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2.
Rev. chil. obstet. ginecol. (En línea) ; 87(5): 360-364, oct. 2022. ilus
Artigo em Espanhol | LILACS | ID: biblio-1423740

RESUMO

El neumotórax espontáneo es una patología extremadamente rara durante la gestación. Se define como la presencia de aire dentro de la cavidad pleural que puede generar principalmente dolor torácico y disnea. Esta patología tiene unas bajas incidencia y prevalencia en el embarazo, pero es relevante por una alta tasa de recurrencia, con un buen pronóstico para la madre y el feto si es tempranamente diagnosticada y oportunamente manejada. Se relaciona con factores de riesgo como las maniobras de Valsalva efectuadas durante el trabajo de parto, además de con comorbilidad como el tabaquismo, y con el biotipo longilíneo, entre otros, por lo que son muy importantes una adecuada anamnesis y la evaluación de la exploración física. El obstetra debe sospecharlo ante la clínica de dolor torácico asociado a disnea en gestantes en el trabajo de parto y el parto, y tenerlo en cuenta como diagnóstico diferencial. Es de vital importancia tener un manejo multidisciplinario compuesto por ginecoobstetra, internista, neumólogo y neonatólogo, incluido el apoyo por una unidad de cuidado intensivo para evitar complicaciones materno-perinatales que se puedan asociar al neumotórax espontáneo.


Spontaneous pneumothorax is an extremely rare pathology during pregnancy. It is defined as the presence of air inside the pleural cavity that can mainly generate chest pain and dyspnea. This pathology has a low incidence and prevalence in pregnancy, but a high rate of recurrence with a good prognosis for the mother and the fetus if it is diagnosed early and managed early. It is related to risk factors such as Valsalva maneuvers performed during labor, in addition to comorbidities such as smoking, longilinear biotype, among others, so it is very important to have an adequate history and evaluation of the physical examination. The obstetrician must be attentive to chest pain symptoms associated with dyspnea in pregnant women during labor and delivery, suspect this pathology and take it into account as a differential diagnosis. It is vitally important to have a multidisciplinary management composed of the gynecologist-obstetrician, internist, pulmonologist, neonatologist, including the support of an intensive care unit to avoid maternal-perinatal complications that may be associated with spontaneous pneumothorax.


Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Adolescente , Pneumotórax/terapia , Pneumotórax/diagnóstico por imagem , Trabalho de Parto , Manobra de Valsalva , Pneumotórax/etiologia , Radiografia Torácica , Tomografia Computadorizada por Raios X
3.
Rev. colomb. psicol ; 30(2): 41-54, July-Dec. 2021. tab
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1388951

RESUMO

Abstract Suicide has increased close to 60% in the last four decades worldwide. In Colombia, during the year 2019, 10,9% of violent deaths were due to suicide. This study aimed to identify risk factors predicting repeated suicide attempts. It also aimed to describe the management of suicidal behaviour within an emergency department of Northern Colombia. Dataset comprised 336 medical records of individuals seeking medical assistance for intentional self-harm between 2008-2019; 136 medical records were associated with previously reported suicide attempts. Results from a multivariate logistic regression showed that suicide ideation and having a history of psychiatric disorders significantly predicted repeated suicide attempts. Furthermore, repeated attempts were more likely in underaged individuals and young adults. Management of patients engaging in suicidal behaviour involved hospitalization and outpatient mental health services. However, a few patients were sent home with recommendations or were non-compliant. Findings from this study highlight the importance to develop evidence-based screening and monitoring protocols that prevent repeated suicide attempts.


Resumen El suicidio ha aumentado en cerca de un 60% en los últimos cuarenta años. En Colombia, para el año 2019, el 10.9% de las muertes violentas se presentaron por suicidio. Este estudio busca identificar los factores de riesgo asociados con los intentos repetidos de suicidio y además realiza un análisis descriptivo del manejo dado a estos pacientes. Esta investigación utiliza la base de datos de la unidad de emergencias en un hospital del norte de Colombia, y se centra en los pacientes que acudieron al hospital por intento de suicidio entre enero de 2008 y junio de 2019. La base de datos presenta 336 casos de los cuales el 81% corresponden a intentos suicidas y 19% a gestos. Resultados de un análisis de regresión logística multivariada mostraron que la ideación suicida y la historia de desorden psiquiátrico predecían significativamente los intentos suicidas repetidos y que los intentos repetidos eran más probables en el grupo de individuos menores de edad y en adultez temprana. El tratamiento administrado a los pacientes fue hospitalización y servicios ambulatorios; un porcentaje fue enviado a casa con recomendaciones. Los hallazgos de este estudio destacan la importancia del desarrollo de protocolos estandarizados basados en evidencia para prevenir los intentos repetidos.

