Biomedical subjects
Publications and source records attributed to M A Fletcher.
The peroxisome assembly factor-1 (PAF-1) is reported here to contain the signature subsequence for a ring finger motif in its carboxyl-terminus. This conserved subsequence in PAF-1 may be the key to a gene expression regulatory pathway important in peroxisome biogenesis.
Children other than neonates infected with human immunodeficiency virus type 1 (HIV-1) have low rates of progression to acquired immunodeficiency syndrome (AIDS). Through 1989, 5.3% of 95 infected hemophiliacs aged 5 to 13 years developed AIDS, compared with 20.3% of 364 aged greater than or equal to 25 years. We asked whether the HIV-1 impact on peripheral blood mononuclear cell subpopulations differed with age using pairwise comparisons of uninfected and infected male children and adult hemophiliacs. Infected children had lesser reductions of total lymphocytes than adults, but proportionately lower numbers of CD2+, CD4+, CD2+CD26+, and CD4+CD29+ counts. CD4+CD45RA+ cell counts were greater than twofold higher in uninfected and infected children than adults; with infection, the CD4+CD45RA+/CD4+ proportion increased by 1.4-fold in adults, but was unchanged in children. Infected adults had highly significantly increased total CD8+ counts; both age groups had elevated CD8+HLA-DR+ counts. Infected children had significantly higher total B-cell counts than infected adults, with a disproportionately lower number of resting B cells (CD20+CD21+). During 2 years of follow-up, infected children and adults had lymphocyte changes in the same directions and these were proportionately equal. The lower rate of HIV-1 progression in children may be partly associated with differences in lymphocyte populations compared with adults; functional properties of immune cells may be equally or more important.
The aim of this study was to examine the hypothesis that a psychosocial model was associated with natural killer cell cytotoxicity (NKCC) in HIV-1 infection. A sample of 62 HIV-1 seropositive homosexual men at CDC stages II and III were given a psychosocial battery assessing life stressors, social support, and coping style. A regression model quantifying these variables along with control variables for alcohol use, substance use and nutritional status was estimated. Active coping style was directly and positively associated with NKCC, and trends toward a negative relationship of life stressors and a buffering effect of social support on lives stressors were also observed. The results suggest that (1) control variables should be included with psychosocial models and that (2) psychosocial factors, especially active coping, may have a deterrent effect on loss of NK cell function. Active coping style may merit a specific focus in future research of life stressors and the immune system.
To gain insight into the immunopathogenesis of drug-induced autoimmune disorders, lymphocyte and immunoglobulin distributions and cytokine levels were monitored in the peripheral blood and pleural fluid of a patient with procainamide-induced lupus and pleural effusion. Approximately 80% of the B cells in both compartments were CD5+ compared to 10% to 25% in normal adults. CD4/CD8 ratio and percentage CD4 were normal in peripheral blood. Serum levels of IgG (particularly IgG2), IL-6, and soluble IL-2R were slightly elevated, and those of IgA were significantly elevated compared to normal controls. Analysis of the pleural effusion revealed an increased CD4/CD8 ratio because of an increased percentage of CD4+CD29+ helper memory T cells, lack of expression of the resting B-cell marker CD21, immune complex deposition and complement consumption, increased relative levels of ANA, abnormally high levels of IL-6 and soluble IL-2R, and detectable levels of IL-1b, IFN-g and TNF-a. These observations provide evidence for the involvement of CD5+ B cells and differential helper T-cell activity in procainamide-induced lupus and for an association between local lymphocyte activation and organ pathology.
