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Biomedical subjects

N Silverman

Publications and source records attributed to N Silverman.

14 recordsLinked to original sources
PubMed1992

Genetic isolation of ADA2: a potential transcriptional adaptor required for function of certain acidic activation domains.

We have devised a genetic strategy to isolate the target of acidic activation domains of transcriptional activators based on toxicity in yeast cells of the chimeric activator, GAL4-VP16. Toxicity required the integrity of both the VP16 acidic activation domain and the GAL4 DNA-binding domain, suggesting that inhibition resulted from trapping of general transcription factors at genomic sites. Mutations that break the interaction between GAL4-VP16 and general factors would alleviate toxicity and identify transcriptional adaptors, if adaptors bridged the interaction between activators and general factors. We thus identified ADA1, ADA2, and ADA3. Mutations in ADA2 reduced the activity of GAL4-VP16 and GCN4 in vivo. ada2 mutant extracts exhibited normal basal transcription, but were defective in responding to GAL4-VP16, GCN4, or the dA:dT activator. Strikingly, the mutant extract responded like wild type to GAL4-HAP4. We conclude that ADA2 potentiates the activity of one class of acidic activation domain but not a second class.

Amino Acid Sequence↗
PubMed1991

Valve replacement in patients with endocarditis and cerebral septic emboli.

Cerebral septic emboli complicate the cases in 20% to 40% of patients with left-sided endocarditis but the management of these patients who require a valvar operation remains unclear. From 1980 to 1988, the incidence of cerebral septic embolus was 42% (n = 45) among 106 patients with endocarditis who underwent valve replacement at the University of Illinois Hospital in Chicago. Of these 45 patients, 69% (n = 31) had symptomatic cerebral septic infarctions and 31% (n = 14) were asymptomatic. Findings on cerebral computed tomographic scans included ischemic infarcts (n = 36, 80%), hemorrhagic infarcts (n = 5, 11%), normal studies (n = 2, 4%), and unknown (n = 2, 4%). Neurological complications after valve replacement included postoperative strokes (n = 6, 6%), cerebral abscesses (n = 2, 2%), and seizure (n = 1, 1%). The presence of a hemorrhagic infarct preoperatively predisposed to a perioperative stroke (p less than 0.05). In conclusion, cerebral septic infarctions, both symptomatic and asymptomatic, are common among patients with endocarditis referred for valvar operation. In the absence of a hemorrhagic infarct, valve replacement can be performed with minimal risk of a perioperative stroke.

Adolescent↗
PubMed1986

Diminished response of Werner's syndrome fibroblasts to growth factors PDGF and FGF.

Patients with Werner's syndrome, an autosomal recessive disorder, undergo an accelerated aging process that leads to premature death. Fibroblasts from such patients typically grow poorly in culture. Here it is shown that fibroblasts from a patient with Werner's syndrome have a markedly attenuated mitogenic response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). In contrast, they have a full mitogenic response to fetal bovine serum. Both PDGF binding and receptor numbers per cell are unaltered. The Werner's syndrome cells express high constitutive levels of collagenase in vitro. Although PDGF enhances collagenase expression through increased levels of hybridizable collagenase messenger RNA in normal skin fibroblasts, no induction of collagenase occurs in the Werner's syndrome fibroblasts. Moreover, the failure to respond to this agonist effect of PDGF is not restored by fetal bovine serum. The data suggest that failure of one or more PDGF-mediated pathways in Werner's syndrome cells may contribute to the phenotypic expression of the disorder.

Cell Division↗
PubMed1986

Oxygen utilization during isovolumic pressure-volume loading: effects of prolonged extracorporeal circulation and cardioplegic arrest.