4.
Dev Biol ; 462(2): 119-128, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32169553

RESUMO

Arl13b is a gene known to regulate ciliogenesis. Functional alterations in this gene's activity have been associated with Joubert syndrome. We found that in Arl13 null mouse embryos the orientation of the optic cup is inverted, such that the lens is abnormally surrounded by an inverted optic cup whose retina pigmented epithelium is oddly facing the surface ectoderm. Loss of Arl13b leads to the disruption of optic vesicle's patterning and expansion of ventral fates. We show that this phenotype is consequence of miss-regulation of Sonic hedgehog (Shh) signaling and demonstrate that the Arl13b-/- eye phenotype can be rescued by deletion of Gli2, a downstream effector of the Shh pathway. This work identified an unexpected role of primary cilia during the morphogenetic movements required for the formation of the eye.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Cílios/metabolismo , Olho/embriologia , Fatores de Ribosilação do ADP/genética , Animais , Padronização Corporal/genética , Proteína Morfogenética Óssea 4/metabolismo , Cílios/genética , Desenvolvimento Embrionário , Olho/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Cristalino/embriologia , Cristalino/metabolismo , Masculino , Camundongos , Camundongos Knockout , Morfogênese , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Organogênese , Epitélio Pigmentado da Retina/embriologia , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/metabolismo , Proteína Homeobox SIX3
5.
Stem Cell Rev Rep ; 15(5): 690-702, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31317505

RESUMO

Pharmaceuticals and cell-based regenerative medicine for Parkinson's disease (PD) offer palliative relief but do not arrest the disease progression. Cell therapy has emerged as an experimental treatment, but current cell sources such as human umbilical cord blood (hUCB) stem cells display only partial recapitulation of mature dopaminergic neuron phenotype and function. Nonetheless, stem cell grafts ameliorate PD-associated histological and behavioral deficits likely through stem cell graft-secreted therapeutic substances. We recently demonstrated the potential of hUCB-derived plasma in enhancing motor capabilities and gastrointestinal function, as well as preventing dopaminergic neuronal cell loss, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) rodent model of PD. Recognizing the translational need to test in another PD model, we now examined here the effects of an intravenously transplanted combination of hUCB and plasma into the 6-hydroxydopamine (6-OHDA) lesioned adult rats. Animals received three separate doses of 4 × 106 hUCB cells with plasma beginning at 7 days after stereotaxic 6-OHDA lesion, then behaviorally and immunohistochemically evaluated over 56 days post-lesion. Whereas vehicle-treated lesioned animals exhibited the typical 6-OHDA neurobehavioral symptoms, hUCB and plasma-treated lesioned animals showed significant attenuation of motor function, gut motility, and nigral dopaminergic neuronal survival, combined with diminished pro-inflammatory microbiomes not only in the nigra, but also in the gut. Altogether these data support a regenerative medicine approach for PD by sequestering inflammation and neurotoxicity through correction of gut dysbiosis.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Microbioma Gastrointestinal , Inflamação/prevenção & controle , Intoxicação por MPTP/terapia , Fármacos Neuroprotetores/administração & dosagem , Medicina Regenerativa , Cordão Umbilical/citologia , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/citologia , Inflamação/etiologia , Inflamação/patologia , Intoxicação por MPTP/etiologia , Intoxicação por MPTP/patologia , Masculino , Transtornos Motores/etiologia , Transtornos Motores/patologia , Transtornos Motores/prevenção & controle , Ratos , Ratos Sprague-Dawley , Substância Negra/citologia
6.
Theranostics ; 9(4): 1029-1046, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867814