OBJECTIVES: To determine (1) whether there were differences in cognition between HIV-1-seropositive and HIV-1-seronegative homosexual men and (2), if so, whether these differences could be explained by the degree of immunosuppression [i.e., CD4 cell count and immunoglobulin A (IgA) levels]. DESIGN: A cross-sectional design was used to compare 66 HIV-1-seropositives (Centers for Disease Control stages II and III, n = 56; stages IVA and IVC-2, n = 10) and 37 HIV-1-seronegatives. The HIV-1-seropositives were classified into three immune groups based on their CD4 cell count (x 10(6)/l) and serum IgA level (mg/dl): (1) moderate [(n = 35) CD4 greater than 400, IgA less than 300]; (2) mixed [(n = 22) either CD4 greater than 400 and IgA greater than 300 or CD4 less than 400 and IgA less than 300] and (3) poor [(n = 9) CD4 less than 400, IgA greater than 300]. HIV-1-seronegatives formed the 'good' immune group (CD4 greater than 400 and IgA less than 300). METHODS: The four groups were compared on tests of verbal and visual memory, information-processing speeds, visuospatial skills, language processes, attention, psychomotor reaction time, and mental status. Factors other than HIV-1 sero-status that can influence cognitive performance were tested as covariates. RESULTS: HIV-1-seropositives had slower information-processing speeds and decreased verbal and visual memory, compared with HIV-1-seronegatives. These differences in cognition were not due to differential immunosuppression or to clinical status among the HIV-1-seropositives. CONCLUSIONS: Cognitive alterations occur in HIV-1-infected individuals before AIDS and appear to be independent of clinical status and degree of immunosuppression as measured by CD4 cell count and IgA levels.
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We have investigated the acute changes in cytokine gene expression patterns and immune status in vivo and ex vivo in a patient on chronic hemodialysis with cuprophane membranes before and after two hemodialysis sessions with either cuprophane or polysulfone membranes. Results show that both dialyzer membranes have differential acute effects on the immune system and that the concomitant use of reverse-transcriptase-coupled polymerase chain reaction, solid-phase and radioimmunoassays, and flow-cytometric analysis may be useful in the longitudinal assessment of patients on chronic hemodialysis.
Recent evidence suggests that pentoxifylline (PTX) may be useful in the treatment of sepsis. We examined effects of PTX in a conscious swine model of sepsis. Yucatan minipigs (20-30 kg) were anesthetized and instrumented with catheters in the vena cava, aortic arch, pulmonary artery (Swan-Ganz thermodilution catheter), and peritoneum. Twenty-four hours after surgery, sepsis was induced by intraperitoneal (ip) injection of Escherichia coli bacteria (2 x 10(10) cfu/kg). Nonseptic pigs received intraperitoneal saline (5 ml/kg). PTX treatment (3 mg/kg/hr, iv; 1 mg/ml in 0.9% saline) and maintenance fluid (5 ml/kg/hr, iv) were started with bacterial infusion. An additional 60 cc/kg 0.9% saline bolus was administered iv at 1 hr. Pigs were monitored before and 1, 2, 5, and 24 hr after bacterial injection. Intraperitoneal injection of bacteria led to significant reductions in blood pressure and cardiac output and elevations in pulmonary wedge pressure and pulmonary vascular resistance. These effects were attenuated by PTX treatment. All septic animals demonstrated elevated creatinine, blood urea nitrogen, circulating endotoxin (LPS), and tumor necrosis factor concentrations, reductions in white blood cell and platelet counts, and peritonitis. None of these responses was altered by PTX treatment. We conclude that PTX may prove to be a useful therapeutic tool in the early treatment of septic shock but is limited in the scope of its effects.
Depending on the dose and dosing, pentoxifylline (PTX) treatment can improve or worsen survival from lipopolysaccharide (LPS) shock in rats. Intraperitoneal (i.p.) PTX, 20 mg/kg, administered once 15 min after intravenous (i.v.) LPS (17 mg/kg), significantly improved survival in unanesthetized LPS-shocked rats. Multiple 20 mg/kg PTX injections (five total, spaced at 45 min intervals starting 15 min after LPS) significantly worsened survival. A lower dose, 12 mg/kg, given as a single or multiple injections, did not alter survival. We tested the ex vivo contractile response to norepinephrine (NE) of aortic rings isolated 3.75 hr after i.v. injection of PBS or LPS. Both untreated LPS-shocked and multiple 12 mg/kg PTX treated normal rats (i.v. PBS) had significantly diminished maximum contractility. The ex vivo vascular hypocontractility found in untreated LPS-shocked rats was not aggravated nor ameliorated by multiple 12 mg/kg PTX injections. The ex vivo effects on contractility of multiple 20 mg/kg PTX treatment of LPS shock could not be studied because survival times were shorter than 3.5 hr. In using PTX to treat LPS shock, potentially harmful vasodilation must be considered.
