Biomedical subjects
J Mills
Publications and source records attributed to J Mills.
Human immunodeficiency virus-infected monocyte-derived macrophages express surface gp120 and fuse with CD4 lymphoid cells in vitro: a possible mechanism of T lymphocyte depletion in vivo.
Monocyte-derived macrophages (MDM) infected in vitro with a macrophage-tropic strain of human immunodeficiency virus (HIV) fused with uninfected, CD4-expressing T lymphoblastoid cells, but not with a subclone of these cells lacking surface CD4. Infected MDM also fused with uninfected autologous and heterologous MDM. Recombinant soluble CD4 protein (rsCD4) (10 micrograms/ml) and full-length recombinant glycosylated gp120 (20 micrograms/ml) each inhibited fusion by 94-99%; the inhibition was dose-dependent. The N-terminal portion of gp120 did not inhibit syncytium formation. Fusion was also inhibited by a monoclonal antibody to an epitope which binds gp120 (S3.5), but not by antibody to an epitope not involved in gp120 binding (OKT4). HIV-infected MDM specifically bound fluorescein-conjugated rsCD4, and virus could be visualized budding from the surface of these cells. HIV-infected MDM express viral gp120 on their surface and fuse with CD4-bearing cells in a fashion similar to lymphoid cells. Macrophages may contribute to CD4 lymphocyte depletion in vivo by this fusion mechanism.
Role of the infectious disease specialist in AIDS-related clinical research.
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Comparison of the Western immunoblot assay and a glycoprotein G enzyme immunoassay for detection of serum antibodies to herpes simplex virus type 2 in patients with AIDS.
Herpes simplex virus type 2 (HSV-2) seroprevalence in 68 patients with AIDS was 77% by Western blot (immunoblot) and 44% by glycoprotein G-2 immunoassay. Each of 16 patients with culture-proven HSV-2 infection was positive by Western blot versus 8 by glycoprotein G-2 immunoassay. No differences in age, race, duration of AIDS, acyclovir usage, or HSV-1 seroprevalence were found to explain differences in sensitivity.
Autonomous staff selection teams.
Although some other organizations encourage staff input into employee selection, the advanced care department at Bellin Hospital in Green Bay, Wisconsin has taken this concept to a new level by implementing an autonomous interview team. This team is empowered to make hiring decisions for all positions within the department without management influence or interference.
A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.
BACKGROUND AND METHODS: Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both foscarnet and vidarabine. We conducted a randomized trial to compare foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine. RESULTS: The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after foscarnet was discontinued. CONCLUSIONS: For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.
Infectious complications with respiratory pathogens despite ciprofloxacin therapy.
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Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection.
OBJECTIVE: To determine whether foscarnet has potential efficacy in the treatment of acyclovir-resistant mucocutaneous varicella-zoster infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Open-label study. SETTING: Three university medical centers. PATIENTS: Five patients with AIDS who were infected with thymidine-kinase-deficient or -altered strains of varicella-zoster virus. INTERVENTION: Foscarnet, 40 mg/kg body weight every 8 hours in 1-hour infusions for 10 or more days. MAIN RESULTS: Four patients had healing in response to foscarnet therapy, and each of four tested patients became culture negative for virus during foscarnet therapy. Results of fluorescent antigen testing remained positive during therapy in two patients; one of these patients had concomitant clinical failure but the other patient healed fully. One patient had complete healing despite the emergence of resistance to foscarnet in serial specimens obtained during foscarnet therapy. CONCLUSION: Foscarnet is a potentially effective and tolerable antiviral agent for patients with acyclovir-resistant, varicella-zoster virus infection; however, the optimal dosage and duration of therapy require further study, as does the relation between clinical findings and in-vitro susceptibility results.
Lack of evidence of occult human immunodeficiency virus in seronegative individuals at very high risk of infection.
Reports of human immunodeficiency virus (HIV) infection in seronegative individuals prompted the authors to investigate subjects who are at very high risk of acquisition of HIV in San Francisco. Nine HIV seronegative subjects were evaluated extensively, eight of whom were drawn from a well-characterized cohort of seropositive and seronegative homosexual men who have been followed prospectively since 1983-1984. These men have calculated probabilities of infection based on a fitted model of between 0.22 and 0.94. One additional subject is an intravenous drug user who has shared needles with HIV-infected individuals extensively. Peripheral blood lymphocytes and monocytes were separately cultured from each subject and evidence of HIV infection was sought by a reverse transcriptase assay, enzyme immunoassay, and immunocytofluorographic analysis for HIV antigens, in situ hybridization, RNA slot blot analysis, and polymerase chain reaction amplification of HIV cDNA. Uncultured monocytes and lymphocytes from each donor were also examined by these techniques. Evidence of HIV infection was not found in the peripheral blood mononuclear cells of these high risk individuals.