RESUMO

International Stem Cell Corporation human parthenogenetic neural stem cells (ISC-hpNSC) have potential therapeutic value for patients suffering from traumatic brain injury (TBI). Here, we demonstrate the behavioral and histological effects of transplanting ISC-hpNSC intracerebrally in an animal model of TBI. Methods: Sprague-Dawley rats underwent a moderate controlled cortical impact TBI surgery. Transplantation occurred at 72 h post-TBI with functional readouts of behavioral and histological deficits conducted during the subsequent 3-month period after TBI. We characterized locomotor, neurological, and cognitive performance at baseline (before TBI), then on days 0, 1, 7, 14, 30, 60, and 90 (locomotor and neurological), and on days 28-30, 58-60, and 88-90 (cognitive) after TBI. Following completion of behavioral testing at 3 months post-TBI, animals were euthanized by transcardial perfusion and brains harvested to histologically characterize the extent of brain damage. Neuronal survival was revealed by Nissl staining, and stem cell engraftment and host tissue repair mechanisms such as the anti-inflammatory response in peri-TBI lesion areas were examined by immunohistochemical analyses. Results: We observed that TBI groups given high and moderate doses of ISC-hpNSC had an improved swing bias on an elevated body swing test for motor function, increased scores on forelimb akinesia and paw grasp neurological tests, and committed significantly fewer errors on a radial arm water maze test for cognition. Furthermore, histological analyses indicated that high and moderate doses of stem cells increased the expression of phenotypic markers related to the neural lineage and myelination and decreased reactive gliosis and inflammation in the brain, increased neuronal survival in the peri-impact area of the cortex, and decreased inflammation in the spleen at 90 days post-TBI. Conclusion: These results provide evidence that high and moderate doses of ISC-hpNSC ameliorate TBI-associated histological alterations and motor, neurological, and cognitive deficits.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Regeneração do Cérebro , Células-Tronco Neurais/fisiologia , Transplante de Células-Tronco/métodos , Animais , Cognição , Modelos Animais de Doenças , Humanos , Locomoção , Ratos Sprague-Dawley , Resultado do Tratamento
7.
Stem Cell Rev Rep ; 15(2): 256-275, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30739275

RESUMO

Stroke remains a major unmet clinical need that warrants novel therapies. Following an ischemic insult, the cerebral vasculature secretes inflammatory molecules, creating the stroke vasculome profile. The present study evaluated the therapeutic effects of endothelial cells on the inflammation-associated stroke vasculome. qRT-PCR analysis revealed that specific inflammation-related vasculome genes BRM, IκB, Foxf1, and ITIH-5 significantly upregulated by oxygen glucose deprivation (OGD. Interestingly, co-culture of human endothelial cells (HEN6) with human endothelial cells (EPCs) during OGD significantly blocked the elevations of BRM, IκB, and Foxf1, but not ITIH-5. Next, employing the knockdown/antisense technology, silencing the inflammation-associated stroke vasculome gene, IκB, as opposed to scrambled knockdown, blocked the EPC-mediated protection of HEN6 against OGD. In vivo, stroke animals transplanted with intracerebral human EPCs (300,000 cells) into the striatum and cortex 4 h post ischemic stroke displayed significant behavioral recovery up to 30 days post-transplantation compared to vehicle-treated stroke animals. At 7 days post-transplantation, quantification of the fluorescent staining intensity in the cortex and striatum revealed significant upregulation of the endothelial marker RECA1 and a downregulation of the stroke-associated vasculome BRM, IKB, Foxf1, ITIH-5 and PMCA2 in the ipsilateral side of cortex and striatum of EPC-transplanted stroke animals relative to vehicle-treated stroke animals. Altogether, these results demonstrate that EPCs exert therapeutic effects in experimental stroke possibly by modulating the inflammation-plagued vasculome.


Assuntos
Biomarcadores/análise , Células Progenitoras Endoteliais/citologia , Inflamação/complicações , Neovascularização Patológica/prevenção & controle , Transplante de Células-Tronco/métodos , Acidente Vascular Cerebral/terapia , Animais , Comportamento Animal , Técnicas de Cocultura , Células Progenitoras Endoteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
8.
J Cereb Blood Flow Metab ; 39(9): 1750-1758, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29569981

