RESUMO
SUMMARY: Optimal timing and procedure selection that define staged treatment strategies can affect outcomes dramatically and remain an area of major debate in the treatment of multiply injured orthopaedic trauma patients. Decisions regarding timing and choice of orthopaedic procedure(s) are currently based on the physiologic condition of the patient, resource availability, and the expected magnitude of the intervention. Surgical decision-making algorithms rarely rely on precision-type data that account for demographics, magnitude of injury, and the physiologic/immunologic response to injury on a patient-specific basis. This study is a multicenter prospective investigation that will work toward developing a precision medicine approach to managing multiply injured patients by incorporating patient-specific indices that quantify (1) mechanical tissue damage volume; (2) cumulative hypoperfusion; (3) immunologic response; and (4) demographics. These indices will formulate a precision injury signature, unique to each patient, which will be explored for correspondence to outcomes and response to surgical interventions. The impact of the timing and magnitude of initial and staged surgical interventions on patient-specific physiologic and immunologic responses will be evaluated and described. The primary goal of the study will be the development of data-driven models that will inform clinical decision-making tools that can be used to predict outcomes and guide intervention decisions.
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Traumatismo Múltiplo , Procedimentos Ortopédicos , Ortopedia , Humanos , Traumatismo Múltiplo/cirurgia , Medicina de Precisão , Estudos ProspectivosRESUMO
OBJECTIVE: To identify changes in concentrations of inflammatory mediators in plasma and urine after traumatic spinal cord injury (SCI) and before the occurrence of a first pressure ulcer. DESIGN: Retrospective; secondary analysis of existing data. SETTING: Acute hospitalization and inpatient rehabilitation sites at a university medical center. PARTICIPANTS: Individuals with a pressure ulcer and plasma samples (n=17) and individuals with a pressure ulcer and urine samples (n=15) were matched by age and plasma/urine sample days to individuals with SCI and no pressure ulcer (N=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plasma and urine samples were assayed in patients with SCI, capturing samples within 4 days after the SCI to a week before the formation of the first pressure ulcer. The Wilcoxon signed-rank test was performed to identify changes in the inflammatory mediators between the 2 time points. RESULTS: An increase in concentration of the chemokine interferon-γ-induced protein of 10kd/CXCL10 in plasma (P<.01) and a decrease in concentration of the cytokine interferon-α in urine (P=.01) were observed before occurrence of a first pressure ulcer (â¼4d) compared with matched controls. CONCLUSIONS: Altered levels of inflammatory mediators in plasma and urine may be associated with pressure ulcer development after traumatic SCI. These inflammatory mediators should be explored as possible biomarkers for identifying individuals at risk for pressure ulcer formation.
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Mediadores da Inflamação/metabolismo , Úlcera por Pressão/metabolismo , Traumatismos da Medula Espinal/reabilitação , Centros Médicos Acadêmicos , Adulto , Biomarcadores , Quimiocina CXCL10/sangue , Quimiocina CXCL10/urina , Diagnóstico Precoce , Feminino , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/urina , Interferon-alfa/sangue , Interferon-alfa/urina , Masculino , Pessoa de Meia-Idade , Úlcera por Pressão/sangue , Úlcera por Pressão/urina , Estudos RetrospectivosRESUMO
BACKGROUND: Eosinophilic esophagitis (EoE) is an allergen-mediated, clinicopathological condition affecting all ages. The characteristics of children with EoE in the southwestern USA have not been fully described. Furthermore, very little is known about the relationship between parental allergies and risk of EoE in their offspring in this patient population. AIMS: To characterize children with EoE and to examine the relationship between prevalence of parental allergies and occurrence of EoE in their offspring at a single referral pediatric center in the southwestern USA. METHODS: Demographic and clinical information of 126 children (≤18 years of age) with EoE was abstracted in a pre-determined data extraction form and analyzed. The allergy history was collected from biological parents of 61 children (parent-child cluster) with EoE in a standardized questionnaire and analyzed. RESULTS: The median age at presentation was 8 years (interquartile range 4-13). The majority of our patients were male (71 %) and Caucasian (59 %). Overall, 84 % of children reported allergies. Prevalence of food allergy was significantly higher compared to environmental allergies (P = 0.001). At least 46 % of parents reported allergies. A significantly higher proportion of fathers had developed allergies during their childhood compared to adulthood (P = 0.03). CONCLUSIONS: The characteristics of EoE in our patients were similar to those reported from other parts of the country. Childhood onset of paternal allergies appears to be a risk factor for occurrence of EoE in their offspring. Additional research to elucidate the relationship between parental allergies and occurrence of EoE in their offspring is warranted.
