Magnitude of Mycobacterium tuberculosis transmission among household and non-household contacts of TB patients.

The household and non-household contacts of patients with tuberculosis (TB) face varying degrees of risk of infection by Mycobacterium tuberculosis. To quantify new infection and to determine the risk factors associated with new infection among named contacts in San Francisco, CA, USA. We performed a cohort study in patients with culture-positive pulmonary TB. We analyzed patient, contact, environmental and bacterial characteristics. Of the 2422 contacts named by 256 patients, 149 (6.2%) had new infection due to recent transmission from 79 (30.9%) patients. Of the 149 new infections, 87 (58.4%) occurred among household contacts and 62 (41.6%) among non-household contacts. Numerous acid-fast bacilli in sputum (odds ratio [OR] 2.64, 95%CI 1.32-5.25) and contacts being named by more than one patient (OR 2.90, 95%CI 1.23-6.85) were associated with new infection among household contacts. Being older than 50 years (OR 1.93, 95%CI 1.09-3.41) and an Asian/Pacific Islander (OR 3.09, 95%CI 1.50-6.37) were associated with new infection among non-household contacts. Fewer than one third of patients caused new infection to his/her contacts. A substantial proportion of transmission resulting in new infection occurred outside of the household. The risk factors for infection among household and non-household contacts are different and should be considered when prioritizing control interventions. .

Interplay of strain and race/ethnicity in the innate immune response to M. tuberculosis.

BACKGROUND: The roles of host and pathogen factors in determining innate immune responses to M. tuberculosis are not fully understood. In this study, we examined host macrophage immune responses of 3 race/ethnic groups to 3 genetically and geographically diverse M. tuberculosis lineages. METHODS: Monocyte-derived macrophages from healthy Filipinos, Chinese and non-Hispanic White study participants (approximately 45 individuals/group) were challenged with M. tuberculosis whole cell lysates of clinical strains Beijing HN878 (lineage 2), Manila T31 (lineage 1), CDC1551 (lineage 4), the reference strain H37Rv (lineage 4), as well as with Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA) and TLR4 agonist lipopolysaccharide (TLR4/LPS). Following overnight incubation, multiplex assays for nine cytokines: IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα, and GM-CSF, were batch applied to supernatants. RESULTS: Filipino macrophages produced less IL-1, IL-6, and more IL-8, compared to macrophages from Chinese and Whites. Race/ethnicity had only subtle effects or no impact on the levels of IL-10, IL-12p70, TNFα and GM-CSF. In response to the Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA), Filipino macrophages again had lower IL-1 and IL-6 responses and a higher IL-8 response, compared to Chinese and Whites. The TLR2/LTA-stimulated Filipino macrophages also produced lower amounts of IL-10, TNFα and GM-CSF. Race/ethnicity had no impact on IL-12p70 levels released in response to TLR2/LTA. The responses to TLR4 agonist lipopolysaccharide (TLR4/LPS) were similar to the TLR2/LTA responses, for IL-1, IL-6, IL-8, and IL-10. However, TLR4/LPS triggered the release of less IL-12p70 from Filipino macrophages, and less TNFα from White macrophages. CONCLUSIONS: Both host race/ethnicity and pathogen strain influence the innate immune response. Such variation may have implications for the development of new tools across TB therapeutics, immunodiagnostics and vaccines.

Impact of Euro-American sublineages of Mycobacterium tuberculosis on new infections among named contacts.

BACKGROUND: The impact of demographic, clinical, and bacterial factors on new infection by Euro-American lineage Mycobacterium tuberculosis among contacts of patients with tuberculosis (TB) has not been evaluated. OBJECTIVE: To describe the risk factors for new infection by Euro-American M. tuberculosis sublineages in San Francisco, California. DESIGN: We included contacts of patients with TB due to Euro-American M. tuberculosis. Sublineages were determined by large-sequence polymorphisms. We used tuberculin skin testing or QuantiFERON®-TB Gold In-Tube to identify contacts with new infection. Regression models with generalized estimating equations were used to determine the risk factors for new infection. RESULTS: We included 1488 contacts from 134 patients with TB. There were 79 (5.3%) contacts with new infection. In adjusted analyses, contacts of patients with TB due to region of difference 219 M. tuberculosis sublineage were less likely to have new infection (OR 0.23, 95%CI 0.06-0.84) than those with other sublineages. Other risk factors for new infection were contacts exposed to more than one patient with TB, contacts exposed for 30 days, or contacts with a history of smoking or excessive alcohol consumption. CONCLUSIONS: In addition to well-known exposure and clinical characteristics, bacterial characteristics independently contribute to the transmissibility of TB in San Francisco.