RESUMO

Regulatory T-cells (Tregs) may exert a neuroprotective effect on ischemic stroke by inhibiting both inflammation and effector T-cell activation. Transplantation of human bone marrow-derived stem cells (BMSCs) in ischemic stroke affords neuroprotection that results in part from the cells' anti-inflammatory property. However, the relationship between Tregs and BMSCs in treatment of ischemic stroke has not been fully elucidated. Here, we tested the hypothesis that Tregs within the BMSCs represent active mediators of immunomodulation and neuroprotection in experimental stroke. Primary rat neuronal cells were subjected to an oxygen-glucose deprivation and reperfusion (OGD/R) condition. The cells were re-perfused and co-cultured with Tregs and/or BMSCs. We detected a minority population of Tregs within BMSCs with both immunocytochemistry (ICC) and flow cytometry identifying cells expressing phenotypic markers of CD4, CD25, and FoxP3 protein. BMSCs with the native population of Tregs conferred maximal neuroprotection compared to the treatment conditions containing 0%, 10%, and 100% relative ratio Tregs. Increasing the Treg population resulted in increased IL6 secretion and decreased FGF-ß secretion by BMSCs. This study shows that a minority population of Tregs exists within the therapeutic BMSC population, which serves as robust mediators of the immunomodulatory and neuroprotective effect provided by BMSC transplantation.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Acidente Vascular Cerebral/terapia , Linfócitos T Reguladores/imunologia , Imunidade Adaptativa , Animais , Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Células Cultivadas , Citocinas/imunologia , Humanos , Imunomodulação , Masculino , Camundongos Endogâmicos C57BL , Neuroproteção , Ratos , Acidente Vascular Cerebral/imunologia
9.
Ginecol. obstet. Méx ; 86(4): 239-246, feb. 2018. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-984427

RESUMO

Resumen Objetivo Describir las indicaciones, complicaciones y repercusiones de la amniocentesis. Materiales y métodos Estudio descriptivo, observacional y transversal de las amniocentesis efectuadas de 2009 a 2015 en dos unidades de medicina materno fetal de Bogotá, Colombia. Se evaluaron las características de las pacientes, indicación de los procedimientos y las complicaciones. Además, los hallazgos se compararon con reportes de diferentes estudios de la bibliografía internacional. Resultados Se incluyeron 748 amniocentesis. La mediana de edad de las pacientes fue de 29 años (límites 23 y 37). La indicación más común fue el estudio genético en 508 casos (67.9%). Se reportaron 89 (17.5%) casos de cromosomopatías, y de éstas la de mayor frecuencia fue la trisomía 21 en 41 pacientes (46%). La mayor parte de las complicaciones se registró en embarazos que superaron las 20 semanas. La pérdida del embarazo y la amenaza de parto pretérmino atribuibles a la amniocentesis fueron de 0.9 y 2.5%, respectivamente. Conclusión Las características de la amniocentesis permitieron conocer sus repercusiones, complicaciones, tasa de pérdida real o factores asociados, con miras a explorar los factores maternos y fe tales en embarazos únicos y múltiples en dos unidades de Medicina Materno Fetal latinoamericanas.


Abstract Objective The purpose of this paper is to describe the indications, complications and results of amniocentesis performed in two fetal maternal medicine units in Bogota Colombia between 2009 and 2015. Materials and methods Cross-sectional observational descriptive study; 770 amniocentesis performed during 6 years (2009 - 2015) with evaluation of the characteristics of the patients, procedures and complications observed were evaluated. In addition, the findings were compared with reports from different studies of the world literature. Results 748 amniocentesis data were included, statistically analyzing the clinical characteristics of the patients and the results, indications and complications of the procedure. The median age was 29 years (RIQ: 23-37). The most common indication was genetic in 508 cases (67.9%). 89 (17.5%) cases of chromosomopathies were reported, with trisomy 21 being more frequently observed in 41 patients (46%). The loss of pregnancy and the threat of preterm labor attributable to amniocentesis were 0.94% and 2.54%, respectively. Conclusion The characteristics of amniocentesis allow us to know statistics of outcomes, complications, actual loss rate or associated factors, with a view to exploring both maternal and fetal factors in single and multiple pregnancies in two units of Latin American Fetal Maternal Medicine.

10.
Prog Neurobiol ; 158: 94-131, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28743464

RESUMO

Ischemic stroke is a leading cause of death worldwide. A key secondary cell death mechanism mediating neurological damage following the initial episode of ischemic stroke is the upregulation of endogenous neuroinflammatory processes to levels that destroy hypoxic tissue local to the area of insult, induce apoptosis, and initiate a feedback loop of inflammatory cascades that can expand the region of damage. Stem cell therapy has emerged as an experimental treatment for stroke, and accumulating evidence supports the therapeutic efficacy of stem cells to abrogate stroke-induced inflammation. In this review, we investigate clinically relevant stem cell types, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), very small embryonic-like stem cells (VSELs), neural stem cells (NSCs), extraembryonic stem cells, adipose tissue-derived stem cells, breast milk-derived stem cells, menstrual blood-derived stem cells, dental tissue-derived stem cells, induced pluripotent stem cells (iPSCs), teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N), c-mycER(TAM) modified NSCs (CTX0E03), and notch-transfected mesenchymal stromal cells (SB623), comparing their potential efficacy to sequester stroke-induced neuroinflammation and their feasibility as translational clinical cell sources. To this end, we highlight that MSCs, with a proven track record of safety and efficacy as a transplantable cell for hematologic diseases, stand as an attractive cell type that confers superior anti-inflammatory effects in stroke both in vitro and in vivo. That stem cells can mount a robust anti-inflammatory action against stroke complements the regenerative processes of cell replacement and neurotrophic factor secretion conventionally ascribed to cell-based therapy in neurological disorders.


