B. Frank Polk

PREDIAGNOSTIC SERUM SELENIUM AND RISK OF CANCER

Selenium levels in serum samples collected in 1973 from 111 subjects in whom cancer developed during the subsequent 5 years were compared with those in serum samples from 210 cancer-free subjects matched for age, race, sex, and smoking history. The mean selenium level of cases (0.129 +/- SEM 0.002 micrograms/ml) was significantly lower than that of controls (0.136 +/- 0.002 micrograms/ml). The risk of cancer for subjects in the lowest quintile of serum selenium was twice that of subjects in the highest. Multivariate adjustment for geographical area and serum levels of lipids, vitamins A and E, and carotene, did not alter this relation. The association between low selenium level and cancer was strongest for gastrointestinal and prostatic cancers. Serum levels of vitamins A and E compounded the effect of low selenium; relative risks for the lowest tertile of selenium were 2.4 and 3.9 in the lowest tertiles of vitamins E and A, respectively.

Hodgkin's disease and Epstein-Barr virus. Altered antibody pattern before diagnosis.

In patients with Hodgkins disease, titers of IgG antibody against viral capsid antigen of Epstein-Barr virus and the prevalence of antibodies against early antigen are higher than expected. To evaluate whether this condition antedates diagnosis, we identified 43 persons with Hodgkins disease, from whom blood had been drawn and stored for an average of 50.5 months before diagnosis, and 96 controls from the same populations, from whom blood had been drawn at the same time. The relative risks of Hodgkins disease associated with elevated levels of IgG and IgA antibodies against capsid antigen were 2.6 (90 percent confidence interval, 1.1 to 6.1) and 3.7 (1.4 to 9.3), respectively. For Epstein-Barr nuclear antigen, the relative risk was 4.0 (1.4 to 11.4), and for early antigen D it was 2.6 (1.1 to 6.1). However, the prevalence of IgM antibody against capsid antigen was substantially lower in patients with Hodgkins disease (0.22 [0.04 to 1.3]). These associations were stronger in serum samples obtained at least three years before diagnosis than in serum samples obtained closer to diagnosis. We conclude that the development of Hodgkins disease may in some patients be preceded by enhanced activation of Epstein-Barr virus. Whether Epstein-Barr virus has a direct role in the pathogenesis of the disease or is simply a marker for a more fundamental factor affecting the immune control of latent infections is unknown.

Endocrine disorders in men infected with human immunodeficiency virus

Gonadal, adrenal, and thyroid functions were evaluated in 70 men seropositive for human immunodeficiency virus (HIV) infection, clinically categorized as asymptomatic (n = 19), AIDS-related complex (ARC) (n = 9), or acquired immunodeficiency syndrome (AIDS) (n = 42). Twenty of 40 men (50 percent) with AIDS were hypogonadal. Mean serum testosterone concentrations in both ARC (292 +/- 70 ng/dl) and AIDS (401 +/- 30 ng/dl) men were significantly less than in asymptomatic (567 +/- 49 ng/dl) or normal men (608 +/- 121 ng/dl). Of these hypogonadal men, 18 of 24 (75 percent) had hypogonadotropic hypogonadism. Seven of eight hypogonadal men (88 percent) had a normal gonadotropin response to gonadotropin-releasing hormone administration. Hypogonadism correlated with lymphocyte depletion and weight loss. Adrenal cortisol reserve, evaluated by adrenocorticotropin stimulation, was normal in 36 of 39 patients (92 percent) with AIDS. Indices of thyroid function were normal with the exception of one ARC man with a low free thyroxine index. In conclusion, hypogonadism is common in men with HIV infection and may be the first or most sensitive endocrine abnormality.

