Self-assembling nanostructured intercalates via ion-dipole bonding.

A new system of highly ordered self-assembly intercalated polymer/clay nanocomposite is reported. These systems appear to be driven by entropic forces and are nanostructured but self-assemble across the micron scale. The systems exhibit extremely good gas barrier properties which do not fit the traditional tortuous path model of diffusion. In these complexes the intercalated system behaves differently than the bulk polymer. This behaviour can be explained by constrained polymer theory. The paper presents structural characteristics of the intercalates as well as gas barrier properties of films produced with the intercalated systems. A new radical approach to food packaging is proposed and demonstrated.

Radioimmunoassay for measurement of triiodothyronine in human serum.

A convenient, specific, precise, and reproducible radioimmunoassay system for measurement of triiodothyronine (T(3)) in human serum has been developed. The procedure compares the ability of standards and unknowns to compete with radioactive T(3) for binding sites on a T(3)-binding antiserum produced in rabbits by immunization with human thyroglobulin. The assay is set up in the presence of 250 ng thyroxine (T(4)) in all tubes, to mobilize T(3) from its binding with the thyronine-binding globulin (TBG), and athyreotic sheep serum in standards to correct for the TBG in the unknowns. The method regularly detected 0.4 ng T(3), which would correspond to a T(3) concentration of 100 ng/100 ml when 400 mul of serum is analyzed. The mean recovery of unlabeled T(3) added to normal serum pools was 106%. Serial dilution of hyperthyroid sera containing high concentrations of T(3) with athyreotic sheep serum yielded expected values. The serum T(3) concentration in 80% of 31 euthyroid normal subjects was less than 100 ng/100 ml (range < 100-170 ng/100 ml); it was greater than 170 ng/100 ml in 89% of 27 sera of hyperthyroid patients with untreated Graves' disease (range < 100-1300, mean 519 in 25 sera with detectable T(3)). The concentration of serum T(3) fell, frequently to undetectable levels, during treatment of hyperthyroid patients with antithyroid drugs. The serum T(3) concentration in four hypothyroid patients was less than 100 ng/100 ml.

Rabbits immunized with thyroid-stimulating hormone produce autoantiidiotypic thyroid-stimulating antibodies.

We immunized rabbits with thyroid-stimulating hormone (TSH) to investigate the hypothesis that such immunization could result in production of thyroid-stimulating autoantiidiotypic antibodies to anti-TSH. Thyroid-stimulating immunoglobulin (TSI) appeared in the serum of several rabbits after immunization. At 160 d, TSI equivalent to 6-18 microU TSH/1.5 mg IgG was present in two of six human (h)TSH-, two of six hTSH beta chain-, and two of the four surviving bovine (b)TSH-immunized animals. Control (human serum albumin-immunized rabbits) serum TSI was 4.3 +/- 0.4 (mean +/- SD) at this time. Antiidiotypic antibodies that could bind to monoclonal anti-hTSH were found in the sera of the bTSH-immunized rabbits. The peak TSI activity occurred 3 mo after a TSH booster immunization and declined gradually during subsequent weeks. Evidence that antiidiotypic antibodies to anti-TSH can cause thyroid stimulation strengthens the notion that such antibodies may be the cause of Graves' hyperthyroidism.

Neutralizing and non-neutralizing antibodies to bovine thyroid-stimulating hormone and its subunits.

To test the possibility that the long-acting thyroid stimulator (LATS) might represent an immune complex either of thyroid-stimulating hormone (TSH) with anti-TSH or of a subunit of TSH with an appropriate antibody, we immunized rabbits with bovine TSH (bTSH), bLH (luteinizing hormone), and their alpha and beta subunits (bTSHalpha and bTSHbeta). Binding, neutralizing, and nonneutralizing antibodies were demonstrated in the antisera obtained. First, antisera to TSH, TSHbeta, and TSHalpha all bound [(125)I]TSH and [(125)I]TSHbeta. Anti-bTSHbeta antisera bound [(125)I]bTSHbeta better than did anti-TSH sera, while the binding of [(125)I]bTSH was similar with both types of antiserum. Second, the thyroid-stimulating activity (McKenzie bioassay) of TSH could be neutralized by incubation with various dilutions of anti-TSH or anti-TSHbeta. Finally, when incubation mixtures containing TSH and dilutions of anti-TSHbeta antisera that only partially neutralized TSH were treated with an antiserum against rabbit immunoglobulins to precipitate immune complexes, the bioassay response of the TSH was abolished. This phenomenon was not observed when antiserum to the intact hormone was substituted in the incubation mixture. The removal of TSH biological activity from a mixture of TSH and anti-bTSHbeta by addition of an anti-immunoglobulin indicated that biologically active immune complexes were formed between TSH and anti-TSHbeta but not between TSH and anti-TSH. The time-course of the bioactivity and several other characteristics of these complexes differentiate them from LATS.