Assuntos
Morte Celular/fisiologia , Inflamação/terapia , Transplante de Células-Tronco , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Animais , Humanos , Inflamação/etiologia
11.
Int J Mol Sci ; 18(7)2017 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-28671601

RESUMO

Administration of the hematopoietic growth factor granulocyte-colony stimulating Factor (G-CSF) has been reported to enhance recovery from controlled cortical impact (CCI) in rodent models. G-CSF exerts actions in both the periphery (stimulation of hematopoiesis) and in the brain, where it serves as a neurotrophic factor, promoting neuronal survival and stimulating neural stem/progenitor cell proliferation in the hippocampus. In order to distinguish the direct CNS actions of G-CSF from its peripheral actions, experiments were designed to block the recruitment of peripheral monocytes to the site of the lesion produced by CCI. The selective C-C motif receptor 2 (CCR2) antagonist (RS504303) was co-administered with G-CSF for three days after CCI in a chimeric mouse previously transplanted with GFP-expressing (GFP+) blood stem-progenitor cells. RESULTS: The drug significantly impaired infiltration of GFP+ bone marrow-derived cells to the frontal cortex and striatum without impeding recovery performance and hippocampal neurogenesis in the behavioral test, the Radial Arm Water Maze (RAWM). Administration of the CCR2 antagonist alone, without G-CSF, was effective in promoting recovery in RAWM. These results support the hypothesis that the direct action of G-CSF on neural cells, independent of its hematopoietic effects, is primarily responsible for enhanced recovery from CCI. In addition, this study confirms the importance of CCR2 and its ligand, monocyte chemotactic protein-1 (MCP-1), in mediating the inflammatory response following CCI.


Assuntos
Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/imunologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Neurogênese/efeitos dos fármacos , Receptores CCR2/antagonistas & inibidores
12.
Front Cell Dev Biol ; 5: 51, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28540289

RESUMO

Notch-induced mesenchymal stromal cells (MSCs) mediate a distinct mechanism of repair after brain injury by forming a biobridge that facilitates biodistribution of host cells from a neurogenic niche to the area of injury. We have observed the biobridge in an area between the subventricular zone and the injured cortex using immunohistochemistry and laser capture. Cells in the biobridge express high levels of extracellular matrix metalloproteinases (MMPs), specifically MMP-9, which co-localized with a trail of MSCs graft. The transplanted stem cells then become almost undetectable, being replaced by newly recruited host cells. This stem cell-paved biobridge provides support for distal migration of host cells from the subventricular zone to the site of injury. Biobridge formation by transplanted stem cells seems to have a fundamental role in initiating endogenous repair processes. Two major stem cell-mediated repair mechanisms have been proposed thus far: direct cell replacement by transplanted grafts and bystander effects through the secretion of trophic factors including fibroblast growth factor 2 (FGF-2), epidermal growth factor (EGF), stem cell factor (SCF), erythropoietin, and brain-derived neurotrophic factor (BDNF) among others. This groundbreaking observation of biobridge formation by transplanted stem cells represents a novel mechanism for stem cell mediated brain repair. Future studies on graft-host interaction will likely establish biobridge formation as a fundamental mechanism underlying therapeutic effects of stem cells and contribute to the scientific pursuit of developing safe and efficient therapies not only for traumatic brain injury but also for other neurological disorders. The aim of this review is to hypothetically extend concepts related to the formation of biobridges in other central nervous system disorders.