Assuntos
Esofagite Eosinofílica/genética , Hipersensibilidade/genética , Adolescente , Adulto , Alérgenos , Asma , Criança , Pré-Escolar , Esofagite Eosinofílica/epidemiologia , Esofagite Eosinofílica/patologia , Feminino , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/patologia , Masculino , Texas/epidemiologiaRESUMO
We sought to investigate the expression of the cell death protein BNIP3 in hypoxic hepatocytes, as well as the role that hypoxia-inducible factor 1 (HIF-1α) plays in the upregulation of BNIP3 in hypoxic primary mouse hepatocytes and in the livers of mice subjected to ischemia-reperfusion. Freshly isolated mouse hepatocytes were exposed to 1% hypoxia for 1, 3, 6, 24, and 48 h, and the RNA and protein were isolated for reverse transcriptase-polymerase chain reaction and Western blot analysis. Similarly, livers from mice subjected to segmental (70%) hepatic warm ischemia for 30 min or 1 h, or to 1-h ischemia followed by 0.5- to 4-h reperfusion, were collected and subjected to Western blot analysis for HIF-1α protein. We showed that hypoxic stress increases the formation of the BNIP3 homodimer while decreasing the amount of the monomeric form of BNIP3 in primary mouse hepatocytes. In contrast to RAW264.7 macrophages, there is a basal expression of HIF-α protein in normoxic primary mouse hepatocytes that does not change significantly upon exposure to hypoxia. Using siRNA technology, we demonstrated that reduced HIF-1α protein levels did not block the hypoxia-induced overexpression of BNIP3. In contrast to the effect on BNIP3 expression reported previously, livers from ischemic animals demonstrated only a modest increase in HIF-1α protein as compared with resting livers from control animals; and this expression was not statistically different from sham controls. These results suggest that HIF-1α does not mediate the hypoxia-induced upregulation of BNIP3 in mouse hepatocytes in vitro and possibly in the liver in vivo.
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Hipóxia Celular/fisiologia , Hepatócitos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Western Blotting , Hipóxia Celular/genética , Linhagem Celular , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Hepatócitos/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , RNA Interferente PequenoRESUMO
Trauma and hemorrhagic shock elicit an acute inflammatory response, predisposing patients to sepsis, organ dysfunction, and death. Few approved therapies exist for these acute inflammatory states, mainly due to the complex interplay of interacting inflammatory and physiological elements working at multiple levels. Various animal models have been used to simulate these phenomena, but these models often do not replicate the clinical setting of multiple overlapping insults. Mathematical modeling of complex systems is an approach for understanding the interplay among biological interactions. We constructed a mathematical model using ordinary differential equations that encompass the dynamics of cells and cytokines of the acute inflammatory response, as well as global tissue dysfunction. The model was calibrated in C57Bl/6 mice subjected to (1) various doses of lipopolysaccharide (LPS) alone, (2) surgical trauma, and (3) surgery + hemorrhagic shock. We tested the model's predictive ability in scenarios on which it had not been trained, namely, (1) surgery +/- hemorrhagic shock + LPS given at times after the beginning of surgical instrumentation, and (2) surgery + hemorrhagic shock + bilateral femoral fracture. Software was created that facilitated fitting of the mathematical model to experimental data, as well as for simulation of experiments with various inflammatory challenges and associated variations (gene knockouts, inhibition of specific cytokines, etc.). Using this software, the C57Bl/6-specific model was recalibrated for inflammatory analyte data in CD14-/- mice and was used to elucidate altered features of inflammation in these animals. In other experiments, rats were subjected to surgical trauma +/- LPS or to bacterial infection via fibrin clots impregnated with various inocula of Escherichia coli. Mathematical modeling may provide insights into the complex dynamics of acute inflammation in a manner that can be tested in vivo using many fewer animals than has been possible previously.
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Simulação por Computador , Inflamação/fisiopatologia , Modelos Biológicos , Animais , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Knockout , RatosRESUMO
OBJECTIVE: To determine the feasibility and potential usefulness of mathematical models in evaluating immunomodulatory strategies in clinical trials of severe sepsis. DESIGN: Mathematical modeling of immunomodulation in simulated patients. SETTING: Computer laboratory. MEASUREMENTS AND MAIN RESULTS: We introduce and evaluate the concept of conducting a randomized clinical trial in silico based on simulated patients generated from a mechanistic mathematical model of bacterial infection, the acute inflammatory response, global tissue dysfunction, and a therapeutic intervention. Trial populations are constructed to reflect heterogeneity in bacterial load and virulence as well as propensity to mount and modulate an inflammatory response. We constructed a cohort of 1,000 trial patients submitted to therapy with one of three different doses of a neutralizing antibody directed against tumor necrosis factor (anti-TNF) for 6, 24, or 48 hrs. We present cytokine profiles over time and expected outcome for each cohort. We identify subgroups with high propensity for being helped or harmed by the proposed intervention and identify early serum markers for each of those subgroups. The mathematical simulation confirms the inability of simple markers to predict outcome of sepsis. The simulation clearly separates cases with favorable and unfavorable outcome on the basis of global tissue dysfunction. Control survival was 62.9% at 1 wk. Depending on dose and duration of treatment, survival ranged from 57.1% to 80.8%. Higher doses of anti-TNF, although effective, also result in considerable harm to patients. A statistical analysis based on a simulated cohort identified markers of favorable or adverse response to anti-TNF treatment. CONCLUSIONS: A mathematical simulation of anti-TNF therapy identified clear windows of opportunity for this intervention as well as populations that can be harmed by anti-TNF therapy. The construction of an in silico clinical trial could provide profound insight into the design of clinical trials of immunomodulatory therapies, ranging from optimal patient selection to individualized dosage and duration of proposed therapeutic interventions.