RESUMO
Hemorrhagic shock and subsequent resuscitation can cause significant dysregulation of critical systems, including the vascular endothelium. Following hemorrhage, the endothelial lining (glycocalyx) can shed, causing release of glycocalyx components, endothelial activation, and systemic inflammation. A canine model of hemorrhagic shock was used to evaluate five resuscitation fluids, including Lactated Ringers+Hetastarch, Whole Blood (WB), Fresh Frozen Plasma+packed Red Blood Cells (FFP+pRBC), and two hemoglobin-based oxygen carrier (HBOC) fluids, for their impact on glycocalyx shedding. Under anesthesia, purpose-bred adult canines were instrumented and subjected to a controlled hemorrhage with blood being drawn until a mean arterial pressure of <50â¯mmHg was reached or 40â¯% of the estimated blood volume was removed. Canines were left in shock for 45â¯mins before being resuscitated with one of the resuscitation fluids over 30â¯mins. Following resuscitation, the dogs were monitored up to 2 weeks. Following an additional 3-4 weeks for washout, the canines repeated the protocol, undergoing each resuscitation fluid individually. Blood samples were collected during each round at various timepoints for serum isolation, which was used for detection of glycocalyx biomarker. Comparison of baseline and post-hemorrhage alone showed a significant reduction in serum protein (p<0.0001), heparan sulfate (p<0.001), and syndecan-1 (p<0.0001) concentrations, and a significant increase in hyaluronan (p<0.0001) concentration. Intercomparisons of resuscitation fluids indicated minimal differences in glycocalyx markers over time. Comparisons within each fluid showed dynamic responses in glycocalyx biomarkers over time. Relative to individual baselines, syndecan-1 was significantly reduced after resuscitation in most cases (p<0.0001), excluding WB and FFP+pRBC. In all cases, VE-cadherin was significantly elevated at 24â¯hr compared to baseline (p<0.001). Hyaluronan was significantly elevated by 3â¯hr in all cases (p<0.01), except for HBOC fluids. Total glycosaminoglycans were significantly reduced only at 3â¯hr (p<0.001) for non-HBOC fluids. Similarly, heparan sulfate was significantly reduced with all fluids between resuscitation and 24â¯hr (p<0.01), except WB. The temporal changes in canine glycocalyx biomarkers were atypical of hemorrhage response in other species. This suggests that the hemorrhage lacked severity and/or typical glycocalyx biomarkers do not reflect the canine endothelium compared to other species. Further research is needed to characterize the canine endothelium and the response to resuscitation fluids.
RESUMO
BACKGROUND: Treatment of severe hemorrhagic shock typically involves hemostatic resuscitation with blood products. However, logistical constraints often hamper the wide distribution of commonly used blood products like whole blood. Shelf-stable blood products and blood substitutes are poised to be able to effectively resuscitate individuals in hemorrhagic shock when more conventional blood products are not readily available. METHODS: Purpose-bred adult dogs (n = 6) were anesthetized, instrumented, and subjected to hemorrhagic shock (mean arterial pressure <50 mm Hg or 40% blood volume loss). Then each dog was resuscitated with one of five resuscitation products: (1) lactated ringers solution and hetastarch (LRS/Heta), (2) canine chilled whole blood (CWB), (3) fresh frozen plasma (FFP) and packed red blood cells (pRBC), (4) canine freeze-dried plasma (FDP) and hemoglobin-based oxygen carrier (HBOC), or (5) HBOC/FDP and canine lyophilized platelets (LyoPLT). Each dog was allowed to recover after the hemorrhage resuscitation event and was then subjected to another hemorrhage event and resuscitated with a different product until each dog was resuscitated with each product. RESULTS: At the time when animals were determined to be out of shock as defined by a shock index <1, mean arterial pressure (mmHg) values (mean ± standard error) were higher for FFP/pRBC (n = 5, 83.7 ± 4.5) and FDP/HBOC+LyoPLT (n = 4, 87.8 ± 2.1) as compared with WB (n = 4, 66.0 ± 13.1). A transient increase in creatinine was seen in dogs resuscitated with HBOC and FDP. Albumin and base excess increased in dogs resuscitated with HBOC and FDP products compared with LRS/heta and CWB ( p < 0.01). CONCLUSION: Combinations of shelf-stable blood products compared favorably to canine CWB for resolution of shock. Further research is needed to ascertain the reliability and efficacy of these shelf-stable combinations of products in other models of hemorrhage that include a component of tissue damage as well as naturally occurring trauma.
Assuntos
Modelos Animais de Doenças , Ressuscitação , Choque Hemorrágico , Animais , Cães , Choque Hemorrágico/terapia , Ressuscitação/métodos , Plasma , Substitutos Sanguíneos , Derivados de Hidroxietil Amido/administração & dosagemRESUMO
The TEG 6s (Haemonetics) point-of-care viscoelastic analyzer is portable, compact, simple to use, and has the potential for rapid viscoelastic analysis that can guide the treatment of veterinary patients at the site of care. Although approved for use in people, the TEG 6s has yet to be evaluated for hemostatic analysis in veterinary medicine. Citrated whole blood (CWB) was collected from 27 healthy dogs. An aliquot of CWB from each dog was diluted by 33% with an isotonic crystalloid, representing an in vitro model of hemodilution. Unaltered and diluted CWB samples were analyzed using 2 TEG 6s and 6 TEG 5000 (Haemonetics) analyzers. The 6 TEG 5000 analyzers ran duplicate analyses of either unaltered or diluted samples using 1 of 3 reagents (Haemonetics): Kaolin TEG, RapidTEG, or TEG Functional Fibrinogen. Duplicate TEG 5000 analyses were averaged and compared with a single TEG 6s analysis. Lin concordance correlation coefficient and Bland-Altman plots were used to evaluate agreement of reaction time, kinetic time, alpha angle, maximum amplitude (MA), and G value (G) for samples activated with Kaolin TEG, and agreement of MA for samples activated with RapidTEG between the 2 machines. Overall, agreement between the TEG 6s and TEG 5000 analyzers was poor. Viscoelastic measurements by the TEG 6s and TEG 5000 in healthy dogs were not all interchangeable. Agreement was satisfactory only for MA and G measurements of diluted blood samples activated with Kaolin TEG, and MA measurements for both unaltered and diluted blood samples activated with RapidTEG.