13.
Restor Neurol Neurosci ; 34(3): 415-31, 2016 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-26923619

RESUMO

PURPOSE: The overall objective was to elucidate cellular mechanisms by which G-CSF enhances recovery from traumatic brain injury in a hippocampal-dependent learning task. METHODS: Chimeric mice were prepared by transplanting bone marrow cells that express green fluorescent protein (GFP+) from a transgenic "green" mice into C57BL/6 mice. Two months later, the animals sustained mild controlled cortical impact (CCI) to the right frontal-parietal cortex, followed by G-CSF (100 µg/kg) treatment for 3 consecutive days. The primary behavioral end-point was performance on the radial arm water maze (RAWM) assessed before and after CCI (days 7 and 14). Secondary endpoints included a), motor performance on a rotating cylinder (rotarod), b) measurement of microglial and astroglial response, c) hippocampal neurogenesis, and d) measures of neurotrophic factors (BDNF, GDNF) in brain homogenates. RESULTS: G-CSF treatment resulted in significantly better performance on the rotorod at one week, and in the RAWM after one and two weeks. The cellular changes found 2 wks after CCI in the G-CSF group included increased numbers of hippocampal newborn neurons as well as astrocytosis and microgliosis in striatum and frontal cortex on both sides of brain. GFP+ cells that co-labeled with Iba1 (microglial marker) comprised a significant proportion of striatal microglia in G-CSF treated animals, indicating the capacity of G-CSF to increase microglial recruitment to the site of injury. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF treated mice. CONCLUSIONS: G-CSF serves as a neurotrophic factor that increases hippocampal neurogenesis (or enhances survival of new-born neurons), and activates astrocytes and microglia. In turn, these activated glia release a plethora of cytokines and neurotrophic factors that contribute, in a poorly understood cascade, to the brain's repair response. G-CSF also acts directly on bone marrow-derived cells to enhance recruitment of microglia to the site of CCI from circulating monocytes to the site of CCI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fatores de Crescimento Neural/metabolismo , Neuroglia/patologia , Recuperação de Função Fisiológica/fisiologia , Animais , Transplante de Medula Óssea , Lesões Encefálicas Traumáticas/cirurgia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Regulação da Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora/fisiologia , Fatores de Crescimento Neural/genética , Neuroglia/metabolismo , Neuropeptídeos/metabolismo , Equilíbrio Postural , Desempenho Psicomotor
14.
CNS Neurosci Ther ; 22(4): 306-15, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26842647

RESUMO

BACKGROUND: Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug-like inhibitors of XPO1, with potent anti-cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors. AIMS AND RESULTS: Here, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-(k)B, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF-α (20 ng/mL)-induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non-treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague-Dawley rats treated post-injury with SINE compounds exhibited significant reductions in TBI-induced behavioral and histological deficits. Animals that received KPT-350 orally starting at 2 h post-TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100-200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT-350 dosing, and throughout the 18-day post-TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT-350 reduced cortical core impact area and peri-impact cell death compared to vehicle treatment (P's < 0.05). CONCLUSIONS: Both in vitro and in vivo experiments revealed that KPT-350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF-(k)B expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Lesões Encefálicas Traumáticas/fisiopatologia , Morte Celular/fisiologia , Núcleo Celular/metabolismo , Acrilamidas/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Hidrazinas/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , NF-kappa B/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Proteínas Repressoras/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Cell Transplant ; 25(10): 1853-1861, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26892497

RESUMO

Targeted microlesions of the hippocampus have been reported to enhance neurogenesis in the subgranular zone (SGZ). The potential therapeutic impact of transient insertion of a microneedle was investigated in a mouse model of Alzheimer's disease (AD). We tested the hypothesis that transient microinjury to the brain elicits cellular responses that mediate beneficial regenerative processes. Brief stereotaxic insertion and removal of a microneedle into the right hippocampus of 14-month-old APP/PS1 mouse brains resulted in (a) stimulation of hippocampal neurogenesis and (b) reduction of amyloid-ß plaque number in the CA-1 region. This treatment also resulted in a trend toward improved performance in the radial arm water maze (RAWM). Further studies of fundamental cellular mechanisms of the brain's response to microinjury will be useful for investigation of potential neuroprotective and deleterious effects of targeted microlesions and deep brain stimulation in AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Modelos Animais de Doenças , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agulhas , Neurogênese , Oligopeptídeos/genética , Oligopeptídeos/metabolismo
16.
Cell Transplant ; 25(8): 1453-60, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26883984

