Construction and biological characterization of an HB-GAM/FGF-1 chimera for vascular tissue engineering.

OBJECTIVE: Cardiovascular tissue engineering approaches to vessel wall restoration have focused on the potent but relatively nonspecific and heparin-dependent mesenchymal cell mitogen fibroblast growth factor 1 (FGF-1). We hypothesized that linking FGF-1 to a sequence likely to bind to cell surface receptors relatively more abundant on endothelial cells (ECs) might induce a relative greater EC bioavailability of the FGF-1. We constructed a heparin-binding growth-associated molecule (HB-GAM)/FGF-1 chimera by linking full-length human HB-GAM to the amino-terminus of human FGF-1beta (21-154) and tested its activities on smooth muscle cells (SMCs) and ECs. METHODS: Primary canine carotid SMCs and jugular vein ECs were plated in 96-well plates in media containing 10% fetal bovine serum and grown to approximately 80% confluence. After being growth arrested in serum-free media for 24 hours, the cells were exposed to concentration ranges of cytokines and heparin, and proliferation was measured with tritiated-thymidine incorporation. Twenty percent fetal bovine serum was used as positive control, and phosphate-buffered saline was used as negative control. RESULTS: In the presence of heparin the HB-GAM/FGF-1 chimera stimulated less SMC proliferation than did the wild-type FGF-1 with a median effective dose of approximately 0.3 nmol versus approximately 0.1 nmol (P <.001). By contrast, the chimera retained full stimulating activity on EC proliferation with a median effective dose of 0.06 nmol for both cytokines. Unlike the wild-type protein, the chimera possessed heparin-independent activity. In the absence of heparin, the chimera induced dose-dependent EC and SMC proliferation at 0.06 nmol or more compared with the wild-type FGF-1, which stimulated minimal DNA synthesis at 6.0-nmol concentrations. CONCLUSIONS: The HB-GAM/FGF-1 chimera displays significantly greater and uniquely heparin-independent mitogenic activity for both cell types, and in the presence of heparin it displays a significantly greater EC specificity.

The impact of prophylaxis on outcome and resource utilization in Pneumocystis carinii pneumonia.

STUDY OBJECTIVE: Pneumocystis carinii pneumonia (PCP) is a major late complication of HIV infection associated with morbidity and mortality. Because chemoprophylaxis is highly effective, cases of PCP can be viewed as failures in the management of HIV disease. METHODS: We reviewed demographic, clinical, and cost data for all cases of confirmed HIV-related PCP at The Johns Hopkins Hospital in 1991 to determine consequences of missed prophylaxis. We also analyzed hospital discharge data for Maryland in 1991 to assess hospital charges, length of stay, and outcome for all patients with a principal diagnosis of HIV-related PCP. RESULTS: Pneumocystis carinii pneumonia was diagnosed in 79 patients. Of the 79 patients, 61 (77%) did not receive prophylaxis, including 26 who were not previously known to have HIV infection, 17 who did not have prophylaxis prescribed, and 18 who had prophylaxis prescribed, but were not compliant with the regimen. Patients not taking prophylaxis accounted for all 12 deaths ascribed to PCP. This group also accounted for 85% of the hospital days, 100% of the ICU days, and 89% of the inpatient charges. The total hospital charges were $849,540. Extrapolation of these figures for the state of Maryland suggest that the failure to receive prophylaxis in 1991 resulted in 62 patient deaths and a cost of approximately $4.7 million. CONCLUSION: Patients who developed PCP despite prophylaxis had a better outcome and used fewer resources than patients not receiving preventive therapy. This study emphasizes the impact of PCP prophylaxis on the morbidity, mortality, and economics of HIV health care.

Functional status of persons with HIV infection in an ambulatory setting.

The objective of this project was to study the functional status of HIV-infected persons seen in an ambulatory care setting. We reviewed baseline clinical and demographic data on patients with HIV infection presenting for care between December 1988 and May 1991 at the HIV Clinic of the Johns Hopkins Hospital, an urban, primary care institution. Functional status was assessed at baseline in a comprehensive psychosocial assessment. Patients were asked to report on their ability to perform six activities of daily living (ADL) and nine instrumental activities of daily living (IADL). The main outcome measures were dependency in one or more ADL and death as ascertained by review of clinic death records and Maryland State Death Registries. All 728 patients had assessments of functional status. Of these, 18% reported dependencies in one or more activity, with most of these (14%) reporting dependencies in IADLs only. Dependencies were more common in persons with an AIDS diagnosis (32% vs. 15%, p < 0.001). The majority of the dependencies reported by AIDS patients were also in IADLs. Mean CD4 counts were lower for persons reporting dependencies than for those who reported no dependencies (p = 0.02). No independent associations were found between functional limitation and demographic variables. The risk of death was greater in patients with dependencies than in patients with no dependencies, even when adjusting for CD4 count and AIDS diagnosis (O.R. = 2.32, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of supervised, intermittent therapy for tuberculosis in HIV-infected patients.