In canine hearts supported by cardiopulmonary bypass, isovolumic peak developed pressure (PDP, mm Hg) and myocardial oxygen consumption (MVO2, ml O2 X 10(-2)/beat/100 gm left ventricular [LV] weight) were determined at 5-ml increments of LV balloon inflation before and after either 2 hours of potassium cardioplegic arrest (ischemia, N = 7) or a comparable period of normothermic perfusion without ischemia (control, N = 6). The sensitivity of MVO2 as a marker of ischemic injury was compared with preservation of both adenosine triphosphate (ATP) stores and systolic pump function. Over a physiological range of end-diastolic volumes (5 to 35 ml) and end-diastolic pressures (0 to 18 mm Hg), the Frank-Starling curves were not depressed following both cardioplegic arrest and prolonged nonischemic perfusion. Although ATP stores decreased by 26% and 22% (ischemia and control groups, respectively; not significant), these levels did not distinguish the effects of cardioplegic arrest from prolonged perfusion. At the preinterventional measurement in both groups, PDP between 50 and 200 correlated with MVO2 from 3.0 to 10.0 (r = +0.84). Following cardioplegic arrest, postischemic MVO2 increased 137 +/- 6% when measured over the PDP range of 75 to 200 mm Hg (p less than 0.01). This change was not evident at a PDP of less than 75, in the empty beating heart, or in control hearts subjected to nonischemic extracorporeal perfusion. These data suggest that increased utilization of oxygen to develop physiological pressures may be a more sensitive indicator of ischemic injury than shifts in the pressure-volume relationship or depletion of adenine nucleotide stores.

Adenosine Triphosphate↗
PubMed1986

Direct effect of high-dose insulin on the depressed heart after beta-blockade or ischemia.

The direct cardiac effects of high-dose insulin (HDI) were assessed in 13 canine hearts supported by cardiopulmonary bypass. Isovolumic peak developed pressure (PDP, mmHg), coronary blood flow (CBF, ml/beat/100 g LV) and myocardial oxygen consumption (MVO2, ml O2/beat/100 g LV) were determined during incremental left ventricular balloon inflation before and after functional depression by beta-blockade (0.2 mg/kg propranolol) or 2 hours cardioplegic ischemia at 28 degrees C. The 2 regimens gave an overall functional reduction of 46 +/- 3% and 42 +/- 2%, respectively. The hearts were then challenged with an aortic root bolus of 1000 IU insulin. A glucose clamp was maintained at physiological levels. Insulin reversed the negative inotropic effect of propranolol to 80% of control function and normalized heart rate. Despite the significant amelioration of systolic function by HDI, MVO2 indexed for cardiac effort did not change. Neither systolic function nor heart rate was changed in the ischemically depressed hearts. In conclusion, HDI reverses the negative inotropic effect of beta-adrenergic receptor blockade without augmenting oxygen utilization. Apart from effects ascribable to systemic vasodilation and metabolic shifts, no direct cardiac inotropic stimulation can be expected on the post-ischemically depressed, nondiabetic myocardium unless there is a persistent negative effect of beta-blockers.

Animals↗
PubMed1986

Myocardial energetics after thermally graded hyperkalemic crystalloid cardioplegic arrest.

Previous studies assessing the efficacy of myoprotective regimens have compared preischemic and postischemic myocardial oxygen consumption within a limited range of cardiac performance. However, recent data suggest that ischemia-induced perturbations in myocardial energetics may occur only when the left ventricle develops physiologic pressures. Therefore, in canine hearts supported by cardiopulmonary bypass, myocardial oxygen consumption (ml oxygen X 10(-2)/beat/100 gm left ventricular weight) was determined during incremental isovolumic pressure-volume loading before and 30 minutes after 2 hours of cardioplegic arrest. The ischemic insult was graded by maintaining myocardial temperature at 12 degrees C (Group I, n = 6), 20 degrees C (Group II, n = 7), or 28 degrees C (Group III, n = 6). Postischemic Starling curves were unchanged in Groups I and II but depressed 53% in Group III hearts (p less than 0.005). In Group I, postischemic myocardial oxygen consumption at specific peak developed pressures was similar to preischemic oxygen consumption. In contrast, postischemic Group II and III hearts consumed 39% more oxygen than preischemically when peak developed pressure exceeded 75 mm Hg (p less than 0.01). Postischemic hearts demonstrated reciprocal changes in arteriovenous oxygen content difference (24%, 30%, and 34% lower than preischemic values for Groups I, II, and III, respectively) and coronary blood flow (156%, 195%, and 192% higher than preischemic values for Groups I, II, and III, respectively). Only in Group II and III hearts did the increased coronary blood flow offset the defect in oxygen extraction such that myocardial oxygen consumption was increased. These data suggest that inefficient utilization of oxygen when the heart is developing physiologic pressures is a sensitive marker for myocardial injury after crystalloid cardioplegic arrest.

Animals↗
PubMed1983

Cardioplegia does not prevent reperfusion injury induced by intracoronary platelet deposition.