Clinical and bacteriological characteristics associated with clustering of multidrug-resistant tuberculosis.

SETTING: The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics. OBJECTIVE: To determine factors associated with genotypic clustering of MDR-TB in a community-based study. DESIGN: We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations. RESULTS: Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering. CONCLUSION: Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

A 13-year molecular epidemiological analysis of tuberculosis in San Francisco.

BACKGROUND: We examined the molecular epidemiology of tuberculosis (TB) in San Francisco during a 13-year period encompassing the peak of TB resurgence and subsequent decline to historic low levels. OBJECTIVE: To compare rates of TB caused either by rapid progression of recent Mycobacterium tuberculosis infection or by reactivation of latent infection. METHODS: All TB cases reported from 1991 to 2003 were included. Genotyping was performed to identify clustered cases. RESULTS: The annual TB case rate decreased significantly from 50.8 to 28.8 cases/100000 persons from 1992 to 1999 (P < 0.0001). After 1999, no significant decrease was observed for the population as a whole or in any subgroup examined. Similarly, the rate of clustered cases decreased significantly from 1992 to 1999 (11.4 to 3.1 cases/100000, P < 0.0001). Although the rate of non-clustered cases also declined significantly (25.6 to 17.6 cases/100,000, P < 0.0001), there was a disproportionate reduction in clustered cases (94.7% vs. 50.8%, P < 0.0001). Neither clustered nor non-clustered cases decreased significantly after 1999. CONCLUSIONS: TB case rates reached a plateau despite ongoing application of control measures implemented in 1993. These data suggest that intensification of measures designed to identify and treat persons with latent TB infection will be necessary to further reduce TB incidence.

Friend or foe? How primary care physicians perceive hospitalists.

BACKGROUND: Increased use of hospitalists is redefining the role of primary care physicians. Whether primary care physicians welcome this transition is unknown. We examined primary care physicians' perceptions of how hospitalists affect their practices, their patient relationships, and overall patient care. METHODS: A mailed survey of randomly selected general internists, general pediatricians, and family practitioners with experience with hospitalists practicing in California. MAIN OUTCOME MEASURES: Physicians' self-reports of hospitalists' effects on quality of patient care and on their own practices. RESULTS: Seven hundred eight physicians were eligible for this study, and there was a 74% response rate. Of the 524 physicians who responded, 34% were internists, 38% were family practitioners, and 29% were pediatricians. Of the 524 respondents, 335 (64%) had hospitalists available to them and 120 (23%) were required to use hospitalists for all admissions. Physicians perceived hospitalists as increasing (41%) or not changing (44%) the overall quality of care and perceived their practice style differences as neutral or beneficial. Twenty-eight percent of primary care physicians believed that the quality of the physician-patient relationship decreased; 69% reported that hospitalists did not affect their income; 53% believed that hospitalists decreased their workload; and 50% believed that hospitalists increased practice satisfaction. In a multivariate model predicting physician perceptions, internists, physicians who attributed loss of income to hospitalists, and physicians in mandatory hospitalist systems viewed hospitalists less favorably. CONCLUSIONS: Practicing primary care physicians have generally favorable perceptions of hospitalists' effect on patients and on their own practice satisfaction, especially in voluntary hospitalist systems that decrease the workload of primary care physicians and do not threaten their income. Primary care physicians, particularly internists, are less accepting of mandatory hospitalist systems. Arch Intern Med. 2000;160:2902-2908

Reduced sensitivity of the QuantiFERON(®) test in diabetic patients with smear-negative tuberculosis.