The effects on rabbits of immunization with bovine thyroid-stimulating hormone and its subunits.

Rabbits were immunized with bovine thyroid-stimulating hormone (bTSH), bovine Inteinizing hormone (bLH), and their subunits. In two immunization experiments, thyroid-stimulating activity was found in the serum of 6 out of 12 rabbits immunized with bTSHbeta subunits. The thyroid-stimulating activity in the anti-bTSHbeta sera was greater at 2 h than at 8, was eluted with the globulin fraction from Sephadex G-100, was completely neutralized by both anti-bTSH and anti-rabbit gamma globulin, and was completely suppressed by administration of triiodothyronine (T(3)) to the immunized rabbit. These findings led to the conclusion that the thyroid-stimulating activity resided in soluble complexes of rabbit TSH bound to anti-bTSHbeta. Two of nine rabbits immunized with bTSH developed thyroid-stimulating activity in their serum, but it was nonsuppressible by T(3). None of the animals immunized with bTSHalpha, bLH, bLHbeta, or bLHalpha developed serum thyroid-stimulating activity.Hypopituitary hypothyroidism, evidenced by decreased serum thyroxine (T(4)) and thyroidal (131)I uptake and by the histologic appearance of large follicles with flat cells, was found in the bTSHbeta- and bTSH-immunized animals, despite the presence of thyroid-stimulating activity in the serum of many. The reasons for this paradox are unclear; possibly the complexes block the effect of TSH on the rabbit thyroid.

A comparison of the effectiveness of three regimens in the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients.

BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and the leading cause of death in patients with the acquired immunodeficiency syndrome. The prevention of the occurrence and recurrence of PCP is a cornerstone in the treatment of patients infected with the human immunodeficiency virus. There are few studies comparing PCP prophylactic regimens. METHODS: The efficacy of three regimens for prophylaxis against PCP was assessed in a retrospective chart review of 211 human immunodeficiency virus-infected patients at risk for the disease. Over the course of the 2-year study period, 133 patients were prescribed trimethoprim-sulfamethoxazole (one double-strength tablet twice a day, thrice weekly) for a mean of 7.4 months (range, 1 to 25 months). Seventy-seven patients received dapsone (50 mg daily) for a mean of 5.7 months (range, 1 to 23 months), and 125 patients received aerosolized pentamidine (300 mg via nebulizer once monthly) for a mean of 9.3 months (range, 1 to 21 months). The majority of patients (62%) received primary prophylaxis; 38% had one or more previous episodes of PCP; and 73% were receiving concomitant antiretroviral therapy. RESULTS: Pneumocystis carinii pneumonia did not develop in any patient receiving trimethoprim-sulfamethoxazole in 981 patient-months. Five patients receiving dapsone for 437 patient-months and 17 patients receiving aerosolized pentamidine for 1166 patient-months developed PCP. Fifty-six percent of the trimethoprim-sulfamethoxazole group and 55% of the dapsone group changed drug due to adverse reactions, while only 2% in the aerosolized pentamidine group required drug change. CONCLUSION: Despite its adverse reaction profile, trimethoprim-sulfamethoxazole is the most effective agent to prevent the occurrence and recurrence of PCP.

HIV-seropositive thrombocytopenia: the action of zidovudine.

