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Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people.
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Lesões Encefálicas Traumáticas , Linfócitos T CD8-Positivos , Camundongos Endogâmicos C57BL , Animais , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Masculino , Envelhecimento/efeitos dos fármacos , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologiaRESUMO
INTRODUCTION: Trauma during pregnancy is the leading cause of non-obstetric maternal death and complicates up to 5%-7% of pregnancies. This systematic review without meta-analysis explores the current literature regarding the assessment and management of pregnant trauma patients to provide evidence-based recommendations to guide the general surgeon regarding the prognostic value of laboratory testing including Kleihauer-Betke testing, duration of maternal and fetal monitoring, the use of tranexamic acid, the safety of radiographic studies, and the utility of perimortem cesarean section to improve maternal and fetal mortality. MATERIALS AND METHODS: A systematic search of MEDLINE (Ovid), the Cochrane Library (Wiley), and Embase (Elsevier) was performed. The reference lists of included studies were reviewed for relevant citations. RESULTS: Of the 45 studies included in this review, there was reasonable evidence to suggest that the minimally injured pregnant trauma patient should be observed for a minimum of 4 h, CT scans to rule out traumatic injury are necessary and safe, perimortem cesarean sections should be performed as soon as maternal cardiac arrest occurs. CONCLUSIONS: We recommend delivery by perimortem cesarean section as soon as possible after maternal cardiac arrest, to provide TXA to the hemorrhaging pregnant trauma patient, to obtain trauma CT scans as indicated, and to observe the injured pregnant patient for a minimum of at least 4 h. Additional high-quality studies focusing on the prognostic potential of KB tests and other laboratory studies are needed.
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Cesárea , Parada Cardíaca , Gravidez , Humanos , FemininoRESUMO
BACKGROUND: Traumatic brain injury (TBI) is an under-recognized public health threat. Even mild brain injuries can lead to long-term neurologic impairment. Microglia play a fundamental role in the development and progression of this ensuing neurologic impairment. Despite this, a microglia-specific injury signature has yet to be identified. We hypothesized that TBI would lead to long-term changes in the transcriptional profile of microglial pathways associated with the development of subsequent neurologic impairment. MATERIALS AND METHODS: Male C57BL/6 mice underwent TBI via a controlled cortical impact and were followed longitudinally. FACSorted microglia from TBI mice were subjected to Quantiseq 3'-biased RNA sequencing at 7, 30, and 90 d after TBI. K-means clustering on 396 differentially expressed genes was performed, and gene ontology enrichment analysis was used to determine corresponding enriched processes. RESULTS: Differentially expressed genes in microglia exhibited four main patterns of expression over the course of TBI. In particular, we identified four gene clusters which corresponded to the host defense response, synaptic plasticity, lipid remodeling, and membrane polarization. CONCLUSIONS: Transcriptional profiling within individual populations of microglia after TBI remains a critical unmet research need within the field of TBI. This focused study identified several physiologic processes within microglia that may be associated with development of long-term neurologic impairment after TBI. These data demonstrate the capability of longitudinal transcriptional profiling to uncover potential cell-specific targets for the treatment of TBI.
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Lesões Encefálicas Traumáticas/patologia , Microglia/patologia , Doenças do Sistema Nervoso/patologia , Transdução de Sinais/genética , Animais , Lesões Encefálicas Traumáticas/complicações , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Família Multigênica/genética , Doenças do Sistema Nervoso/etiologia , Plasticidade Neuronal/genética , Fatores de Tempo , Regulação para CimaRESUMO
Traumatic brain injury (TBI) results in rapid recruitment of leukocytes into the injured brain. Monocytes constitute a significant proportion of the initial infiltrate and have the potential to propagate secondary brain injury or generate an environment of repair and regeneration. Monocytes are a diverse population of cells (classical, intermediate, and nonclassical) with distinct functions, however, the recruitment order of these subpopulations to the injured brain largely remains unknown. Thus, we examined which monocyte subpopulations are required for the generation of early inflammatory infiltrate within the injured brain, and whether their depletion attenuates secondary injury or neurocognitive outcome. Global monocyte depletion correlated with significant improvements in brain edema, motor coordination, and working memory, and abrogated neutrophil infiltration into the injured brain. However, targeted depletion of classical monocytes alone had no effect on neutrophil recruitment to the site of injury, implicating the nonclassical monocyte in this process. In contrast, mice that have markedly reduced numbers of nonclassical monocytes (CX3CR1-/-) exhibited a significant reduction in neutrophil infiltration into the brain after TBI as compared with control mice. Our data suggest a critical role for nonclassical monocytes in the pathology of TBI in mice, including important clinical outcomes associated with mortality in this injury process.