Ocular Manifestations of Acquired Immune Deficiency Syndrome

The ocular complications of acquired immune deficiency syndrome (AIDS) include: (1) a noninfectious microangiopathy, most often seen in the retina, consisting of cotton-wool spots with or without intraretinal hemorrhages and other microvascular abnormalities; (2) opportunistic ocular infections, primarily cytomegalovirus (CMV) retinitis; (3) conjunctival, eyelid, or orbital involvement by those neoplasms seen in patients with AIDS (i.e., Kaposis sarcoma and lymphoma); and (4) neuro-ophthalmic lesions. In a series of 200 AIDS patients evaluated clinically, AIDS retinopathy was present in 66.5%. Sixty-four percent had cotton-wool spots, and 12% had intraretinal hemorrhages. Cytomegalovirus retinitis was diagnosed in 28% of AIDS patients. Neuro-ophthalmic lesions were found in 8% of all AIDS patients and were present in 33% of those patients with cryptococcal meningitis. Acquired immune deficiency syndrome retinopathy was present in 40% of 35 patients with the AIDS-related complex (ARC) and in 1.3% of 232 patients with asymptomatic human immunodeficiency virus (HIV) infection, evaluated photographically. These results suggest that the prevalence of AIDS retinopathy increases with increasing severity of HIV infection, and that CMV retinitis presents a significant vision-threatening problem in AIDS patients.

RISK FACTORS FOR SEROCONVERSION TO HUMAN IMMUNODEFICIENCY VIRUS AMONG MALE HOMOSEXUALS: Results from the Multicenter AIDS Cohort Study

2507 homosexual men who were seronegative for human immunodeficiency virus (HIV) at enrollment were followed for six months to elucidate risk factors for seroconversion to HIV. 95 (3.8%) seroconverted. Of men who did not engage in receptive anal intercourse within six months before baseline and in the six-month follow-up period, only 0.5% (3/646) seroconverted to HIV. By contrast, of men who engaged in receptive anal intercourse with two or more partners during each of these successive six-month intervals, 10.6% (58/548) seroconverted. No HIV seroconversions occurred in 220 homosexual men who did not practise receptive or insertive anal intercourse within twelve months before the follow-up visit. On multivariate analysis receptive anal intercourse was the only significant risk factor for seroconversion to HIV, the risk ratio increasing from 3-fold for one partner to 18-fold for five or more partners. Furthermore, data for the two successive six-month periods show that men who reduced or stopped the practice of receptive anal intercourse significantly lowered their risk of seroconversion to 3.2% and 1.8%, respectively. Receptive anal intercourse accounted for nearly all new HIV infections among the homosexual men enrolled in this study, and the hazards of this practice need to be emphasised in community educational projects.

Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings.

Twenty-eight health care workers who had a poor antibody response when initially vaccinated with hepatitis B vaccine were revaccinated with three additional 20-microgram doses. Eight of the twenty nonresponders, who had levels of antibody to hepatitis B surface antigen (anti-HBs) of less than 8 estimated radioimmunoassay (RIA) units, and all 8 of the hyporesponders, who had anti-HBs levels of 8 or 16 RIA units, attained anti-HBs levels of 36 RIA units or more after revaccination. Tests for HLA-A, B, C, and DR; for complement proteins C2, C4A, C4B, and BF; and for the erythrocyte enzyme glyoxalase I were done in 17 nonresponders and 3 hyporesponders. Nine (45%) had HLA-DR7 and 8 (40%) had HLA-DR3, compared with an expected rate of 23% in the general population. At least one of two extended haplotypes (B44, DR7, FC31 or B8, DR3, SCO1) were detected in 6 of the 9 who did not respond to revaccination, compared with 2 of 11 who responded to a second course of vaccine. Poor responders to vaccine may benefit from revaccination, and genetic factors may modulate the immune response to vaccination.