The action of zidovudine when administered to individuals with severe HIV thrombocytopenia was investigated. Four individuals with platelets less than 50 x 10(9)/l and CD4 cells greater than 200 x 10(6)/l were treated with 600 mg zidovudine per day for 6 weeks, no drug for 6 weeks, 1200 mg zidovudine per day for 6 weeks, then no drug for 6 weeks. Glycocalicin, a platelet protein which correlates inversely with platelet survival, was assayed before and after treatment. Glycocalicin indices were also measured in four additional individuals with HIV thrombocytopenia. Platelet counts rose 2.5-fold [95% confidence interval (Cl), 2.0-3.0)] for four subjects who received 600 mg zidovudine per day and 4.9-fold (95% Cl, 4.0-5.8) for three subjects receiving 1200 mg zidovudine per day. Platelet counts declined during drug-free intervals. Plasma glycocalicin indices were elevated in all with untreated HIV thrombocytopenia. Indices fell after zidovudine treatment in six of seven individuals, suggesting that zidovudine prolonged platelet survival. Analysis of 170 HIV-seropositive asymptomatic individuals [mean CD4 count 474 x x 10(6)/l, standard deviation (s.d.) 245 x 10(6)/l] revealed that 14 (8%) had less than 125 x 10(9)/l platelets but only 2 (1%) had less than 50 x 10(9)/l platelets. Platelet counts increased spontaneously in eight individuals with mild HIV thrombocytopenia among the 10 for whom repeat counts were available.

Pneumonia in HIV-infected patients: a case-control survey of factors involved in risk and prevention.

OBJECTIVE: To assess the factors that increase or decrease the risk of pneumonia with particular attention to immunization with pneumococcal and influenza vaccines in a group of HIV-infected persons. DESIGN: A retrospective, case-control study based on information entered into a standard database and the medical record. SETTING: Patients attending a referral clinic specializing in AIDS/HIV care at a public hospital. PATIENTS: Among over 2000 subjects entered into a database in 8 years, 127 incidents of pneumonia were identified from the record. These cases were matched with 127 CD4 cell count matched, concurrent controls. INTERVENTIONS: None. MAIN OUTCOME MEASURE: The principal hypothesis was that chart review would find a decreased frequency of pneumococcal immunization in the pneumonia cases compared with matched controls. RESULTS: Pneumococcal immunization was associated with a reduction of the risk of pneumonia by nearly 70%. The effect was seen even when immunization was given with a CD4 cell count of less than 100/mm3. Injection drug users and African-Americans had a twofold increased risk of pneumonia. CONCLUSION: The study provides data to support the current recommendation for pneumococcal immunization of all HIV-infected persons. Although this conclusion could lead to renewed enthusiasm for increasing pneumococcal immunization rates in HIV-infected persons, it must be recognized that the study is observational and ascertainment bias cannot be excluded.

Incidence and factors associated with extrapulmonary cryptococcosis among persons with HIV infection in Los Angeles County.

OBJECTIVE: To determine the incidence and factors associated with extrapulmonary cryptococcosis among a cohort of persons with HIV in Los Angeles County. DESIGN: Records-based cohort study. METHODS: Data were analysed from a cohort of 3836 persons aged > or = 13 years with HIV infection enrolled from four outpatient facilities in Los Angeles from 1990 to 1995. The potential association between cryptococcosis and demographic risk behavior and clinical factors was assessed. Possible seasonal clustering was evaluated and an estimate of survival following cryptococcosis was calculated. Multivariate analysis was performed using a Cox proportional hazards approach. RESULTS: Cryptococcosis was identified in 112 patients (2.9%) representing a crude incidence rate of 1.7 cases per 100 person-years experience. The rate of cryptococcosis was higher among men than women (1.9 and 0.6, respectively; P < 0.01) and in Hispanics than in whites (2.3 and 1.2, respectively, P < 0.01). A significant trend of decreasing cryptococcosis was observed with increasing age (P < 0.01). Cryptococcosis increased with declining CD4+ lymphocyte count, with risk being greatest at CD4+ cell counts below 100 x 10(6)/l (P < 0.001). In bivariate analysis persons with a history of antifungal medication had a marginally lower rate of cryptococcosis, but this difference was not statistically significant. The rate of cryptococcosis was significantly higher in fall and winter months [rate ratio (RR), 1.45; 95% confidence interval (CI), 1.0-2.3; P = 0.05]. After controlling for other variables, cryptococcosis was more common in men than women (adjusted RR, 3.2; 95% CI, 1.0-10.4) and in Hispanics than whites (adjusted RR, 1.6; 95% CI, 0.9-2.7). Both CD4+ count and age continued to be strongly associated with the occurrence of cryptococcosis. After controlling for other factors a substantial protective effect was observed for antifungal therapy (adjusted RR, 0.48; 95% CI, 0.29-0.79). CONCLUSION: Our data suggest that HIV-infected men, Hispanics, persons aged under 45 years and those with CD4+ counts under 100 x 10(6)/l have an increased risk of extrapulmonary cryptococcosis. A fall-winter seasonality in the occurrence of cryptococcosis may exist. Significant primary protection against cryptococcal disease is afforded by antifungal therapy. These results may provide insight into possible routes of transmission and sources of cryptococcal infection and help guide both primary prophylaxis and early recognition and diagnosis in persons likely to be at increased risk.

