Faculty Bibliography

Psychosocial interviews with 2320 male survivors of acute myocardial infarction, participants in the beta-Blocker Heart Attack Trial, permitted the definition of two variables strongly associated with an increased three-year mortality risk. With other important prognostic factors controlled for, the patients classified as being socially isolated and having a high degree of life stress had more than four times the risk of death of the men with low levels of both stress and isolation. An inverse association of education with mortality in this population reflected the gradient in the prevalence of the defined psychosocial characteristics. High levels of stress and social isolation were most prevalent among the least-educated men and least prevalent among the best-educated. The increase in risk associated with stress and social isolation applied both to total deaths and to sudden cardiac deaths and was noted among men with both high and low levels of ventricular ectopy during hospitalization for the acute infarction

An investigation of relatives of 652 patients entered on studies of the Polycythemia Vera Study Group yielded five documented cases of the disease among the parents of patients. When compared with expected values based on the Connecticut Tumor Registry and other population studies a significant increase was found in the lifetime incidence of polycythemia vera in parents of these patients

Conventional treatment of polycythemia vera (PV) with radioactive phosphorus or alkylating agents is associated with a significant excess of acute leukemia and cancer of the gastrointestinal tract and skin. There is thus a need for a nonmutagenic agent in the treatment of this disorder. Hydroxyurea (HU) was administered to 118 patients with a loading dose of 30 mg/kg/day for 1 week, which was then reduced to 15 mg/kg/day. Initial control of the elevated hematocrit and platelet count was achieved within 12 weeks in over 80% of patients. Long-term disease control was defined and the accumulative 1-year failure-free survival was 73% in the previously untreated patients and 59% in those patients previously treated with other myelosuppressive modalities. The HU was well tolerated and cytopenia, which generally occurred within the first 8 weeks of therapy, was transient and of little clinical significance. However, it is recommended because of this toxicity that HU be administered initially at a dose of 15-20 mg/kg/day. Three patients developed acute leukemia; two were untreated and one had had myelosuppressive therapy. Hydroxyurea is an effective agent in the treatment of PV, but continued assessment of its mutagenic potential is necessary

The effect of an intracarotid artery infusion of etoposide on blood-brain barrier (BBB) integrity was investigated in a rat model system. The external carotid arteries of Sprague-Dawley rats were catheterized in a retrograde manner. Etoposide in a dose range from 3.0 mg/kg to 22.5 mg/kg was infused into the internal carotid artery by this technique. BBB disruption was evaluated qualitatively by the appearance in the infused hemisphere of the systemically administered dye Evans blue and quantitatively by the ratio of counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the infused to the noninfused hemisphere. Evidence of increased BBB permeability was seen at all doses of etoposide. Degree of BBB disruption increased with increasing doses of etoposide. The intracarotid infusion and subsequent BBB disruption were well tolerated. Further clinical trials employing the intracarotid administration of etoposide should be cognizant of the potential for BBB disruption

The ontogenic switch from fetal to adult hemoglobin could be due to gradual replacement of fetal by adult erythroid progenitor cells, each with unique potential hemoglobin expression programs. We have studied globin synthesis in single colonies derived from the BFU-E of human newborn infants and rhesus monkey fetuses, both at the time of the switch. In the 140-day rhesus fetal colonies, beta synthesis ranged from 8% to 44% of (beta + gamma) in 47 colonies. When fetal colonies were arbitrarily defined as those with below 26% beta, and adult colonies those with above 26% beta, we predicted that there would be 12 adult colonies; 14 were observed. The rhesus fetal results were compatible with the presence of two or more classes of progenitors within the population seen at the time of the switch. In the human newborn study, the number of colonies increased fourfold from day 14 to day 21 in culture. beta synthesis also increased. These increases occurred even in cultures from which red, well-hemoglobinized colonies were completely removed as they appeared. New cohorts of late-appearing colonies were derived from immature progenitors. The early colonies showed correlation of G gamma and beta synthesis, but the late colonies did not show this correlation. We had found the latter pattern previously in adult, fetal-like colonies. Thus fetal progenitors in man have high levels of Hb F and G gamma, with correlation of these parameters at the level of single-progenitor-derived colonies; these fetal progenitors are found in fetuses and newborns. Adult, fetal-like progenitors have lower levels of Hb F and G gamma, without any correlation between the levels of each. The adult progenitors appear in newborn infants as the switch occurs, and they are the only class found in adults. Our observations in the simian and human studies support a clonal model for hemoglobin switching.

