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1.
J Orthop Trauma ; 36(Suppl 1): S14-S20, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34924514

ABSTRACT

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.


Subject(s)
Multiple Trauma , Orthopedic Procedures , Orthopedics , Humans , Multiple Trauma/surgery , Precision Medicine , Prospective Studies
2.
Shock ; 36(2): 196-202, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21558981

ABSTRACT

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.


Subject(s)
Cell Hypoxia/physiology , Hepatocytes/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Membrane Proteins/metabolism , Mitochondrial Proteins/metabolism , Animals , Blotting, Western , Cell Hypoxia/genetics , Cell Line , Cell Survival/genetics , Cell Survival/physiology , Cells, Cultured , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Hepatocytes/cytology , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mitochondrial Proteins/genetics , RNA, Small Interfering
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