Failure to demonstrate anti-lymphocytic antibody in serum of patients with AIDS.

Several studies have produced evidence for anti-lymphocytic antibodies (ALA) in AIDS. We attempted to demonstrate ALA by immunofluorescent flow cytometry. Normal human peripheral blood lymphocytes (PBL) and the T-cell line, CEM, were incubated with sera from patients with AIDS, patients with chronic HIV infection and HIV-seronegative blood donors. ALA were not detected in the AIDS sera with fluorescein isothiocyanate (FITC)-labelled rabbit anti-mu, anti-alpha or the F(ab)2 fragment of anti-human gamma. A small number of CEM cells (2%) fluoresced with either AIDS or normal serum. A larger proportion of PBL were immunofluorescent after serum treatment but there was no difference between normal and AIDS serum. We were able to detect ALA in the serum of patients with systemic lupus erythematosus with both CEM and PBL. In contrast, incubation of either CEM or PBL with some AIDS sera, and to a lesser degree normal sera, enhanced the binding of intact FITC-rabbit anti-gamma. Anti-gamma was not bound by CEM cells unexposed to human serum. The binding was blocked by rabbit immunoglobulin, demonstrable with CEM fixed in 1% formalin, and unrelated to the density of CD4 on CEM cells.

Emerging patterns of HIV transmission: the value of alternative surveillance methods.

OBJECTIVE: To assess the current patterns of HIV transmission in Los Angeles County and determine if AIDS surveillance data accurately reflect these patterns. DESIGN: Records-based cohort study. METHODS: The demographic and HIV risk characteristics of persons considered to be recently infected with HIV (CD4+ count > 700 x 10(6)/l) were determined and compared with the characteristics of persons meeting the Centers for Disease Control and Prevention (CDC) 1993 AIDS case definition. Data were obtained for patients with HIV infection enrolled from four HIV outpatient clinics and analyzed between August 1991 and July 1993. RESULTS: The patient cohort included 1857 persons with HIV infection; 1096 (59.1%) met the CDC 1993 AIDS case definition and 134 (7.2%) had a CD4+ lymphocyte count > 700 x 10(6)/l. The median CD4+ count for the group presumed to be recently infected was 809 x 10(6)/l. Persons considered recently infected with HIV were more likely than those meeting the AIDS case definition to be female (26.1 and 14.5%, respectively; P < 0.001), black (28.4 and 18.2%, respectively; P = 0.001), or male homosexual injecting drug users (IDU; 6.7 and 3.4%, respectively; P = 0.05). After controlling for confounding variables by logistic regression, persons recently infected were more likely to be female [adjusted odds ratio (OR), 3.4; 95% confidence interval (CI), 1.8-6.5; P < 0.001], black (adjusted OR, 1.6; 95% CI, 1.1-2.5; P = 0.02) or male homosexual IDU (adjusted OR, 2.4; 95% CI, 1.1-5.2; P = 0.02) than persons with AIDS. CONCLUSIONS: Our results suggest that the HIV epidemic in Los Angeles County is currently advancing into different subpopulations and indicate that the current patterns of HIV transmission in the County are not fully reflected in standard AIDS surveillance activities. However, our data must be interpreted cautiously because of potential selection and misclassification biases. These findings illustrate the benefits of alternative surveillance mechanisms in detecting important changes in HIV transmission and defining groups at risk, especially in jurisdictions without HIV reporting.