SETTING: Immunosuppressive conditions have been associated with low sensitivity of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for the diagnosis of tuberculosis (TB). However, no systematic analysis of patient and bacterial characteristics has been performed before. OBJECTIVE: To determine the sensitivity and the risk factors for false-negative QuantiFERON(®)-TB (QFT) assay and TST in TB patients. DESIGN: We performed a retrospective analysis of data collected in a community-based study of TB in San Francisco, CA, USA. We included 300 TB patients who underwent QFT and TST. RESULTS: The risk factors for false-negative QFT were human immunodeficiency virus infection and the use of QuantiFERON(®)-TB Gold. In patients with sputum smear-negative TB, diabetes mellitus (DM) was associated with false-negative QFT (OR 2.85, 95%CI 1.02-7.97, P = 0.045). TST sensitivity was higher than QFT sensitivity in DM patients (OR 9.46, 95%CI 2.53-35.3). CONCLUSIONS: In San Francisco, QFT sensitivity was lower than that of TST, especially in patients with DM. Stratified analysis by sputum smear results showed that this association was specific to smear-negative TB. In contrast, TST was not affected by the presence of DM.

Immune activation markers and AIDS prognosis.

Four assays for serum levels of cellular products of immune activation were examined as prognostic markers for AIDS in a prospective study of asymptomatic HIV-seropositive homosexual men. Baseline serum values of beta 2-microglobulin (beta 2M), neopterin, soluble CD8 (sCD8), and soluble interleukin-2 receptor (sIL-2R) for 185 men were examined univariately and multivariately as predictors of AIDS during 36 months of follow-up. Thirty-three cases of AIDS (18%) were diagnosed during the follow-up period. All four assays correlated highly with each other (r = 0.48-0.63), and all four were good univariate predictors of AIDS and comparable to CD4 lymphocyte count. beta 2M, neopterin, and sCD8 predicted AIDS independently of both CD4 count and HIV p24 antigen or p24 antibody in multivariate analysis. Within the range of CD4 count 200-499 x 10(6) cells/l, an immune activation marker used in combination with an assay for p24 antigen identifies those at 3-6% risk of AIDS over 36 months (low risk on both assays) and those at 63-86% risk (high risk on both assays). These results can be used to guide physicians and patients making decisions about treating asymptomatic HIV infection with zidovudine in individuals with CD4 lymphocyte count of 200-499 x 10(6) cells/l.

Differences in laboratory values in HIV infection by sex, race, and risk group.

OBJECTIVES: To determine differences in CD4+ and CD8+ lymphocyte values, beta 2-microglobulin (beta 2M), and HIV p24 antigenemia by sex and race among HIV-seropositive and HIV-seronegative injecting drug users (IDU), and to compare these values with those in homosexual men of equivalent status. DESIGN: Baseline values from a cohort of 206 HIV-seropositive and 173 HIV-seronegative IDU were compared with values from a cohort of 288 HIV-seropositive homosexual men and 176 HIV-seronegative controls, who were prospectively followed at 6-month intervals, to examine differences in laboratory values in HIV-infected individuals by sex, race, and risk group. METHODS: Among HIV-seropositives, we compared white and black IDU only (n = 167), and white male IDU (n = 38) with white homosexual men (n = 256). Laboratory values from the cohort of homosexual men at 24, 36 and 48 months of follow-up were compared with IDU values. RESULTS: HIV-infected female IDU had significantly higher CD4+ lymphocyte counts (P < 0.03) and percentages of CD4+ lymphocytes (P < 0.004) than male IDU, resulting in higher CD4:CD8 ratios (P < 0.002). White IDU had significantly higher serum beta 2M levels than black IDU (P < 0.02). Black female IDU were much less likely to be HIV p24-antigenemic (1%) than all other groups (P < 0.005). Compared with homosexual men, male IDU had significantly elevated beta 2M levels (0.58 mg/l higher). When controlled for CD4+ lymphocyte values as a surrogate for length of time HIV-infected, beta 2M and HIV p24 antigenemia differences persisted. CONCLUSIONS: These differences should be considered when HIV p24 antigen, CD4+ lymphocyte counts and beta 2M levels are used as surrogate markers in clinical trials and management of HIV disease.

Gay men report high rates of unprotected anal sex with partners of unknown or discordant HIV status.