Mediators of fusion between HIV-infected macrophages and lymphoid cells.
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Human immunodeficiency virus: novel enzyme-linked immunoassays for quantitation of envelope glycoprotein 120.
Two novel enzyme-linked immunoassays (ELISA) for the quantitation of human immunodeficiency virus type 1 (HIV-1) coded glycoprotein with an Mr 120 (gp120) are described. These are based on the highly specific interaction between gp120 and the mannose-specific lectins from Narcissus pseudonarcissus (NPL) and Galanthus nivalis (GNL). Two systems were developed: (1) an HIV-protein ELISA using HIV-protein (also containing HIV-gp120) for the solid phase and NPL as a detector and (2) a lectin-ELISA using the NPL bound to the solid phase and GNL as detector. The HIV-protein ELISA was validated for quantitation of gp120 within the range 3 to 600 ng/ml; the lectin-ELISA for concentrations between 0.6 and 20000 ng gp120/ml. Serum components did not interfere with the binding of gp120 to the lectins. The ELISAs were used for the quantitation of gp120 in HIV-infected CEM cells in vitro. It was found that gp120 appeared in the medium earlier after infection than HIV-p24 and reverse transcriptase, suggesting that gp120 is released as free glycoprotein. Moreover, the ELISAs were also applied successfully for the detection of compounds that bind to gp120 and for the identification of antibodies directed against the highly pathogenic mannan portion of gp120. These ELISAs are considered to be suitable also for the detection of gp120 in the serum of HIV-infected individuals.
In vivo additive antiretroviral effect of combined zidovudine and foscarnet therapy for human immunodeficiency virus infection (ACTG Protocol 053).
Zidovudine and foscarnet each have antiretroviral activity against human immunodeficiency virus (HIV) and, when combined in vitro, inhibit HIV replication in an additive or synergistic fashion. To determine if an in vivo additive or synergistic antiretroviral effect might result from combined therapy, six symptomatic HIV-infected patients were studied who had persistently quantifiable serum HIV p24 antigen despite 9-27 weeks of full-dose oral zidovudine therapy (1200 mg/day). These patients were given intravenous foscarnet (30 mg/kg every 8h) for 2 weeks with continued oral zidovudine for 14 days, followed by zidovudine alone for 6 months. Serum p24 antigen concentrations decreased in all six patients during the period of combined therapy by a mean 53% (P = .005). Subsequently, serum p24 antigen levels rose to the baseline value in four patients after 4-14 weeks. As predicted from in vitro studies, combined treatment with zidovudine and foscarnet resulted in an additive in vivo effect, but the effect was transient.
Clinical and serologic features of herpes simplex virus infection in patients with AIDS.
We studied the natural history of herpes simplex virus (HSV) infection and its association with specific serum antibody in a sample of 68 HIV-infected patients with a first episode of Pneumocystis carinii pneumonia at San Francisco General Hospital in 1986. Seroprevalence was 66 and 77% for HSV-1 and HSV-2 antibody, respectively, by immunoblot assay. Twenty-seven patients had 45 HSV outbreaks diagnosed during 739 patient-months of follow-up. Median frequency of recurrence resulting in a medical visit was once every 6.5 months, and median duration of treated outbreak was 10 days. Fourteen of 48 evaluable patients seropositive for HSV-2 had no outbreak of HSV during a median follow-up of 7.5 months. Our data suggests that neither frequency nor severity of HSV were substantially increased in this group of patients, despite severe immunosuppression caused by HIV. However, validation of these results by a prospective study is required.
Toxoplasma serology, parasitemia and antigenemia in patients at risk for toxoplasmic encephalitis.
In order to further characterize the pathogenesis of Toxoplasma gondii infection in patients with AIDS and AIDS-related complex (ARC), a cohort of HIV- and Toxoplasma-infected individuals were identified and prospectively followed. Four hundred and 10 HIV-infected individuals followed in the San Francisco General Hospital AIDS Clinic were screened for antibodies to Toxoplasma between November 1986 and November 1988. Of the 67 (16%) individuals seropositive for Toxoplasma antibodies, 33 (49%) were followed monthly for a mean duration of 7.5 months. One hundred and 11 follow-up blood samples were obtained in order to determine Toxoplasma serology and the incidence of parasitemia. In general, Toxoplasma immunoglobulin (Ig) G antibodies remained stable over time. Detection of Toxoplasma antigenemia and parasitemia was uniformly negative, including those specimens obtained from two individuals within 45 days of their developing toxoplasmic encephalitis.
Enzyme-linked immunoassay for human immunodeficiency virus type 1 envelope glycoprotein 120.