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Lesões Encefálicas Traumáticas/imunologia , Macrófagos/imunologia , Transtornos Neurocognitivos/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Animais , Lesões Encefálicas Traumáticas/fisiopatologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Microambiente Celular , Edema , Humanos , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos Neurocognitivos/fisiopatologia , Desempenho PsicomotorRESUMO
ABSTRACT: Patients 65 years and older account for an increasing proportion of traumatic brain injury (TBI) patients. Aged TBI patients experience increased morbidity and mortality compared with young TBI patients. We previously demonstrated a marked accumulation of CD8 + T-cells within the brains of aged TBI mice compared with young TBI mice. Therefore, we hypothesized that blocking peripheral T-cell infiltration into the injured brain would improve neurocognitive outcomes in aged mice after TBI. Young and aged male C57BL/6 mice underwent TBI via controlled cortical impact versus sham injury. Two hours after injuries, mice received an anti-CD49d antibody (aCD49d Ab) to block peripheral lymphocyte infiltration or its isotype control. Dosing was repeated every 2 weeks. Mortality was tracked. Neurocognitive testing for anxiety, associative learning, and memory was assessed. Motor function was evaluated. Plasma was collected for cytokine analysis. Flow cytometry was used to phenotype different immune cells within the brains. Consequently, aCD49d Ab treatment significantly improved post-TBI survival, anxiety level, associative learning, memory, and motor function in aged mice 2 months after TBI compared with isotype control treated mice. aCD49d Ab treatment augmented T H 2 response in the plasma of aged mice 2 months after TBI compared with isotype control-treated mice. Notably, aCD49d Ab treatment significantly reduced activated CD8 + cytotoxic T-cells within aged mouse brains after TBI. Contrastingly, no difference was detected in young mice after aCD49d Ab treatment. Collectively, aCD49 Ab treatment reduced T-cells in the injured brain, improved survival, and attenuated neurocognitive and gait deficits. Hence, aCD49d Ab may be a promising therapeutic intervention in aged TBI subjects-a population often excluded in TBI clinical trials.
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Lesões Encefálicas Traumáticas , Humanos , Animais , Camundongos , Masculino , Idoso , Camundongos Endogâmicos C57BL , Lesões Encefálicas Traumáticas/tratamento farmacológico , Encéfalo , Citocinas , Modelos Animais de DoençasRESUMO
Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people. Graphic abstract: Aged brains after TBI comprise two pools of CD8 + T cells . The aged brain has long been resided by a population of CD8 + T cells that's exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8 + T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8 + T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.