OBJECTIVE: To examine patterns and factors that correlate with unprotected anal intercourse (UAI) practices among San Francisco gay men, including UAI with partners of unknown or different HIV antibody status. DESIGN: A longitudinal cohort recruited for the San Francisco Young Men's Health Study in 1992; re-assessed annually. PARTICIPANTS AND METHODS: A sample of 510 unmarried gay men who were 18 to 29 years at baseline were originally recruited as part of a larger population and referral-based sample. Subjects participated in four consecutive waves of data collection. RESULTS: The prevalence of reported unprotected anal intercourse (UAI) increased from 37% to 50% between 1993-1994 and 1996-1997. Almost half of all men who reported UAI in 1996-1997 indicated that it occurred with a partner of unknown or discordant HIV antibody status. This high-risk practice correlated with greater numbers of male sex partners, use of nitrite inhalants, sex in commercial sex environments, perceived difficulty controlling sexual risk-taking, and negative emotional reactions following UAI. CONCLUSIONS: These data on increasing rates of sexual risk-taking further confirm trends in sexual behavior previously suggested by rising rates of rectal gonorrhea in this population. Additional and sustained prevention efforts are urgently needed in light of the very high background rates of HIV infection found among gay men in San Francisco.

Time from HIV seroconversion to oral candidiasis or hairy leukoplakia among homosexual and bisexual men enrolled in three prospective cohorts.

OBJECTIVES: We evaluated time from HIV seroconversion to diagnosis of two common oral lesions associated with HIV infection and disease progression. DESIGN: Oral examinations were performed on homosexual and bisexual men enrolled in prospective cohorts. SETTING: Homosexual and bisexual men were followed in three epidemiologic cohort studies in San Francisco, California, USA. PARTICIPANTS: Data were evaluated from 80 men with well-defined dates of HIV seroconversion from 1984 through 1991. MAIN OUTCOME MEASURES: We determined the cumulative incidence of oral candidiasis and hairy leukoplakia after HIV seroconversion. RESULTS: Four per cent of men developed oral candidiasis within 1 year after HIV seroconversion, 8% within 2, 15% within 3, 18% within 4, and 26% within 5 years. Nine per cent developed hairy leukoplakia within 1 year, 16% within 2, 25% within 3, 35% within 4, and 42% within 5 years. The median CD4+ count was 391 x 10(6)/l when oral candidiasis was first reported and 468 x 10(6)/l when hairy leukoplakia was first reported. CONCLUSIONS: Oral candidiasis or hairy leukoplakia appeared in a significant proportion of HIV-infected homosexual and bisexual men. These lesions occurred relatively soon after HIV seroconversion, typically before AIDS. Evaluation of HIV-infected individuals for these lesions has many potential clinical and research benefits, including the possible use of oral lesions as primary end-points in clinical trials.

Extrarenal prorenin in plasma requires an activator of renal origin.

Plasma prorenin may be of renal or extrarenal origin, and its conversion to renin may be catalyzed by renal or extrarenal enzymes. We tested the effect of bilateral nephrectomy and sham bilateral nephrectomy on plasma renin and prorenin in dogs, using low (3 mg/ml) and high (5 mg/ml) concentrations of trypsin to activate the prorenin. In the nephrectomized dogs, active plasma renin quickly disappeared, whereas plasma prorenin (inactive renin) increased by up to 300% during the first 24 hours after surgery, suggesting that it was released rapidly from a major extrarenal source but not converted to renin in the absence of the kidneys. In the sham surgery (control) group, plasma renin activity increased by up to 400% in the first 24 hours but returned almost to baseline by 48 hours, whereas prorenin remained at the preoperative value or fell below it. The quantity of prorenin varied greatly between the groups according to the time after surgery and the different concentrations of trypsin used. In the nephrectomy group, low and high trypsin levels resulted in similar prorenin values during the first 3 hours, but later on, the high trypsin level resulted in about twice as much prorenin. In the control group, high trypsin levels generally produced lower prorenin values than did low trypsin levels. Since trypsin is believed to interact with endogenous convertase enzymes in converting prorenin, a high requirement for it after bilateral nephrectomy suggests that removal of the kidneys causes a deficiency of such convertases. Conversely, the low requirement for trypsin after the stress of sham surgery suggests enhanced plasma convertase activity in the presence of the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma prorenin in humans and dogs. Species differences and further evidence of a systemic activation cascade.

