull-through surgery (67.9 ± 42.8 months). Additional pathology included stricture and enterocolitis. Although there are multiple causes for poor outcomes following surgical therapy for Hirschsprung disease, abnormal innervation of the bowel used for pull-through is common. We recommend that intraoperative consultation at primary pull-through procedure include frozen section evaluation of the circumference of the bowel to be used for pull-through to confirm histologically the presence of both ganglion cells and normal-caliber nerves. The criteria used in this study are most suitable for infants and young children.