Biomedical subjects
B D Silverman
Publications and source records attributed to B D Silverman.
A measure of DNA periodicity.
A Fourier transform g(n) of a sequence of bases along a given stretch of DNA is defined. The transform is invariant to the labelling of the bases and can therefore be used as a measure of periodicity for segments of DNA with differing base content. It can also be conveniently used to search for base periodicities within large DNA data bases.
Effect of methylation on the conformer stability and reactivity of the bay-region diol-epoxides of chrysene.
The relative stabilities of conformers of the bay-region tetrahydroepoxide of methylated chrysene have been calculated. From these calculations on tetrahydroepoxides, one infers that substitution of a methyl group in the same bay-region as the epoxide should destabilize both syn-diaxial and anti-diequatorial bay-region diol-epoxide diastereomers with respect to the syn-diequatorial and anti-diaxial diastereomers. The results of these calculations, together with recent experimental observations, suggest that the enhanced in vivo binding to DNA of the isomer having the methyl group and the epoxide in the same bay-region (1,2-diol-3,4-epoxide of 5-MeC) might be partially due to this destabilization of the syn-diaxial diastereomer. The carbocation delocalization energies associated with epoxide ring opening of the methylated bay-region tetrahydroepoxide isomers of chrysene are also given.
Clinical effects and side effects of amrinone. A study of 24 patients with chronic congestive heart failure.
Amrinone, a new inotropic agent, was used to treat 24 patients with chronic congestive heart failure who were classified as clinically stable and who were in New York Heart Association's classes II and III. Patients were treated for up to 30 months (mean, 12.5 months). Exercise tolerance improved in 20 patients, but only eight experienced significant improvement in symptoms of fatigue, dyspnea, and orthopnea and only nine tolerated the drug without apparent side effects. Eight were unable to continue amrinone therapy because of limiting side effects. The most significant adverse effects were cardiac arrhythmias, thrombocytopenia, abnormal results of liver function tests, diarrhea, fever, and nausea. Amrinone has a narrow therapeutic-toxic ratio, but a significant proportion (42%) of patients tolerate and benefit from amrinone therapy.
Oral amrinone for the treatment of chronic congestive heart failure: results of a multicenter randomized double-blind and placebo-controlled withdrawal study.
A placebo-controlled study was employed to evaluate the effects of oral amrinone in patients with congestive heart failure. After a baseline period of at least 4 weeks of standard treatment for refractory congestive heart failure, oral amrinone was added to the treatment regimen of 173 patients. Patients were predominantly male (89%), aged 24 to 76 years (mean 54), with ischemic (52%) or idiopathic (37%) dilated cardiomyopathy, in New York Heart Association functional class II (40%), III (59%) and IV (1%) and having a mean (+/- standard deviation) left ventricular ejection fraction of 25 +/- 15%. Phase 1: After the addition of amrinone (113 +/- 33 mg three times daily), 52 patients (30%) showed a maximal increase in treadmill exercise time exceeding 2 minutes (Naughton protocol), 72 (42%) had a lesser increase, 24 (14%) developed limiting adverse reactions, 20 (12%) died and 5 dropped out of the study. Fifty-two "responders" (30%) who were free of limiting side effects and had a greater than 2 minute increase in exercise time were randomized in double-blind fashion to continued amrinone or switched to placebo (each plus standard treatment) for an additional 12 weeks. Phase 2: Comparison of 31 of these 52 responders who continued to receive amrinone with the remaining 21 randomized to placebo revealed no significant differences in vital signs, indexes of left ventricular size and function, systolic time intervals or maximal exercise time. Continued follow-up study of patients receiving either amrinone or placebo revealed decreases in exercise times of 7 and 10%, respectively (both p less than 0.05 compared with before randomization). Episodes of worsened congestive heart failure severe enough to mandate termination of double-blind treatment were as frequent in patients taking placebo (4[18%] of 21) as in those taking amrinone (4[13%] of 31; p = NS). The average symptom score and functional class of each treatment group remained comparable. Adverse effects such as gastrointestinal and central nervous system complaints were more common with amrinone treatment as were elevations of serum liver enzymes and reduced platelet counts. This large multicenter, randomized double-blind withdrawal study revealed no change in estimates of cardiac performance after the discontinuation of amrinone. These findings suggest that amrinone, in the dosages tested, does not importantly improve cardiac function beyond that provided by standard treatment with digoxin, diuretic drugs and vasodilators.
Mitral valve prolapse: its symptom complex and its association with DaCosta's syndrome.
Symptoms of DaCosta's syndrome include effort fatigue and breathlessness, chest pain, palpitation, and dizziness. Considered purely functional and anxiety-related by DaCosta, the syndrome has since been related to the mitral valve prolapse (MVP) syndrome and autonomic hyperreactivity. We studied these specific symptoms in similar cohorts of 68 patients with and without documented MVP from a single practice of internal medicine and found only 6% of patients having MVP without symptoms compared to 25% of control subjects (P less than .01). Palpitation was present in 71% of patients with MVP and 33% of controls (P less than .001); dyspnea was noted by 50% of those with MVP and 28% of controls (P less than .02), and chest pain by 44% of patients with MVP and 25% of controls (P less than .01). Our results confirm reports that the symptoms of DaCosta's syndrome are more common in patients with MVP and may call the physician's attention to the proper diagnosis.