We have studied the dog as a potential model for the human plasma prorenin-renin system. On a regular sodium intake, healthy conscious dogs apparently have a much lower plasma renin activity (PRA) than healthy human volunteers. Cryoactivation of prorenin is virtually absent in dogs, in contrast to that in humans, but becomes more effective after preacidification of the plasma. The concentration of trypsin required for optimal activation of prorenin is 6 to 10 times higher for dog plasma, revealing a prorenin:renin ratio about 10 times greater than in humans. Dialysis of posttryptic plasma decreases the PRA, but it remains 5 times higher than in pretryptic plasma, indicating that activation is not totally dependent on any renin system component that has been rendered dialyzable by trypsin, e.g., substrate converted to tetradecapeptide (TDP). This argues against the view that tryptic activation is attributable to angiotensin production from TDP by the action of cathepsin D, rather than from new renin converted from prorenin. The posttryptic increase in PRA is evident whether plasma incubation is carried out at pH 6.0 or at 7.4, and can be largely blocked by pepstatin, which also implicates a prorenin-renin mechanism rather than TDP-cathepsin. The low PRA in dogs, the negligible cryoactivation and its improvement by preacidification, and the requirement and tolerance of high trypsin concentrations, all point to greater protease inhibition in dog plasma and/or departures from the enzyme(s) responsible for human prorenin activation. Moreover, the tryptic activation of prorenin is not completed quickly as in human plasma, but carries over into the posttryptic stage of angiotensin generation, even in the presence of excess soybean trypsin inhibitor (SBTI), and other potent inhibitors. Such ongoing prorenin activation cannot be attributed only to trypsin itself, nor to kallikrein (both are inhibited by SBTI), but rather to some other enzyme(s) derived by the action of trypsin. This new prorenin convertase activity (possibly renin itself) can be effectively transferred from trypsinized to control dog plasma, in which it greatly accelerates prorenin activation. Thus, contrary to other reports, dog plasma has a high content of activatable prorenin, and with appropriate methodological changes, the dog can be used as an animal model for physiological and biochemical studies of the prorenin-renin system.

Fibrinolysis, renin activity, and prorenin in normal women: effects of exercise and oral contraceptive medication.

PIP: 25 young women, 13 of whom on oral contraception (OC), were observed to study the effects of exercise and of OC on the blood fibrinolytic and renin systems. It appeared very clearly that exercise would activate the fibrinolytic system, and that renin activity was also stimulated, suggesting a relationship between the 2 systems. The connection between exercise, fibrinolysis and prorenin activity was evidenced by an exercise-induced drop in the proportion of inactive renin and fibrinolytic activity, and in the presence of contraceptive-induced activation of fibrinolysis. OC did not seem to raise plasma prorenin above the control value, but it did raise active-renin, especially late in the menstrual cycel.^ieng

Regulated systemic activation of rat plasma prorenin.

Nephrectomized rats have above-normal plasma prorenin levels, presumably of extra-renal origin, but essentially no renin, suggesting a lack of "convertase" for prorenin activation. Adrenalectomized rats have low plasma prorenin levels accompanied by high renin activity, suggesting enhanced prorenin activation by the action of a stimulated "convertase" mechanism. Cross-circulation between adrenalectomized and nephrectomized rats for 15 or 30 minutes, dramatically lowered prorenin and raised renin levels in both types of rats, suggesting extensive activation of prorenin to renin. Similarly, in vitro mixing of these bloods (without cross-circulation) raised renin activity over five times the expected calculated level, while prorenin essentially disappeared. In both cases, prorenin from nephrectomized rat plasma apparently was activated to renin by the enhanced action of "convertase" in the adrenalectomized rat plasma. This newly generated renin activity was, like normal plasma renin, almost completely inhibited by a monoclonal antibody against hog renin and generated an immunoreactive angiotensin I. In contrast, cross-circulation or in vitro mixing of blood from normal control and nephrectomized rats produced little detectable activation of prorenin and only modest increments of renin, suggesting relative inactivity of the "convertase" mechanism in normal plasma. Our data suggest that activation of plasma prorenin is a significant regulated pathway for renin production, as it is greatly stimulated after adrenalectomy and deficient after nephrectomy, thereby implicating the kidney as an important contributor to the "convertase" mechanism operating within the circulation.