A double-blind, placebo-controlled trial of thymostimulin in symptomatic HIV-infected patients.

The potential therapeutic efficacy of the thymic hormone preparation, thymostimulin (TP1), in HIV infection has been studied in a multi-institutional, randomized, double-blind, placebo-controlled trial. Fifty evaluable patients with advanced AIDS-related complex (ARC) were injected with TP1 or placebo twice weekly for 6 months after 2 weeks of daily injections. The primary endpoint, progression to AIDS, was reached in nine TP1- and 11 placebo-treated subjects after 1 year. CD4 cell numbers were not affected by administration of the study drug. No toxicity was associated with TP1 treatment. We conclude that TP1 is ineffective in altering the progress of HIV disease in patients with advanced ARC.

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group.

OBJECTIVE: To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING: Five university-affiliated HIV clinics. PATIENTS: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION: Individualized, unrestricted antiretroviral therapy. MEASUREMENTS: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION: Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

Production of human antithyroglobulin in vitro, IV. Specific stimulation by antigen.

Peripheral blood lymphocytes from patients whose serum contains antithyroglobulin are capable of producing antithyroglobulin (anti-Tg) in vitro when stimulated with insolubilized Tg and suboptimal amounts of pokeweed mitogen. Antigen stimulation of anti-Tg production was demonstrated in 6 of 10 experiments in which a 1:10,000 dilution of pokeweed mitogen was also included. Larger concentrations of antigen appeared to inhibit anti-Tg synthesis. Regulation of antigen-stimulated anti-Tg production by the patients' T cells was not different from regulation by the T cells of normal subjects. Both T help and T suppression of antigen-induced antibody synthesis was demonstrated with patients' T cells. These experiments continue to provide evidence that production of the autoantibody anti-Tg is related to an abnormality of B cells.

Antithyroglobulin (ATG) production by peripheral blood leukocytes in vitro.

Antithyroglobulin is produced in vitro by pokeweed mitogen stimulation of peripheral blood lymphocytes from patients whose serum contains the autoantibody. Antithyroglobulin synthesis requires T lymphocyte help but is suppressed by larger numbers of T lymphocytes. T cells from both patients and normals perform both of these functions.

Serum protein inhibition of thyrotropin binding to human thyroid tissue.

We used a modification of the TSH radioreceptor assay to detect TSH-binding inhibition (TBI) activity in serum and serum fractions from normal subjects and patients with Graves' disease. TBI activity is present in normal IgG prepared by DEAE-Sephadex chromatography and in normal globulins prepared by precipitation at 1.6 M ammonium sulfate. Other normal serum proteins also had TBI activity when large concentrations were tested. Gel filtration chromatography and powder block electrophoresis were used to prepare fractions of normal and Graves' disease sera. In these fractions from normal serum. TBI activity was found in both gamma-globulin and alpha-globulin-albumin fractions electrophoretically and in both 7S and 4S peaks from gel filtration. TBI activity from Graves' disease patients' sera was similarly distributed, but relatively more TBI accompanied the electrophoretic gamma-globulins. Sepharose Protein-A and anti-IgG were used as immunoabsorbents to isolate and purify IgG from normal and Graves' disease sera. TBI activity in IgG was proportional to the IgG concentration, indicating that the TBI which migrates as a gamma-globulin electrophoretically is an IgG and thus may possibly be an antibody. Inhibitory activity found in normal serum globulins and the non-IgG fractions of both normal and abnormal sera seriously interferes with attempts to use the TSH radioreceptor assay to study the hypothesized anti-TSH, receptor antibody in the serum of patients with Graves' disease.

The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women.