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BACKGROUND: Injury Severity Score (ISS) is a measurement of injury severity based on the Abbreviated Injury Scale. Because of the difficulty and expense of Abbreviated Injury Scale coding, there have been recent efforts in mapping ISS from administrative International Classification of Diseases ( ICD ) codes instead. Specifically, the open source and freely available International Classification of Diseases Programs for Injury Categorization (ICDPIC) in R (Foundation for Statistical Computing, Vienna, Austria) converts International Classification of Diseases, Ninth Revision, codes to ISS. This study aims to compare ICDPIC calculations versus manually derived Trauma Quality Improvement Program (TQIP) calculations for International Classification of Diseases, Tenth Revision ( ICD-10 ), codes. Moderate concordance was chosen as the hypothetical relationship because of previous work by both Fleischman et al. ( J Trauma Nurs. 2017;24(1):4-14) who found moderate to substantial concordance between ICDPIC and ISS and Di Bartolomeo et al. ( Scand J Trauma Resusc Emerg Med. 2010;18(1):17) who found none to slight concordance. Given these very different findings, we thought it reasonable to predict moderate concordance with the use of more detailed ICD-10 codes. METHODS: This was an observational cohort study of 1,040,728 encounters in the TQIP registry for the year 2018. International Classification of Diseases Programs for Injury Categorization in R was used to derive ISS from the ICD-10 codes in the registry. The resulting scores were compared with the manually derived ISS in TQIP. RESULTS: The median difference between ISS calculated by ICDPIC-2021 using ICD-10, Clinical Modification (ISS-ICDPIC), and manually derived ISS was -3 (95% confidence interval, -5 to 0), while the mean difference was -2.09 (95% confidence interval, -2.10 to -2.07). There was substantial concordance between ISS-ICDPIC and manually derived ISS ( κ = 0.66). The ISS-ICDPIC was a better predictor of mortality (area under the curve, 0.853 vs. 0.836) but a worse predictor of intensive care unit admission (area under the curve, 0.741 vs. 0.757) and hospital stay ≥10 days (AUC, 0.701 vs. 0.743). The ICDPIC has substantial concordance with TQIP for the firearm ( κ = 0.69), motor vehicle trauma ( κ = 0.71), and pedestrian ( κ = 0.73) injury mechanisms. CONCLUSION: When TQIP data are unavailable, ICDPIC remains a valid way to calculate ISS after transition to ICD-10 codes. The ISS-ICDPIC performs well in predicting a number of outcomes of interest but is best served as a predictor of mortality. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.
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Classificação Internacional de Doenças , Ferimentos e Lesões , Humanos , Escala de Gravidade do Ferimento , Melhoria de Qualidade , Escala Resumida de Ferimentos , Prognóstico , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/terapiaRESUMO
ABSTRACT: Aged traumatic brain injury (TBI) patients suffer increased mortality and long-term neurocognitive and neuropsychiatric morbidity compared with younger patients. Microglia, the resident innate immune cells of the brain, are complicit in both. We hypothesized that aged microglia would fail to return to a homeostatic state after TBI and adopt a long-term injury-associated state within aged brains compared with young brains after TBI. Young and aged male C57BL/6 mice underwent TBI via controlled cortical impact versus sham injury and were sacrificed 4 months post-TBI. We used single-cell RNA sequencing to examine age-associated cellular responses after TBI. Brains were harvested, and CD45+ cells were isolated via fluorescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3' Reagent Kit, followed by sequencing on a HiSeq 4,000 instrument and computational analyses. Post-injury, aged mice demonstrated a disparate microglial gene signature and an increase in infiltrating T cells compared with young adult mice. Notably, aged mice post-injury had a subpopulation of age-specific, immune-inflammatory microglia resembling the gene profile of neurodegenerative disease-associated microglia with enriched pathways involved in leukocyte recruitment and brain-derived neurotrophic factor signaling. Meanwhile, post-injury, aged mice demonstrated heterogeneous T-cell infiltration with gene profiles corresponding to CD8 effector memory, CD8 naive-like, CD8 early active T cells, and Th1 cells with enriched pathways, such as macromolecule synthesis. Taken together, our data showed that the aged brain had an age-specific gene signature change in both T-cell infiltrates and microglia, which may contribute to its increased vulnerability to TBI and the long-term sequelae of TBI.