Relationship of CD4 counts to neurophysiological function in HIV-1--infected homosexual men.

OBJECTIVE: To explore the relationship of immune dysfunction to neurophysiological measures of brain-stem conduction time. DESIGN: Three-year longitudinal prospective cohort study; results of time 1 analyses reported. SETTING: San Francisco (California) General Hospital, Departments of Psychiatry and Epidemiology. PATIENTS: Volunteer sample of 55 human immunodeficiency virus (HIV)-positive and 37 HIV-negative homosexual men recruited from a larger cohort of homosexual men followed up since 1983 at San Francisco General Hospital as part of an ongoing study of the natural history and course of HIV type 1 infection. INTERVENTION: None. MAIN OUTCOME MEASURES: Auditory brain-stem responses and somatosensory evoked potentials for subjects stratified separately on HIV serostatus, Centers for Disease Control and Prevention symptom groupings, and absolute CD4 counts. RESULTS: The HIV-positive subjects had an increased wave III-V interpeak latency of the right ear auditory brain-stem response compared with the HIV-negative subjects (t test, P < .05). There were no significant differences among the three Centers for Disease Control and Prevention groupings on any evoked potential measure. When HIV-positive subjects were stratified on a measure of immune functioning, ie, CD4 counts, individuals with greater immune suppression were more impaired on speed of auditory brain-stem conduction time (Mann-Whitney U test, P < .05). Furthermore, 85% of subjects impaired on this evoked potential measure had CD4 counts of less than 0.40 x 10(9)/L (400/microL), whereas only 15% of those impaired on this measure had CD4 counts of greater than 0.40 x 10(9)/L. CONCLUSIONS: Asymptomatic HIV-positive subjects who do not have evidence of immune suppression do not appear to be at greater risk for neurophysiological impairment than HIV-negative subjects. The HIV-positive individuals who are immune suppressed (even while asymptomatic) appear to have an increased likelihood of central conduction time slowing as measured by evoked potential procedures.

Projecting the medical costs of AIDS and ARC in the United States.

We projected the direct medical costs of acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC) for the United States during the period 1987-1991, by applying current epidemiologic projections to state-of-the-art medical decision algorithms for diagnosis and treatment of AIDS-related illnesses. We included the cost of azidothymidine (AZT) therapy, as well as other therapeutic innovations likely to be approved by the FDA, and estimated average ARC patient treatment costs. By combining prospective study data on rates of progression to AIDS with current AIDS incidence data, we arrived at human immunodeficiency virus (HIV) seroprevalence and AIDS incidence projection that were considerably lower than those of the Public Health Service. We estimated the average total medical costs per patient for AIDS in the 1990s at $27,950-$40,455 and for ARC at $3,621-$4,913 per year (1987 U.S. dollars). We projected the medical costs of AIDS and ARC at $2-4 billion annually by 1991, substantially lower than previous estimates. We projected that Pneumocystis carinii pneumonia and other pulmonary complications would account for the largest share (over 40%) of AIDS medical costs, and that AZT therapy and medication would account for more than 25% of total ARC/AIDS treatment costs by 1991. In our estimates, the total medical costs of treating ARC patients could approach one-half of the costs of treating AIDS patients by 1991, primarily due to costs associated with AZT.

Relationship of beta 2 microglobulin and CD4 counts to neuropsychological performance in HIV-1-infected intravenous drug users.