Myelofibrosis has been shown to involve an increase in type III collagen in the marrow. The aminoterminal procollagen III (PC III) peptide fragment is released during the production of PC III by fibroblasts and its serum level is therefore a marker for type III collagen synthesis. Using a recently developed sensitive radioimmunoassay, serum levels of PC III peptide were measured in 30 patients with myeloproliferative disease and 23 normal volunteers. Levels were found to be elevated above normal values in patients with polycythemia vera, even more elevated in patients with polycythemia and evidence of secondary myelofibrosis with myeloid metaplasia, and most strikingly elevated in patients with agnogenic myeloid metaplasia and severe marrow fibrosis. There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies. Serum PC III level appears to be a quantitative marker for myelofibrosis

Several drugs which react with DNA decrease hepatitis B viral (HBV) DNA polymerase activity in vitro. Because such an alteration of viral replication, if produced in patients with hepatitis B surface antigen (HBsAg)-positive chronic hepatitis, may lead to elimination of viral infection, we conducted a controlled trial of the use of the intercalating agent, quinacrine hydrochloride, in treatment of HBsAg-positive chronic hepatitis. No patient converted from HBsAg positive to negative during the trial and no consistent effect on HBV DNA polymerase activity was noted. Following treatment, elevated transaminase values and alterations of HBV markers were observed in several patients. Fluctuations of transaminase values and HBV markers may reflect alterations in host immunity and viral replication. Quinacrine alone is ineffective in therapy of chronic HBV infection. Additional study with intercalating agents, perhaps in conjunction with other drugs, is suggested

Sixty-six patients hospitalized for ulcerative colitis were treated in a prospective, double-blind, clinical trial. They received either 120 U/day of intravenous corticotropin or 300 mg/day of intravenous hydrocortisone. Patients were randomized within strata defined by whether they had received oral corticosteroids continuously for at least 30 days before the study (group A, 35 patients), or whether they had received no such prior treatment (group B, 31 patients). Twenty-eight of the 66 patients (42%) achieved remission. In group B, the proportion of patients entering remission was greater with corticotropin than with hydrocortisone (63% vs. 27%, 0.025 less than p less than 0.05). The opposite trend was observed within group A, for whom hydrocortisone appeared more effective (53% vs. 25%, 0.05 less than p less than 0.10). Impaired adrenal responsiveness, as measured by serum cortisol and dehydroepiandosterone-sulfate levels, did not explain the different responses to therapy within the two study groups. Twenty of 28 patients whose acute therapy was successful were still in remission 1 yr after study. These data suggest that, at the doses used, intravenous corticotropin therapy of severe ulcerative colitis is the more effective choice for those patients not previously treated with corticosteroids, while intravenous hydrocortisone seems preferable for patients already receiving steroid treatment

An animal model for prolonged reversible blood-brain barrier (BBB) disruption has been developed. The external carotid arteries of Osborn-Mendel rats were catheterized in a retrograde manner. Varying concentrations of sodium dehydrocholate were infused into the internal carotid artery by this technique. BBB disruption was evaluated qualitatively by the appearance in the infused hemisphere of the systemically administered dyes Evans blue and sodium fluorescein and quantitatively by the ratio of counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the infused to the noninfused hemisphere. The ability of sodium dehydrocholate to disrupt the BBB was documented with all three markers. As the concentration of the infused dehydrocholate was increased, both the incidence and the degree of BBB disruption increased. Reversibility of BBB disruption was evaluated by the administration of sodium fluorescein and 99mTc-DTPA at varying times after BBB disruption. Depending on the concentration of the infused sodium dehydrocholate, altered BBB permeability can be maintained for over 3 days. This new model of prolonged reversible BBB disruption deserves further investigation both for basic studies of the BBB and for therapeutic studies of drug delivery into the central nervous system