OBJECTIVE: To evaluate the effectiveness of supervised therapy for tuberculosis (TB) in patients with HIV infection. DESIGN: Retrospective, chart review. PATIENTS: Patients with TB and HIV infection. SETTING: Urban, public TB clinic. MAIN MEASURES AND RESULTS: A total of 107 patients with TB and HIV infection were studied. Most were men (78%), African American (91%), uninsured or on Medicaid (88%), and 67% were injecting drug users. TB was diagnosed before AIDS in 31% of subjects, at the time of AIDS in 32%, and after AIDS in 37%. Clinical features varied by stage of HIV disease. Sixteen patients received no therapy and died before TB was diagnosed, 10 died during the first 8 weeks of treatment. Seventy-eight patients received > 8 weeks therapy, of whom 48 (62%) were given directly observed therapy twice weekly and 30 (38%) received self-administered daily therapy. Patients who received directly observed therapy were more likely to complete 6 months of therapy (96 versus 76%, P = 0.02) and more likely to survive after therapy ended (85 versus 57%, P = 0.01). By logistic regression, directly observed therapy, AIDS diagnosed before TB, and age were significantly associated with survival outcome. CONCLUSION: Directly observed therapy for TB in patients with HIV infection is highly effective and associated with better adherence to therapy and survival.

Impact of the 1993 revision of the AIDS case definition on the prevalence of AIDS in a clinical setting.

OBJECTIVE: To determine the impact of the 1993 revision of the Centers for Disease Control and Prevention (CDC) AIDS surveillance case definition on the prevalence of AIDS. DESIGN: Review of prospectively collected baseline clinical and demographic data on HIV-infected patients presenting for care between December 1988 and May 1991. SETTING: The HIV Clinic of the Johns Hopkins Hospital, an urban, primary care institution. MAIN OUTCOME MEASURE: Diagnosis of AIDS by the 1987 (specific indicator diseases) or the 1993 (indicator diseases, pulmonary tuberculosis, recurrent bacterial pneumonia, cervical carcinoma, or CD4 lymphocyte count < 200 x 10(6)/l) CDC case definition. RESULTS: Of 955 patients evaluated, 122 (13%) had AIDS by the 1987 case definition at presentation. An additional 126 (13%) met the 1993 but not the 1987 case definition. Patients meeting only the 1993 case definition were more likely to be female [28 versus 14%; odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2-3.0; P = 0.01] and intravenous drug users (40 versus 26%; OR, 2.0; 95% CI, 1.1-3.3; P = 0.02) than patients meeting the 1987 case definition. Fifty-five per cent of patients meeting only the 1993 case definition were asymptomatic, and 7% (nine patients) had new indicator diseases but CD4 counts > 200 x 10(6)/l. Median time to progression from a diagnosis of AIDS by the 1993 case definition to diagnosis by the 1987 case definition was 435 days. Patients with AIDS by the 1987 case definition had a median survival of 594 days from presentation (2-year survival, 42%), while median survival time for patients with AIDS by the 1993 case definition only was 947 days (2-year survival, 60%; P < 0.005). CONCLUSIONS: The proposed 1993 revision of the AIDS surveillance case definition would double the number of prevalent AIDS cases, with significant increases in the proportion of cases who are female, intravenous drug users, or asymptomatic. Survival of patients meeting the 1993 case definition is significantly longer than that of patients meeting the 1987 case definition. The new AIDS case definition will have a major impact both on AIDS surveillance and on medical and social service programs that use diagnosis of AIDS as a criterion for eligibility for services.

Racial heterogeneity of HIV antigenemia in people with HIV infection.

We compared the prevalence of HIV p24 antigenemia in black and white US patients with HIV infection. The prevalence of HIV antigenemia increased with severity of HIV disease (P less than 0.001). In all clinical categories, whites were more likely to be HIV-antigenemic than blacks (overall prevalence 38 versus 18%; P less than 0.01). Anti-p24 antibodies were detected in a higher proportion of blacks (84%) than whites (65%; P = 0.02). Blacks had significantly higher total serum immunoglobulin levels than whites (median 3.8 versus 3.2 mg/dl; P less than 0.00001). Racial differences in HIV antigen expression may result from differences in humoral response to HIV infection. These differences should be considered when HIV antigen is used as a surrogate marker in clinical trials.