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Combined immunosuppressive therapy with low dose FK506 and antimetabolites in rat allogeneic heart transplantation
Following rat heterotopic heart allotransplantation, low to lethal doses of the antimetabolites mizoribine (MIZ), RS-61443 (RS), and AZA were given alone or in combination with subtherapeutic doses of FK506 (0.04 mg/kg/day) for 14 days after transplantation. With the median effect analysis of Chou and Kahan for quantitative drug interactions, substantial therapeutic synergism was demonstrated between FK506 and nontoxic doses of MĪZ (2.5, 5, and 10 mg/kg/day) or AZA (5, 30, and 45 mg/kg/day), which was particularly evident with the lowest dose MIZ (2.5 mg/kg/day). When FK506 was used in combination with MIZ or AZA but not with RS, the maximum effect (peak median graft survival) was enhanced significantly from 15 days (MIZ alone) to 26 days (P<0.05), and from 19 days (AZA alone) to 32 days (P<0.0l). In contrast, RS interacted with FK506 no more than additively. Although RS was the most powerful single antimetabolite, the best overall survival was obtained by combining AZA and FK506. The addition of FK506 did not significantly increase the percent mortality and LD50 of the antimetabolites. © 1994 by Williams and Wilkins
Origin of Native Driving Force in Protein Folding
We derive an expression with four adjustable parameters that reproduces well
the 20x20 Miyazawa-Jernigan potential matrix extracted from known protein
structures. The numerical values of the parameters can be approximately
computed from the surface tension of water, water-screened dipole interactions
between residues and water and among residues, and average exposures of
residues in folded proteins.Comment: LaTeX file, Postscript file; 4 pages, 1 figure (mij.eps), 2 table
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Elevated plasma levels of TIMP-3 are associated with a higher risk of acute respiratory distress syndrome and death following severe isolated traumatic brain injury.
BackgroundComplications after injury, such as acute respiratory distress syndrome (ARDS), are common after traumatic brain injury (TBI) and associated with poor clinical outcomes. The mechanisms driving non-neurologic organ dysfunction after TBI are not well understood. Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is a regulator of matrix metalloproteinase activity, inflammation, and vascular permeability, and hence has plausibility as a biomarker for the systemic response to TBI.MethodsIn a retrospective study of 182 patients with severe isolated TBI, we measured TIMP-3 in plasma obtained on emergency department arrival. We used non-parametric tests and logistic regression analyses to test the association of TIMP-3 with the incidence of ARDS within 8 days of admission and in-hospital mortality.ResultsTIMP-3 was significantly higher among subjects who developed ARDS compared with those who did not (median 2810 pg/mL vs. 2260 pg/mL, p=0.008), and significantly higher among subjects who died than among those who survived to discharge (median 2960 pg/mL vs. 2080 pg/mL, p<0.001). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of ARDS increased significantly, OR 1.5 (95% CI 1.1 to 2.1). This association was only attenuated in multivariate models, OR 1.4 (95% CI 1.0 to 2.0). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of death increased significantly, OR 1.7 (95% CI 1.2 to 2.3). The magnitude of this association was greater in a multivariate model adjusted for markers of injury severity, OR 1.9 (95% CI 1.2 to 2.8).DiscussionTIMP-3 may play an important role in the biology of the systemic response to brain injury in humans. Along with clinical and demographic data, early measurements of plasma biomarkers such as TIMP-3 may help identify patients at higher risk of ARDS and death after severe isolated TBI.Level of evidenceIII
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