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Lesões Encefálicas Traumáticas , Doenças Neurodegenerativas , Animais , Masculino , Camundongos , Fatores Etários , Lesões Encefálicas Traumáticas/complicações , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Linfócitos T , Adaptação FisiológicaRESUMO
ABSTRACT: Background: Traumatic brain injury (TBI) is an underrecognized public health threat. The constitutive activation of microglia after TBI has been linked to long-term neurocognitive deficits and the progression of neurodegenerative disease. Evolving evidence indicates a critical role for the gut-brain axis in this process. Specifically, TBI has been shown to induce the depletion of commensal gut bacteria. The resulting gut dysbiosis is associated with neuroinflammation and disease. Hypothesis: We hypothesized that fecal microbiota transplantation would attenuate microglial activation and improve neuropathology after TBI. Methods: C57Bl/6 mice were subjected to severe TBI (n = 10) or sham injury (n = 10) via an open-head controlled cortical impact. The mice underwent fecal microbiota transplantation (FMT) or vehicle alone via oral gavage once weekly for 4 weeks after injury. At 59 days after TBI, mice underwent three-dimensional, contrast-enhanced magnetic resonance imaging. Following imaging, mice were killed, brains harvested at 60 DPI, and CD45+ cells isolated via florescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3' Reagent kit followed by sequencing on a HiSeq4000 instrument, and computational analysis was performed. Results: Fecal microbiota transplantation resulted in a >marked reduction of ventriculomegaly (P < 0.002) and preservation of white matter connectivity at 59 days after TBI (P < 0.0001). In addition, microglia from FMT-treated mice significantly reduced inflammatory gene expression and enriched pathways involving the heat-shock response compared with mice treated with vehicle alone. Conclusions: We hypothesized that restoring gut microbial community structure via FMT would attenuate microglial activation and reduce neuropathology after TBI. Our data demonstrated significant preservation of cortical volume and white matter connectivity after an injury compared with mice treated with vehicle alone. This preservation of neuroanatomy after TBI was associated with a marked reduction in inflammatory gene expression within the microglia of FMT-treated mice. Microglia from FMT-treated mice enriched pathways in the heat-shock response, which is known to play a neuroprotective role in TBI and other neurodegenerative disease processes.
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Lesões Encefálicas Traumáticas , Microbiota , Doenças Neurodegenerativas , Camundongos , Animais , Transplante de Microbiota Fecal , Doenças Neuroinflamatórias , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Lesões Encefálicas Traumáticas/microbiologia , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Cromo/metabolismoRESUMO
BACKGROUND: Traumatic brain injury (TBI) is an underrecognized public health threat. Survivors of TBI often suffer long-term neurocognitive deficits leading to the progressive onset of neurodegenerative disease. Recent data suggests that the gut-brain axis is complicit in this process. However, no study has specifically addressed whether fecal microbiota transfer (FMT) attenuates neurologic deficits after TBI. HYPOTHESIS: We hypothesized that fecal microbiota transfer would attenuate neurocognitive, anatomic, and pathologic deficits after TBI. METHODS: C57Bl/6 mice were subjected to severe TBI (nâ=â20) or sham-injury (nâ=â20) via an open-head controlled cortical impact. Post-injury, this cohort of mice underwent weekly oral gavage with a slurry of healthy mouse stool or vehicle alone beginning 1âh post-TBI followed by behavioral testing and neuropathologic analysis. 16S ribosomal RNA sequencing of fecal samples was performed to characterize gut microbial community structure pre- and post-injury. Zero maze and open field testing were used to evaluate post-traumatic anxiety, exploratory behavior, and generalized activity. 3D, contrast enhanced, magnetic resonance imaging was used to determine differences in cortical volume loss and white matter connectivity. Prior to euthanasia, brains were harvested for neuropathologic analysis. RESULTS: Fecal microbiome analysis revealed a large variance between TBI, and sham animals treated with vehicle, while FMT treated TBI mice had restoration of gut dysbiosis back to levels of control mice. Neurocognitive testing demonstrated a rescue of normal anxiety-like and exploratory behavior in TBI mice treated with FMT. FMT treated TBI mice spent a greater percentage of time (22%, Pâ=â0.0001) in the center regions of the Open Field as compared to vehicle treated TBI mice (13%). Vehicle-treated TBI animals also spent less time (19%) in the open areas of zero maze than FMT treated TBI mice (30%, Pâ=â0.0001). Comparing in TBI mice treated with FMT, MRI demonstrated a marked attenuation in ventriculomegaly (Pâ<â0.002) and a significant change in fractional anisotropy (i.e., loss of white matter connectivity) (Pâ<â0.0001). Histologic analysis of brain sections revealed a FMT- injury dependent interaction in the microglia/macrophage-specific ionized calcium-binding protein, Iba1 (Pâ=â0.002). CONCLUSION: These data suggest that restoring a pre-injury gut microbial community structure may be a promising therapeutic intervention after TBI.