We have shown that after global myocardial ischemia, reperfusion injury may be related to platelet deposition in the coronary microcirculation. The purpose of this study was to determine whether multidose hypothermic potassium cardioplegia suppresses platelet deposition during postischemic reperfusion. Platelets labeled with 111In and erythrocytes labeled with 51Cr were injected into dogs subjected to either 120 min of continuous cardiopulmonary bypass (control, n = 4), 60 min of global normothermic myocardial ischemia followed by 50 min of reperfusion (n = 6), or global ischemia with cardioplegia (n = 5). Intracoronary platelet deposition was determined by comparing the double-labeled isotope activity of myocardial biopsy specimens to peripheral blood. Reperfusion after global myocardial ischemia resulted in substantial deposition of platelets within the coronary vasculature in both the cardioplegia-treated (215 +/- 40 platelets/mg) and untreated (269 +/- 95 platelets/mg) groups. These increases were significantly greater than those measured during continuous bypass (48 +/- 2 platelets/mg; p less than .01). Cardioplegia, despite apparent washout of the microcirculation, does not alter platelet deposition. Thus other platelet-stabilizing measures must be used to prevent platelet deposition-induced reperfusion injury after surgical global ischemia.

Animals↗
PubMed1983

Efficacy of pulmonary artery banding in infants with complete atrioventricular canal.

Total correction in infants less than 1 year old with complete atrioventricular (AV) canal carries a significant operative mortality. However, past reports suggest that the alternative palliative procedure, pulmonary artery banding (PAB), may be contraindicated in the presence of severe mitral insufficiency and/or a large left ventricular to right atrial shunt. Contrary to these previous reports, we report the results in 21 consecutive patients with congestive heart failure who underwent PAB at a mean age of 3.9 +/- 2.8 months and at a weight of 3.6 +/- 0.9 kg. (17/21 less than 6 months). Regardless of mitral valve competency, PAB was performed in conjunction with ligation of a patent ductus arteriosus (11 patients) and coarctation repair (two patients) with one death secondary to gastrointestinal bleeding (4.7% in-hospital mortality); one patient required early band readjustment because of hypoxemia. Repeat cardiac catheterization in 10 patients performed 4 to 41 months after PAB showed significant reduction in pulmonary hypertension and flow with no change in pulmonary vascular resistance. All infants were symptomatically improved after PAB and four have undergone successful total correction. Previous reports since 1977 indicate a significantly higher risk for total repair of complete A V canal before 1 year of age (36/147, 24%) than the risk for PAB in this series (p less than .05). Therefore, we believe that PAB is a rational alternative to total repair as the initial surgical treatment for symptomatic infants with complete A V canal, particularly when anatomic variants known to increase operative risk are recognized before cardiotomy.

Cardiac Catheterization↗
PubMedDate not supplied

Effect of palliative and corrective surgery on ventricular volumes in complete atrioventricular canal.

The effect of pulmonary artery banding (PAB) and intracardiac repair on ventricular volumes was studied in 35 patients with uncomplicated complete atrioventricular canal (CAVC). Right ventricular (RV) and left ventricular (LV) end-diastolic volumes (EDV), determined from biplane cineangiograms using Simpson's rule, were expressed as a percent of normal mean (% Nl) for body surface area; normal range (mean +/- 1SD) is equivalent to 75%-125% Nl. In preoperative studies (RV 26, LV 33), EDV averaged 149 +/- 51% and 184 +/- 50% Nl, respectively, P vs Nl less than 0.001 for both. In one of 26 patients, RV was very small (45% Nl), and one of 33 had a small LV (70% NI). In 13 patients studied post-PAB, RVEDV and LVEDV were lower than in the preoperative group (P less than 0.001) and averaged 114 +/- 40% and 126 +/- 52% Nl, respectively. In three of 13, RV was small (67% and 71% Nl) or very small (56% Nl). Three others had a small (71% and 67% Nl) or very small (56% Nl) LV. In serial pre- and post-PAB studies (RV 9, LV 11), EDV was increased or normal in all preoperatively. In seven of nine, RVEDV decreased, falling below normal range in three. In eight of 11, LVEDV decreased, falling below normal in three. Following repair, RV and LVEDV averaged 80 +/- 20% Nl and 126 +/- 23% Nl, respectively, in seven patients. Four of the seven had RVEDV below normal range. Two patients with a small ventricle had intracardiac repair and did well.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Output↗