RESUMO

Blood-brain barrier (BBB) permeabilizers, such as mannitol, can facilitate peripherally delivered stem cells to exert therapeutic benefits on the stroke brain. Although this BBB permeation-aided stem cell therapy has been demonstrated in the acute stage of stroke, such BBB permeation in the chronic stage of the disease remains to be examined. Adult Sprague-Dawley rats initially received sham surgery or experimental stroke via the 1-h middle cerebral artery occlusion (MCAo) model. At 1 month after the MCAo surgery, stroke animals were randomly assigned to receive human umbilical cord stem cells only (2 million viable cells), mannitol only (1.1 mol/L mannitol at 4°C), combined human umbilical cord stem cells (200,000 viable cells) and mannitol (1.1 mol/L mannitol at 4°C), and vehicle (phosphate-buffered saline) only. Stroke animals that received human umbilical cord blood cells alone or combined human umbilical cord stem cells and mannitol exhibited significantly improved motor performance and significantly better brain cell survival in the peri-infarct area compared to stroke animals that received vehicle or mannitol alone, with mannitol treatment reducing the stem cell dose necessary to afford functional outcomes. Enhanced neurogenesis in the subventricular zone accompanied the combined treatment of human umbilical cord stem cells and mannitol. We showed that BBB permeation facilitates the therapeutic effects of a low dose of peripherally transplanted stem cells to effectively cause functional improvement and increase neurogenesis in chronic stroke.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Manitol/metabolismo , Acidente Vascular Cerebral/terapia , Animais , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Modelos Animais de Doenças , Sangue Fetal/citologia , Infarto da Artéria Cerebral Média/terapia , Masculino , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/cirurgia
17.
J Neurosci Res ; 94(5): 409-23, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26822127

RESUMO

Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) represent a novel approach for treatment of traumatic brain injury (TBI). After mild controlled cortical impact (CCI), mice were treated with G-CSF (100 µg/kg) for 3 consecutive days. The primary behavioral endpoint was performance on the radial arm water maze (RAWM), assessed 7 and 14 days after CCI. Secondary endpoints included 1) motor performance on a rotating cylinder (rotarod), 2) measurement of microglial and astroglial response, 3) hippocampal neurogenesis, and 4) measures of neurotrophic factors (brain-derived neurotrophic factor [BDNF] and glial cell line-derived neurotrophic factor [GDNF]) and cytokines in brain homogenates. G-CSF-treated animals performed significantly better than vehicle-treated mice in the RAWM at 1 and 2 weeks but not on the rotarod. Cellular changes found in the G-CSF group included increased hippocampal neurogenesis as well as astrocytosis and microgliosis in both the striatum and the hippocampus. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF-treated mice. These factors along with G-CSF itself are known to promote hippocampal neurogenesis and inhibit apoptosis and likely contributed to improvement in the hippocampal-dependent learning task. Six cytokines that were modulated by G-CSF treatment following CCI were elevated on day 3, but only one of them remained altered by day 7, and all of them were no different from vehicle controls by day 14. The pro- and anti-inflammatory cytokines modulated by G-CSF administration interact in a complex and incompletely understood network involving both damage and recovery processes, underscoring the dual role of inflammation after TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica/fisiologia
18.
J Neuroinflammation ; 12: 174, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26376629

RESUMO

BACKGROUND: Aging is associated with a decline in stem cell proliferation that is thought to be a result of dysregulated signaling in the neurogenic niche. This results in a diminished and less efficient pool of progenitors. The Wnt pathway plays a key role in the proliferation and differentiation of progenitor cells. Recent publications suggest that the age-related decline in the function of Wnt is a contributor to age-dependent decline in neural progenitors. Similarly, the aged neurogenic niche is characterized by higher levels of inflammatory cytokines. This increased inflammation contributes to the declining function of neural progenitor cells. NT-020, a proprietary blend of polyphenols, has been shown to increase proliferation of neural progenitors and improve cognitive function in aged rats. PURPOSE AND METHODS: In this study, we examined the neurogenic niche in the subgranular zone of the dentate gyrus (SGZ) and the subventricular zone (SVZ) of young and aged rats to determine if dietary supplementation with NT-020 could regulate inflammation and oxidative stress response pathways in neurons, astrocytes, and microglia. Further, we examined NT-020's ability to modulate Wnt signaling in the aged neurogenic niche. To accomplish this, we utilized gene PCR arrays and immunohistochemistry. RESULTS: We observed an increase in nuclear localization of immunopositive labeling of ß-catenin, HO-1, and Nrf2 in all subsets of cell types in both young and aged rats in the SGZ and SVZ following NT-020 treatment. NeuN-positive cells showed a basal increase in nuclear ß-catenin in the aged rats, which was not observed in doublecortin (DCX)-labeled cells, microglia, or astrocytes. Reverse transcription polymerase chain reaction (RT-PCR) analysis of isolated hippocampal tissue revealed that a significant percent of genes involved with inflammation are affected by treatment with NT-020. In addition, several genes that regulate Wnt activity were affected by supplementation. CONCLUSIONS: The results suggest that NT-020 activates oxidative stress response pathways and supports pro-neurogenic gene expression in the hippocampus. This may represent the mechanism by which the NT-020 formula enhances performance in learning and memory tasks in aged mice.