Calculated reactivity of the mutagenic cyclopenta-polycyclic aromatic hydrocarbon, 3, 4-epoxycyclopenta[cd]pyrene.
Delocalization energies of the 1- and 4-pyrenyl carbocations resulting from epoxide ring opening of 3, 4-epoxycyclopenta[cd]pyrene have been calculated with semi-empirical and ab-initio molecular orbital procedures. The delocalization energy difference between carbocations is found to be larger than previously obtained from simple pi molecular orbital calculations. Certain general features, expected for the reactivity of the cyclopenta-polycyclic aromatic hydrocarbon series are also pointed out.
Calculated reactivities of potentially carcinogenic intermediates of the cyclopenta-fused isomers of benz[a]anthracene.
Delocalization energies have been calculated for carbocations formed from several epoxide intermediates of the cyclopenta-fused isomers of benz[a]anthracene. Except for the epoxides of benz[l]aceanthrylene, the largest calculated delocalization energies associated with the other benzaceanthrylenes result from ring-opening of the epoxide on the cyclopenta-ring yielding an alpha' type carbocation. Benz[l]aceanthrylene exhibits special behavior resulting from steric crowding in the bay-region of the molecule. For this molecule the calculated ease of epoxide ring opening is essentially the same for the bay-region epoxide and for the epoxide on the five-membered ring. Relative values of delocalization energy should provide an important index for ranking the reactivity of metabolites of the benzaceanthrylenes and benzacephenanthrylene that are potentially involved in the initiation of mutagenesis/carcinogenesis.
Evaluation of the cardiac patient for non-cardiac surgery.
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Benzofluoranthenes: calculated diol epoxide reactivities.
The benzo- and dibenzofluoranthenes, widespread environmental contaminants, have been subjects of continued interest. Calculations of the reactivity of potential ultimate carcinogenic metabolites of the benzofluoranthenes predict unexpected behavior for these non-alternant hydrocarbons.
Heteroatom effects in chemical carcinogenesis: effects of ring heteroatoms on ease of carbocation formation.
The presence of a heteroatom can influence the ease with which a PAH diol-epoxide forms a triol carbocation. The influence of the heteroatom should be greatest when it is located where the PAH undergoes maximum charge change upon ionization. Extended Hückel, INDO and Gaussian 70 calculations on nitrogen substituted benz[a]anthracene verify this reasoning. The sites of maximum effect are easily predicted using a simple Hückel method which does not require use of a computer. The greater carcinogenic activity of methylated benz[c]acridines over benz[a]acridines is an immediate result of these considerations. Methylated benzo[c]phenarsazines are implicated as likely carcinogens.
Determination of the molecular structure of the bay-region epoxides of benzo(a)pyrene by a force-field calculation.
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Tricuspid regurgitation and acute myocardial infarction.
A 71-year-old man had a right ventricular infarct complicated with hypotension and transient complete atrioventricular block. The patient was found to have tricuspid regurgitation, which was corrected with a prosthetic tricuspid valve. After correction, there was dramatic improvement in his clinical status, with correction of persistent hypotension and weakness and early discharge home to full activity. Tricuspid regurgitation is a mechanical defect of acute myocardial infarction that benefits greatly from surgical correction. This therapy should be considered in any individual in whom tricuspid regurgitation complicates acute right ventricular infarction.
Steric crowding and conformer stability of the diol-epoxides of benzo(c)phenanthrene.
The relative stabilities of conformers of the syn and anti-diastereomers of the fjord and bay-region diol-epoxides of benzo(c)phenanthrene (BCP) and benzo(a)anthracene (BA) have been calculated. Steric crowding in the fjord-region of BCP is shown to stabilize the syn-diequatorial and anti-diaxial conformers of BCP. In contrast, the most stable conformers of the bay-epoxides of BA are found to be the syn-diaxial and anti-diequatorial.
Carcinogenicity of methylated hydrocarbons: effect of methylation on the calculated diol-epoxide reactivity.
Methyl substitution of polycyclic aromatic hydrocarbons is known to induce substantial variations in carcinogenicity. The "Bay-region" theory relates carcinogenicity of polycyclic aromatic hydrocarbons to ease of formation of a triol carbocation from a bay-region diol-epoxide. It is shown that an examination of certain simple consequences of molecular orbital theory enables one to identify certain methyl substitutions that do not enhance ease of carbocation formation and hence are the least carcinogenically activating.
Recommendations for phonocardiography.
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Electrocardiographic abnormalities in myocarditis.
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The innocent heart murmur.
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