This study explores the relationship of immune dysfunction to the neuropsychological performance of i.v. drug users (IVDUs) infected with HIV-1. Ninety-seven HIV-positive and 45 HIV-negative former IVDUs on methadone maintenance were evaluated using neuropsychological measures, physical examinations, and measures of immune function, including absolute CD4 counts and beta 2 microglobulin (beta 2-M). There were no significant differences between the HIV-positive and HIV-negative subjects on any single neuropsychological domain. There was, however, a significant group difference on a composite indicator of neuropsychological impairment, with 32% of HIV-positive subjects demonstrating some degree of overall impairment compared with only 13% of HIV-negative subjects. HIV-positive subjects were then stratified according to the Centers for Disease Control (CDC) symptom groupings: group II, asymptomatic, n = 29; group III, lymphadenopathy, n = 30; and group IV A or C-2, symptomatic, non-AIDS, n = 38. There were no significant neuropsychological differences among the three CDC groups. The HIV-positive subjects were also stratified on absolute CD4 counts (< or = 200, 201-400, and > 400) and beta 2-M (> or = 5, 3-5, and < 3). Individuals with greater immune compromise (CD4, < 200, beta 2-M, > or = 5) were more impaired on measures of motor functioning. beta 2-M was found to be a better predictor than CD4 count of impaired neuropsychological performance. Furthermore, individuals with beta 2-M values > or = 5 have more than a threefold increase in the incidence of neuropsychological impairment than those with beta 2-M values < 3.0. These results suggest that beta 2-M may serve as a useful clinical marker for the development of neuropsychological impairment and that the risk of such impairment increases as the immune system weakens.

Immune function and neuropsychological performance in HIV-1-infected homosexual men.

This study explores the relationship of immune dysfunction to the neuropsychological performance of individuals infected with HIV-1. Fifty-five HIV-positive homosexual men and 37 negative homosexual controls were evaluated using neuropsychological measures, physical exams, and measures of immune functioning. There were no significant differences favoring HIV-negative subjects over HIV-positive subjects. HIV-positive subjects, in fact, performed slightly better on attention and memory procedures. The HIV-positive subjects were then stratified according to the Centers for Disease Control symptom groupings (Group II, asymptomatic, n = 19; Group III, lymphadenopathy, n = 17; and Group IVA or C-2, symptomatic, non-AIDS, (n = 19). There were no significant neuropsychological differences among the three CDC groups. The HIV-positive subjects were also stratified on two measures of immune functioning: absolute CD4 counts (< 200, 201-400, > 400) and beta 2-microglobulin (beta 2M) (> or = 5.0, 3.0-5.0, < 3.0). Individuals with greater immune compromise, as measured by beta 2M, were more impaired on measures of attention and memory and had greater overall neuropsychological impairment (p < 0.05). Furthermore, 57% of the subjects who were abnormal on beta 2M were also impaired on measures of attention and memory, whereas only 14% of those with normal beta 2M were impaired on these same measures (p < 0.05). These results suggest that HIV-positive asymptomatics without evidence of immune compromise do not appear to be at greater risk of cognitive impairment than HIV-negative controls. However, for those HIV-positive individuals who are immune-compromised (even while asymptomatic), there is increased risk of neuropsychological impairment. These results also suggest that knowledge of serostatus and the use of the CDC classification system alone are insufficient in exploring the development of neuropsychiatric changes in HIV-1 infection.

Can total prorenin in human plasma be determined by current activation methods?

A proper evaluation of the physiological significance of plasma prorenin depends on its accurate determination. However, current activation methods do not necessarily measure total prorenin, or a known proportion of it, even when carried out to apparent completion. Thus, extending cold activation of human plasma at -4 degrees C generally revealed progressive increments of prorenin, mainly during the first 15 days, but the total and the time required to achieve it varied considerably among individuals. Similarly, the titration curves of individual plasmas varied with increments of added trypsin and achieved totals that were not necessarily greater than those obtained by cold activation. This indicates the inappropriateness of attributing greater effectiveness to one method over the other. When the two methods were paired in sequence, a synergism was apparent in that prorenin estimates increased consistently; in one case more than 10-fold. Thus, total prorenin by any single method generally fell short of the total achieved by double methods. However, this too may still not represent the unknown true total prorenin. The sequence of activation steps was important, providing clues as to the mechanism of the observed synergism. Trypsin-before-cold activation proved to be more effective than trypsin-after-cold activation, with no further advantage being gained from triple treatments involving cold before and after trypsin, or trypsin before and after cold. The inferiority of trypsin-after-cold activation was apparently due to sensitization of the plasma to the destructive effects of trypsin, shifting its titration curve to the left.(ABSTRACT TRUNCATED AT 250 WORDS)