An enzyme-linked immunosorbent assay (ELISA) that can measure picogram quantities of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) in cell culture medium or body fluids has been developed. Recombinant, soluble CD4 immobilized in microtiter trays was used to capture gp120, which was then detected with polyclonal sheep antibody to gp120 followed by biotinylated rabbit anti-sheep immunoglobulin G and an avidin-alkaline phosphatase indicator system. With a reference recombinant gp120, the assay showed a linear relationship between optical density and concentrations ranging from 60 to 6,000 pg/100-microliters well; precision of the assay varied with the concentrations and ranged from +/- 40% with amounts smaller than 200 pg to +/- 10% with amounts larger than 200 pg. In a group of coded samples containing 60 pg (approximately 10(7) molecules) of reference gp120, the assay correctly identified the samples as containing gp120 99% of the time, with no false-positive results recorded for blank samples. Recombinant gp120 prepared in another cell culture system demonstrated a binding coefficient 13-fold lower than that of reference gp120. Mixing standard amounts of reference gp120 with increasing concentrations of human sera reduced assay sensitivity, although the linear relationship between gp120 concentration and optical density remained. With this assay we were able to detect gp120 in HIV-1 suspensions prepared from cultured lymphoblastoid cells and in the sera of HIV-1-infected patients. This ELISA for gp120 should be useful for studying the biological role of gp120 in HIV infection.
Bronchial hyperresponsiveness in normal subjects during attenuated influenza virus infection.
Fourteen healthy male subjects with hemagglutination-inhibition antibody titers of 1:8 or less to homologous influenza A virus were studied. Six subjects received live, attenuated influenza virus by nasal drops and by aerosol. Although infection occurred in these six subjects, with the development of 4-fold or greater increases in hemagglutination-inhibition antibody titers, they remained asymptomatic. Eight subjects received placebo via the same route, and did not develop symptoms and showed no increase in antibody titer. Prior to administration of virus or placebo, histamine diphosphate aerosol increased airway resistance only slightly, and there was no difference between the virus and placebo groups. Two days after inoculation, bronchomotor responses in the placebo group were unchanged (p greater than 0.05), but in the virus-infected group, bronchomotor responses were significantly greater than in the preinfected state (p less than 0.01). Isoproterenol hydrochloride reversed and prevented the increase in airway resistance after histamine, suggesting that the bronchoconstriction was caused by smooth muscle contraction. Our findings indicate that transient, asymptomatic respiratory virus infection augments airway smooth muscle responses.
Morbidity and mortality of patients with AIDS and first-episode Pneumocystis carinii pneumonia unaffected by concomitant pulmonary cytomegalovirus infection.
To determine the significance of cytomegalovirus (CMV) pulmonary coinfection with Pneumocystis carinii pneumonia in AIDS, we examined the association of long- and short-term survival and morbidity (as defined by length of hospital stay) with recovery of CMV from bronchoscopy specimens and an indirect measure of virus titer in bronchoalveolar lavage fluid (the time to develop CMV cytopathology in culture) in 111 patients diagnosed with a first episode of P. carinii pneumonia. Compared with 57 individuals from whom CMV was not isolated, the 54 individuals from whom CMV were isolated did not differ in baseline characteristics, long-term survival (213 versus 275 days, p = 0.97), acute death rate (19% in both, p = 1.0), or length of hospital stay (19.7 versus 21.1 days, p = 0.68). Also, the time to develop CMV cytopathology in culture did not correlate with acute or long-term survival. Our observations thus do not support the use of CMV-specific antiviral therapy in AIDS patients with P. carinii pneumonia who also have evidence of pulmonary CMV infection.
Hidden severe psychiatric morbidity in sentenced prisoners: an Australian study.
OBJECTIVE: The aim of this survey was to estimate the prevalence of severe mental disorders in a representative sample of sentenced prisoners. METHOD: The subjects were selected as a random sample of sentenced prisoners in Melbourne's three metropolitan prisons. Interviews were conducted with 158 men and 31 women. Clinicians used the Structured Clinical Interview for DSM-III-R (SCID) to diagnose psychotic, affective, and substance use disorders. RESULTS: Six prisoners (3%) received current diagnoses of psychotic disorders, and 23 (12%) were diagnosed as having current mood disorders, mainly major depression. A lifetime diagnosis of at least one mental disorder each was made for 82% of the respondents, and in 26% more than one lifetime disorder was diagnosed. Sixty-nine percent received lifetime diagnoses of dependence on or abuse of alcohol, other psychoactive substances, or a combination of these. CONCLUSIONS: These findings do not indicate a large-scale shift of deinstitutionalized psychotically ill people from mental hospitals to prisons. They do, however, highlight the diversion into the corrections system of substance-dependent people and the apparent pool of prisoners with largely untreated major depression.