René Alvarez

Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) beta has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-beta receptors. Three families of Smads have been identified: (i) receptor-regulated Smad2 and -3 (R-Smads); (ii) common partner Smad4 (Co-Smad); and (iii) inhibitory Smad6 and -7 (I-Smads, part of a negative feedback loop). We have investigated the signaling components for the TGF-beta pathway and TGF-beta activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-beta-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-beta signaling events, including phosphorylation of Smad2 and -3, and transcription of the PAI-1 gene are increased in scleroderma fibroblasts, relative to normal fibroblasts. In vitro adenoviral gene transfer with Smad7 restores normal TGF-beta signaling in scleroderma fibroblasts. These results suggest that alterations in the Smad pathway, including marked Smad7 deficiency and Smad3 up-regulation, may be responsible for TGF-beta hyperresponsiveness observed in scleroderma.

Tubulointerstitial changes in the diabetic kidney correlate closely with the decline in glomerular filtration. In this study, we used a cell culture system of mouse proximal tubule epithelial cells to test the effects of glucose on cell growth, size, and matrix biosynthesis. [3H]thymidine incorporation was significantly inhibited in cells grown in 450 mg/dl glucose, compared with cells grown in 100 mg/dl glucose. The cells grown in the higher glucose concentration were slightly larger, their protein content and the total protein synthetic rate were significantly increased, and they secreted approximately twice as much procollagens type IV and type I. Concordantly, steady-state procollagen mRNA levels were also increased: 2.6-fold for the alpha 1(IV) and 2.2-fold for the alpha 2(I) procollagens. Additionally, nuclear run-off studies demonstrated that procollagen gene transcription rate was stimulated approximately 50%; beta-actin transcription rate was not altered. We used chloramphenicol acetyltransferase (CAT) reporter gene constructs to determine whether the increased transcription rate of alpha 2(I) gene was associated with activation of its enhancer sequence. Cells transfected with the enhancer demonstrated more than fivefold increase in CAT activity when cultured in the high-glucose medium. These studies demonstrate a multitude of effects of high ambient glucose concentrations on proximal tubule cell growth and collagen biosynthesis; cell proliferation is decreased although cell hypertrophy occurs. Procollagen gene transcription rate is stimulated and this response contributes to the observed increase in procollagen mRNA content. Activation of an enhancer sequence may be one possible mode through which high glucose levels increase the transcription of procollagen type I, presumably involving trans-acting factor(s).

OBJECTIVES: Determine if clinical parameters of resuscitated patients predict coronary angiography (CATH) performance and if receiving CATH after cardiac arrest is associated with outcome. INTRODUCTION: CATH is associated with survival in patients suffering out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation or ventricular tachycardia(VF/VT). Its effect on outcome in other cohorts is unknown. METHODS: Chart review of resuscitated cardiac arrest patients between 2005 and 2007. EXCLUSION CRITERIA: immediate withdrawal of care, hemodynamic collapse, or neurologic exam under sedation. Clinical parameters included Glasgow Coma Scale (GCS) arrest location, presenting rhythm, age, and acute ischemic ECG changes (new left bundle branch block or ST-elevation myocardial infarction-STEMI). Logistic regression identified clinical parameters predicting CATH. The association between CATH and good outcome (discharge home or to acute rehabilitation facility) was determined using logistic regression adjusting for likelihood of receiving CATH via propensity score. RESULT: Of the 241 patients, 96 (40%) received CATH. Significant disease (>or=70% stenosis) of >or=1 coronary arteries was identified in 69% of patients including 57% of patients without acute ischemic ECG changes. Unadjusted predictors of CATH were sex, method of arrival, OHCA, presenting rhythm, acute ischemic ECG changes, and GCS. Propensity adjusted logistic regression demonstrated an association between CATH and good outcome (OR 2.16; 95% CI 1.12, 4.19; P<0.02). CONCLUSION: CATH is more likely to be performed in certain patients and identifies a significant number of high-grade stenoses in this population. Receiving CATH was independently associated with good outcome.