Assuntos
Caulim , Tromboelastografia , Animais , Coagulação Sanguínea , Testes de Coagulação Sanguínea/veterinária , Citratos , Cães , Hemostasia , Humanos , Tromboelastografia/veterináriaRESUMO
OBJECTIVE: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials. METHODS: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10â mg/kg), isotype control or vehicle for 7, 14 or 28â days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3-8â weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing. RESULTS: Gait deficiency in untreated rats was present 3-7â days after MMT surgery, with a return to normal weight-bearing by days 14-28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3-8â weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats. CONCLUSIONS: These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Cartilagem Articular/lesões , Fator de Crescimento Neural/antagonistas & inibidores , Lesões do Menisco Tibial/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/toxicidade , Artrite Experimental/induzido quimicamente , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos/métodos , Marcha , Masculino , Meniscos Tibiais/diagnóstico por imagem , Meniscos Tibiais/patologia , Radiografia , Ratos Endogâmicos Lew , Lesões do Menisco Tibial/diagnóstico por imagem , Lesões do Menisco Tibial/patologia , Lesões do Menisco Tibial/fisiopatologia , Suporte de Carga , Microtomografia por Raio-XRESUMO
Increased protein levels of striatal-enriched tyrosine phosphatase (STEP) have recently been reported in postmortem schizophrenic cortex. The present study sought to replicate this finding in a separate cohort of postmortem samples and to extend observations to striatum, including subjects with bipolar disorder and major depressive disorder in the analysis. No statistically significant changes between disease and control subjects were found in STEP mRNA or protein levels in dorsolateral prefrontal cortex or associative striatum. Although samples were matched for several covariates, postmortem interval correlated negatively with STEP protein levels, emphasizing the importance of including these analyses in postmortem studies.
Assuntos
Transtorno Bipolar/enzimologia , Transtorno Depressivo Maior/enzimologia , Neostriado/enzimologia , Córtex Pré-Frontal/enzimologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Esquizofrenia/enzimologia , Autopsia , Transtorno Bipolar/genética , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Fosfatases não Receptoras/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esquizofrenia/genéticaRESUMO
An important aspect of the enhanced pre- and postnatal developmental (ePPND) toxicity study in nonhuman primates (NHP) is that it combines in utero and postnatal assessments in a single study. However, it is unclear if NHP ePPND studies are suitable to perform all of the evaluations incorporated into rodent PPND studies. To understand the value of including cognitive assessment in a NHP ePPND toxicity study, we performed a power analysis of object discrimination reversal task data using a modified Wisconsin General Testing Apparatus (ODR-WGTA) from two NHP ePPND studies. ODR-WGTA endpoints evaluated were days to learning and to first reversal, and number of reversals. With α = 0.05 and a one-sided t-test, a sample of seven provided 80% power to predict a 100% increase in all three of the ODR-WGTA endpoints; a sample of 25 provided 80% power to predict a 50% increase. Similar power analyses were performed with data from the Cincinnati Water Maze (CWM) and passive avoidance tests from three rat PPND toxicity studies. Groups of 5 and 15 in the CWM and passive avoidance test, respectively, provided 80% power to detect a 100% change. While the power of the CWM is not far superior to the NHP ODR-WGTA, a clear advantage is the routine use of larger sample size, with a group of 20 rats the CWM provides ~90% power to detect a 50% change. Due to the limitations on the number of animals, the ODR-WGTA may not be suitable for assessing cognitive impairment in NHP ePPND studies.
Assuntos
Transtornos Cognitivos/diagnóstico , Discriminação Psicológica , Desenvolvimento Embrionário , Macaca fascicularis/embriologia , Macaca fascicularis/crescimento & desenvolvimento , Estatística como Assunto , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva , Feminino , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Tamanho da Amostra , Análise e Desempenho de TarefasRESUMO
Behavior patterns (including behavior disorders) of cynomolgus monkeys are established early in life, and exploratory behavior lessens with age. Whether environmental enrichment programs benefit these animals can be questioned, particularly for animals housed short-term. We evaluated the overall effect of our environmental enrichment program in 40 newly arrived male and female adult cynomolgus monkeys to determine whether it impacted animal well-being. Animals allocated into two groups one that received environmental enrichment (the enriched group) and one that did not (the nonenriched, control group) and behaviors were assessed over a 5-week period. We also examined the effect of enrichment on training time for a simple activity (entering a transfer box). Animals that had environmental enrichment made use of additional cage space, toys, and foraging items, but trends in observed in-cage behavior patterns were relatively unchanged throughout the course of the study. After study completion, physical evidence of self-trauma was found in 25% of the nonenriched animals but not in any of those in the enriched group. Enrichment had no notable effect on body weight or training time for a simple activity. Our findings suggest that provision of a comprehensive environmental enrichment program provides a beneficial effect to adult cynomolgus macaques singly housed short-term.