Assuntos
Envelhecimento , Carnosina/uso terapêutico , Colecalciferol/uso terapêutico , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/uso terapêutico , Via de Sinalização Wnt/fisiologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Carnosina/farmacologia , Proliferação de Células/efeitos dos fármacos , Colecalciferol/farmacologia , Biologia Computacional , Citocinas/genética , Citocinas/metabolismo , Giro Denteado/citologia , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neuropeptídeos/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Endogâmicos F344 , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
19.
Stroke ; 46(9): 2616-27, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26219646

RESUMO

BACKGROUND AND PURPOSE: Adult stem cell therapy is an experimental stroke treatment. Here, we assessed homing and anti-inflammatory effects of bone marrow stromal cells (hBMSCs) in chronic stroke. METHODS: At 60 days post stroke, adult Sprague-Dawley rats received intravenous hBMSCs (4×10(6) labeled or nonlabeled cells) or vehicle (saline). A sham surgery group served as additional control. In vivo imaging was conducted between 1 hour and 11 days post transplantation, followed by histological examination. RESULTS: Labeled hBMSCs migrated to spleen which emitted significantly higher fluorescent signal across all time points, especially during the first hour, and were modestly detected in the head region at the 12 hours and 11 days, compared with nonlabeled hBMSCs and vehicle-infused stroke animals, or sham (P<0.05). At 11 days post transplantation, ex vivo imaging confirmed preferential hBMSC migration to the spleen over the brain. Hematoxylin and eosin staining revealed significant 15% and 30% reductions in striatal infarct and peri-infarct area, and a trend of rescue against neuronal loss in the hippocampus. Unbiased stereology showed significant 75% and 60% decrements in major histocompatibility complex II-activated inflammatory cells in gray and white matter, and a 43% diminution in tumor necrosis factor-α cell density in the spleen of transplanted stroke animals compared with vehicle-infused stroke animals (P<0.05). Human antigen immunostaining revealed 0.03% hBMSCs survived in spleen and only 0.0007% in brain. MSC migration to spleen, but not brain, inversely correlated with reduced infarct, peri-infarct, and inflammation. CONCLUSIONS: hBMSC transplantation is therapeutic in chronic stroke possibly by abrogating the inflammation-plagued secondary cell death.


Assuntos
Inflamação/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Baço , Acidente Vascular Cerebral/terapia , Animais , Doença Crônica , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
20.
Salud UNINORTE ; 31(2): 367-384, mayo-ago. 2015. ilus, tab
Artigo em Espanhol | LILACS-Express | LILACS | ID: lil-769284

RESUMO

Este artículo presenta distintas metodologías utilizadas para valorar los impactos que la contaminación ambiental tiene sobre la salud de la población y algunos resultados de los estudios más destacados en el tema. Estos impactos, denominados desde la economía como externalidades, cobran importancia, dado que cuando se toman las decisiones de inversión −como el tipo de tecnología utilizada en un proceso de producción o la ubicación de una planta eléctrica- es evidente que a la sociedad le interesará saber los impactos que se generarán sobre el ambiente y la salud, por tanto, al final se deberán incluir esos efectos externos en el proceso de toma de decisiones. No obstante, la estimación de los efectos de la contaminación sobre la salud trae consigo un alto grado de incertidumbre. Una parte importante de esa incertidumbre no es de carácter científico sino de los resultados de elecciones éticas y por el desconocimiento del futuro. Todo esto implica un análisis de sistemas multidisciplinarios, con aportes de los ingenieros, salubristas, epidemiólogos, ecólogos y economistas.


This paper aims to present different methodologies used to assess the impact of environmental pollution on the health of the population, and some results that have been addressed by the most important studies on the subject. These impacts, known as externalities in economics, become important because when investment decisions are taken, such as the type of technology used in a production process or the location of an electrically plant, it is clear that the society will be interested to know the impacts generated on the environment and health, thus eventually these external effects must be included on the decision-making process. However, the estimation of the effects of pollution on health has a high degree of uncertainty. An important part of that uncertainty is not scientific, but derives from the results of ethical choices and lack of awareness of the future. All this implies a multidisciplinary systems analysis, with input from engineers, public health professionals, epidemiologists, ecologists and economists.

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