Hepatitis B Vaccine in Health Care Personnel: Safety, lmmunogenicity, and Indicators of Efficacy

In a double-blind trial, we randomly assigned 1330 high-risk health care personnel to receive three 20-micrograms doses of hepatitis B vaccine or placebo. Among vaccine recipients 58% responded within 1 month and 97% within 9 months; there was no difference in immune response to the vaccine between men and women. Efficacy was evaluated after a mean follow-up of only 13.2 months, just before the vaccine was released commercially. Five hepatitis B infections were identified in placebo recipients and one in a vaccine recipient. Although the number of infections was too small to allow confident conclusions about protective efficacy of the vaccine, we saw a 67% reduction in the need for hepatitis B immune globulin after accidental hepatitis B inoculation in the vaccine group (relative risk, 5.08; 95% confidence intervals, 1.3 to 19.9). Minor side effects occurred with equal frequency after vaccine (28.7%) and placebo (27.2%) injections; no participant had a severe adverse reaction. Vaccination with the 20-micrograms hepatitis B vaccine was highly immunogenic and safe in health care workers.

Risk Factors for Infection at the Operative Site after Abdominal or Vaginal Hysterectomy

We studied risk factors for postoperative infections at the operative site after hysterectomies. Data were collected prospectively on all women undergoing vaginal hysterectomies (323 patients) or abdominal hysterectomies (1125 patients) at the Boston Hospital for Women between February 1976 and April 1978. Logistic-regression analysis indicated that factors significantly associated (P less than 0.05) with a higher risk of infection at the operative site were increased duration of operation, lack of antibiotic prophylaxis, younger age, being a clinic patient, and an abdominal approach. After these variables were accounted for, the variables of obesity, preoperative functional and anatomical diagnoses, postoperative anatomical and pathological diagnoses, estimated blood loss, menopausal status, and operation by a specific surgeon did not add predictive power. An increasing duration of operation was associated with a decreasing effect of antibiotic prophylaxis, the preventive fraction of which diminished from 80 per cent at one hour to an unmeasurable effect at 3.3 hours.

REDUCTION OF MORTALITY ASSOCIATED WITH NOSOCOMIAL URINARY TRACT INFECTION

A randomised controlled trial was conducted to assess whether bladder catheters with preconnected sealed junctions were associated with a lower risk of urinary-tract infection than were catheters without such junctions, and to determine whether prevention of catheter-associated infection would be accompanied by a reduction of mortality. Among those not taking systemic antibiotics, patients assigned sealed junction catheters had fewer infections and deaths. Before they received antibiotics, the risk of infection among those assigned unsealed catheters was 2.7 times that of patients assigned sealed catheters (95% confidence interval=1.3-5 . 4, p=0 . 007). Among the 220 patients who received no antibiotics, 14% (15/108) of those assigned unsealed catheters and 4% (4/112) of those assigned sealed catheters died. Stratification by important risk factors for mortality yielded an adjusted risk ratio for death of 3.4 (95% CI=1.1-10.7, p=0.03). Among patients who received systemic antibiotic the use of sealed catheters did not affect infection rates (RR=0.9, 95% CI=0.5-1.5, p=0.68) or deaths (RR=1.2, 95% CI=0.6-2.2, p=0.62). These data indicate how the rates of infection and mortality can be reduced in hospital. Since the degree of reduction in mortality corresponded with the degree of reduction of infection, measures to prevent catheter-associated nosocomial urinary tract infection should be implemented.

Treatment of Cytomegalovirus Retinitis with Ganciclovir

Eighteen immunocompromised patients with cytomegalovirus (CMV) retinitis were treated with ganciclovir, an investigational antiviral drug. CMV retinitis in association with acquired immune deficiency syndrome (AIDS) developed in 17 patients; CMV retinitis developed in one patient after cardiac transplantation. Fourteen patients responded to ganciclovir treatment with improvement in CMV retinitis. In 11 patients, the response was classified as complete; in three patients, the response was partial. Continued improvement in the retinitis was often seen while the patient was on maintenance treatment. Maintenance ganciclovir therapy was required; relapse occurred in five of seven patients in whom ganciclovir treatment was interrupted. The major limiting toxic side effect of ganciclovir was neutropenia, which necessitated temporary discontinuation of ganciclovir in five patients but was reversible in all cases. Ganciclovir appears to be an effective therapy for CMV retinitis, but chronic maintenance therapy is required.