Measurements of total and free testosterone levels in women have lacked precision and accuracy because of limited assay sensitivity. The paucity of normative data on total and free testosterone levels in healthy women has confounded interpretation of androgen levels in women with human immunodeficiency virus (HIV) infection and other disease states. Therefore, the objectives of this study were to develop sensitive assays for the measurement of the low total and free testosterone levels in women to define the range for these hormones during the normal menstrual cycle and assess the total and free testosterone levels in HIV-infected women. By using a larger volume of serum, increasing the incubation time, and reducing the antibody concentration, the sensitivity of the total testosterone assay was increased to 0.008 nmol/L, and that of the free testosterone assay was increased to 2 pmol/L. The mean percent free testosterone was 1.0 +/- 0.1% of the total testosterone. Serum total and free testosterone levels in the follicular and luteal phases were not significantly different, but both demonstrated a modest preovulatory increase, 3 days before the LH peak. Serum total [0.50 +/- 0.32 (14.60 +/- 9.22) vs. 1.2 +/- 0.7 nmol/L (34.3 +/- 21.0 ng/dL); P < 0.0001] and free testosterone levels (5.56 +/- 2.70 (1.58 +/- 0.80) vs. 12.8 +/- 5.5 pmol/L (3.4 +/- 1.7 pg/mL); P < 0.0001) were significantly lower in HIV-infected women (n = 37) than in healthy women (n = 34). Serum total and free testosterone levels were also significantly lower in HIV-infected women who were menstruating normally. There were no significant differences in serum total and free testosterone levels between those who had lost weight and those who had not. Testosterone levels correlated inversely with plasma HIV ribonucleic acid copy number. Serum FSH, but not LH, levels were significantly higher in HIV-infected women than in controls. Using assays with sufficient sensitivity, we defined the range for total and free testosterone levels during the normal menstrual cycle. Serum total and free testosterone levels are lower in HIV-infected women and correlate inversely with plasma HIV ribonucleic acid levels. The hypothesis that androgen deficiency contributes to wasting in HIV-infected women remains to be tested.

Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels.

Although weight loss associated with human immunodeficiency virus (HIV) infection is multifactorial in its pathogenesis, it has been speculated that hypogonadism, a common occurrence in HIV disease, contributes to depletion of lean tissue and muscle dysfunction. We, therefore, examined the effects of testosterone replacement by means of Androderm, a permeation-enhanced, nongenital transdermal system, on lean body mass, body weight, muscle strength, health-related quality of life, and HIV-disease markers. We randomly assigned 41 HIV-infected, ambulatory men, 18-60 yr of age, with serum testosterone levels below 400 ng/dL, to 1 of 2 treatment groups: group I, two placebo patches (n = 21); or group II, two testosterone patches designed to release 5 mg testosterone over 24 h. Eighteen men in the placebo group and 14 men in the testosterone group completed the 12-week treatment. Serum total and free testosterone and dihydrotestosterone levels increased, and LH and FSH levels decreased in the testosterone-treated, but not in the placebo-treated, men. Lean body mass and fat-free mass, measured by dual energy x-ray absorptiometry, increased significantly in men receiving testosterone patches [change in lean body mass, +1.345 +/- 0.533 kg (P = 0.02 compared to no change); change in fat-free mass, +1.364 +/- 0.525 kg (P = 0.02 compared to no change)], but did not change in the placebo group [change in lean body mass, 0.189 +/- 0.470 kg (P = NS compared to no change); change in fat-free mass, 0.186 +/- 0.470 kg (P = NS compared to no change)]. However, there was no significant difference between the 2 treatment groups in the change in lean body mass. The change in lean body mass during treatment was moderately correlated with the increment in serum testosterone levels (r = 0.41; P = 0.02). The testosterone-treated men experienced a greater decrease in fat mass than those receiving placebo patches (P = 0.04). There was no significant change in body weight in either treatment group. Changes in overall quality of life scores did not correlate with testosterone treatment; however, in the subcategory of role limitation due to emotional problems, the men in the testosterone group improved an average of 43 points of a 0-100 possible score, whereas those in the placebo group did not change. Red cell count increased in the testosterone group (change in red cell count, +0.1 +/- 0.1 10(12)/L) but decreased in the placebo group (change in red cell count, -0.2 +/- 0.1 10(12)/L). CD4+ and CD8+ T cell counts and plasma HIV copy number did not significantly change during treatment. Serum prostate-specific antigen and plasma lipid levels did not change in either treatment group. Testosterone replacement in HIV-infected men with low testosterone levels is safe and is associated with a 1.35-kg gain in lean body mass, a significantly greater reduction in fat mass than that achieved with placebo treatment, an increased red cell count, and an improvement in role limitation due to emotional problems. Further studies are needed to assess whether testosterone supplementation can produce clinically meaningful changes in muscle function and disease outcome in HIV-infected men.