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Lesões Encefálicas Traumáticas , Microbioma Gastrointestinal , Doenças Neurodegenerativas , Animais , Lesões Encefálicas Traumáticas/patologia , Disbiose/terapia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/genética , Humanos , CamundongosRESUMO
The CDC estimate that nearly 3 million Americans sustain a traumatic brain injury (TBI) each year. Even when medical comorbidities are accounted for, age is an independent risk factor for poor outcome after TBI. Nonetheless, few studies have examined the pathophysiology of age-linked biologic outcomes in TBI. We hypothesized that aged mice would demonstrate more severe neuropathology and greater functional deficits as compared to young adult mice after equivalent traumatic brain injuries. Young adult (14-week-old) and aged (80-week-old) C57BL/6 male mice underwent an open-head controlled cortical impact to induce TBI or a sham injury. At 30-days post-injury groups underwent behavioral phenotyping, magnetic resonance imaging, and histologic analyses. Contrary to our hypothesis, young adult TBI mice exhibited more severe neuropathology and greater loss of white matter connectivity as compared to aged mice after TBI. These findings correlated to differential functional outcomes in anxiety response, learning, and memory between young adult and aged mice after TBI. Although the mechanisms underlying this age-effect remain unclear, attenuated signs of secondary brain injury in aged TBI mice point towards different inflammatory and repair processes between age groups. These data suggest that age may need to be an a priori consideration in future clinical trial design.
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Envelhecimento/patologia , Envelhecimento/fisiologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/patologia , Recuperação de Função Fisiológica/fisiologia , Animais , Imageamento por Ressonância Magnética/métodos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Resultado do TratamentoRESUMO
Traumatic brain injury (TBI) has a bimodal age distribution with peak incidence at age 24 and age 65 with worse outcomes developing in aged populations. Few studies have specifically addressed age at the time of injury as an independent biologic variable in TBI-associated secondary pathology. Within the framework of our published work, identifying age related effects of TBI on neuropathology, cognition, memory and motor function we analyzed fecal pellets collected from young and aged TBI animals to assess for age-induced effects in TBI induced dysbiosis. In this follow up, work we hypothesized increased dysbiosis after TBI in aged (80-week-old, N=10) versus young (14-week-old, N=10) mice. C57BL/6 males received a sham incision or TBI via open-head controlled cortical impact. Fresh stool pellets were collected 1-day pre-TBI, then 1, 7, and 28-days post-TBI for 16S rRNA gene sequencing and taxonomic analysis. Data revealed an age induced increase in disease associated microbial species which were exacerbated by injury. Consistent with our hypothesis, aged mice demonstrated a high number of disease associated changes to the gut microbiome pre- and post-injury. Our data suggest divergent microbiome phenotypes in injury between young and aged reflecting a previously unknown interaction between age, TBI, and the gut-brain axis implying the need for different treatment strategies.
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The Centers for Disease Control and Injury Prevention estimate that almost 2 million people sustain a traumatic brain injury (TBI) every year in the United States. In fact, TBI is a contributing factor to over a third of all injury-related mortality. Nonetheless, the cellular and molecular mechanisms underlying the pathophysiology of TBI are poorly understood. Thus, preclinical models of TBI capable of replicating the injury mechanisms pertinent to TBI in human patients are a critical research need. The controlled cortical impact (CCI) model of TBI utilizes a mechanical device to directly impact the exposed cortex. While no model can full recapitulate the disparate injury patterns and heterogeneous nature of TBI in human patients, CCI is capable of inducing a wide range of clinically applicable TBI. Furthermore, CCI is easily standardized allowing investigators to compare results across experiments as well as across investigative groups. The following protocol is a detailed description of applying a severe CCI with a commercially available impacting device in a murine model of TBI.