Pharmacokinetics of a novel testosterone matrix transdermal system in healthy, premenopausal women and women infected with the human immunodeficiency virus.

The clinical consequences of androgen deficiency in human immunodeficiency virus (HIV)-infected women remain underappreciated. The pharmacokinetics of transdermally administered testosterone in premenopausal women and HIV-infected women have not been studied. In this study we compared the pharmacokinetics of a novel testosterone matrix transdermal system (TMTDS) in healthy premenopausal women and women infected with HIV. Eight menstruating HIV-infected women, 18-50 yr of age, who had been receiving stable antiretroviral therapy, including a protease inhibitor, for at least 12 weeks and nine healthy, menstruating women of comparable age were enrolled. After baseline sampling during a 24-h control period in the early follicular phase (days 1-6), two TMTDS patches were applied with an expected delivery rate of 300 microg testosterone daily over an application period of 3-4 days. After 72 h, the patches were removed, a second set of two patches was applied, and blood samples were drawn over 96 h. Baseline serum total and free testosterone levels were lower in HIV-infected women than in healthy women. A diurnal rhythm of testosterone secretion, with higher levels in the morning and lower levels in the late afternoon, was apparent in both groups of women. Free testosterone levels were in the midnormal range at baseline in healthy women and increased above the upper limit of normal during TMTDS application. In HIV-infected women, free testosterone levels were in the low normal range at baseline and rose into the upper normal range during patch application. Serum total testosterone levels increased into the midnormal range in HIV-infected women and into the upper normal range in healthy women during patch application. The mean increments in free and total testosterone levels were significantly lower in HIV-infected women than in healthy women. Testosterone bioavailability, expressed as the mean +/- SEM baseline-subtracted area under the total testosterone curve, was significantly greater in healthy women than in HIV-infected women [3323 +/- 566 ng/dL x h (115 +/- 20 nmol/L x h) vs. 1506 +/- 316 ng/dL x h (52 +/- 11 nmol/ L x h); P = 0.016]. Assuming a daily testosterone delivery rate of 300 microg/day, the apparent plasma clearance was significantly higher in HIV-infected women than in healthy women (2531 +/- 469 vs. 1127 +/- 217 L/day1 P = 0.022), respectively. There was no significant change from baseline in serum LH, sex hormone-binding globulin, and estradiol levels in either group. Serum FSH levels showed a greater decrease from baseline in healthy women. A regimen of two testosterone patches applied twice a week can maintain serum total and free testosterone levels in the mid- to upper normal range, respectively, in HIV-infected women with low testosterone levels. During TMTDS application, the increments in serum total and free testosterone levels are lower in HIV-infected women than in healthy women, presumably due to increased plasma clearance or decreased absorption. Further studies are needed to assess the effects of physiological androgen replacement in HIV-infected women.

An electrocardiographic pattern of acute myocardial infarction associated with excessive use of aerosolized isoproterenol.

A 39-year-old women inhaled approximately 675 mg of aerosolized isoproterenol in less than three days during an asthmatic attack. Serial enzyme and ECGs were consistent with acute myocardial necrosis. During a three-year-followup period, no clinical evidence or predisposing factors for coronary artery disease were revealed. The close temporal relation of isoproterenol overdosage with mycardial necrosis provides presumptive evidence that the well-documented association of myocardial necrosis with high dosage catecholamines in animals may also occur in man. While in no way detracting from the value of isoproterenol in standard doses, this report alerts physicians to the possibility of another hazard in those who may use this drug to excess.