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Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Animais , Masculino , CamundongosRESUMO
To assess the degree of lymphocyte apoptosis and survival in mice treated with small interfering RNA (siRNA) targeted to Bim, a proapoptotic molecule from the Bcl-2 family, within a clinically relevant model of sepsis. C57BL/6 mice were treated with a single dose of Bim siRNA complexed in cationic liposomes via tail vein injection. Approximately 24 h later, mice were subjected to either cecal ligation and puncture (CLP) or sham surgery. Animals were killed at 20 h postsurgery, and spleens were harvested for fluorescence-activated cell sorting analysis using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling as a marker for apoptosis. A second cohort of mice was followed for survival for 7 days. The degree of lymphocyte apoptosis in Bim siRNA-treated mice was markedly decreased compared with controls. Fluorescent activated cell sorter analysis demonstrated 13.1% +/- 1.2% B-cell apoptosis and 11.5% +/- 1.5% T-cell apoptosis in control mice compared with 2.7% +/- 0.4% B-cell apoptosis and 3.9% +/- 0.3% T-cell apoptosis in Bim siRNA-treated mice after CLP (P < 0.001 and P < 0.01, respectively). This striking difference in lymphocyte apoptosis correlated with a significant survival advantage in Bim siRNA-treated mice. At 7 days, there was 90% overall survival in Bim siRNA-treated septic mice compared with 50% overall survival in control septic mice (P < 0.05). Treatment with Bim siRNA in vivo has the potential to be an effective therapy in the treatment of sepsis.
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Proteínas Reguladoras de Apoptose/genética , Apoptose/genética , Linfócitos/patologia , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/fisiologia , Sepse/mortalidade , Sepse/terapia , Animais , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/deficiência , Proteína 11 Semelhante a Bcl-2 , Células Cultivadas , Modelos Animais de Doenças , Raios gama , Humanos , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Peritonite/metabolismo , Peritonite/mortalidade , Peritonite/terapia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/deficiência , Sepse/metabolismo , Análise de SobrevidaRESUMO
Lymphocyte apoptosis plays a central role in the pathophysiology of sepsis. Lymphocyte apoptosis was examined in mice with defective death receptor pathways due to transgenic expression of a dominant negative mutant of Fas-associated death domain (FADD-DN) or Bid-/- and in mice with defective mitochondrial-mediated pathways due to loss of Bim-/-, Puma-/-, or Noxa-/-. FADD-DN transgenic and Bid-/- mice had significant albeit incomplete protection, and this protection was associated with increased survival. Surprisingly, splenic B cells were also protected in FADD-DN mice although transgene expression was confined to T cells, providing evidence for an indirect protective mechanism. Bim-/- provided virtually complete protection against lymphocyte apoptosis whereas Puma-/- and Noxa-/- mice had modest or no protection, respectively. Bim-/- mice had improved survival, and adoptive transfer of splenocytes from Bim-/- mice into Rag 1-/- mice demonstrated that this was a lymphocyte intrinsic effect. The improved survival was associated with decreased interleukin (IL) -10 and IL-6 cytokines. Collectively, these data indicate that numerous death stimuli are generated during sepsis, and it therefore appears unlikely that blocking a single "trigger" can inhibit apoptosis. If siRNA becomes practical therapeutically, proapoptotic proteins would be potential targets.
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Apoptose/fisiologia , Linfócitos/citologia , Mitocôndrias/fisiologia , Receptores de Morte Celular/fisiologia , Sepse/patologia , Animais , Caspase 8/genética , Caspase 8/metabolismo , Citocinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
This is the case of a 70-year-old woman who presented to the emergency department complaining of 2 hours of acute-onset epigastric pain. She had experienced this pain once before which had spontaneously resolved. Axial imaging demonstrated the cecum in an abnormal position within the lesser sac, as well as compression of the inferior vena cava and portal vein. She was taken emergently to the operating room for laparotomy, where a free-floating cecum and ascending colon was identified without ischemia, and a right hemicolectomy was performed. Foramen of Winslow hernias are rare internal hernias with a high rate of strangulation and bowel ischemia, requiring urgent surgical intervention. Operative treatment depends on the type of herniated viscera. Spontaneous reduction is not well documented.