The present study concurrently measured psychological distress (state anxiety, depression, confusion, and intrusive thoughts), neuroendocrine (plasma cortisol concentrations), and immunologic [lymphocyte proliferative responses to phytohemagglutinin (PHA) and pokeweed mitogen (PWM)] changes in the 5-week periods preceding and following serostatus notification among asymptomatic Human Immunodeficiency Virus-type 1 (HIV-1) seropositive and seronegative gay men. Seropositives, as opposed to seronegatives, showed a disparity in predicted relationships among distress, cortisol, and immunologic measures across the prenotification to postnotification period. Individual difference analyses suggested that among seropositives, in contrast to seronegatives, plasma cortisol concentrations were negatively correlated with psychological distress and positively correlated with responses to PHA (assessed at study entry and after serostatus notification). This pattern in seropositives could not be explained by differences in prenotification perceived risk of infectivity, extraneous environmental stressors, or CD4 cell counts within the seropositive group.
Forty-seven asymptomatic, healthy gay men were randomly assigned to a cognitive-behavioral stress management (CBSM) condition or an assessment-only control group 5 weeks before being notified of their HIV-1 antibody status. Seventy-two hours before and 1 week after serostatus notification, blood samples and psychometric data were collected. Control subjects showed significant increases in depression, but only slight decrements in mitogen responsivity and lymphocyte cell counts pre- to postnotification of seropositivity. Seropositive CBSM Ss did not show significant pre-post changes in depression, but did reveal significant increases in helper-inducer (CD4) and natural killer (CD56) cell counts as well as a slight increment in proliferative responses to phytohemagglutinin (PHA). Individual difference analyses suggest that the psychological buffering and immunomodulating effects of the CBSM manipulation may be attributable, in part, to relaxation skills learned and practiced or to a general willingness to comply with the intervention guidelines.
Increases in physical fitness are often associated with improvements in certain chronic diseases, such as hypertension and coronary heart disease. Recent evidence has shown that exercise also influences the neuroendocrine and immune systems, resulting in a potential to benefit those with chronic immunodeficiency diseases. Therefore, exercise may prove to have a profound impact on the management of the acquired immunodeficiency syndrome (AIDS). Our current work includes the investigation of the immunologic and stress-attenuating effects of an aerobic exercise training program for individuals at risk for AIDS. Upon completion of training, the subjects showed a significant increase in helper/inducer (CD4) cells and the inducer subset (CD45RA+CD4+) which activate suppressor/cytotoxic (CD8) cells. These increases, which average about 50 cells per cubic millimeter, are comparable to those observed in some studies of the AIDS drug comparable to those observed in some studies of the AIDS drug azidothymidine (AZT), but without the accompanying side effects. Also, individuals undergoing aerobic training reported no increases in anxiety and depression in response to notification of a positive HIV-1 serologic status. These findings taken together indicate that an aerobic exercise training program may enhance certain critical components of cellular immunity as well as acting as a buffer for the detrimental mood changes that typically accompany stress, thus providing a timely, promising behavioral approach to helping HIV-1-infected individuals.
To determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-alpha and zidovudine therapy in AIDS-related Kaposi's sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-alpha was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-alpha (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-alpha and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p less than 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p less than 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p less than 0.001) and a pretreatment CD4 cell count greater than or equal to 200 cells/mm3 (p = 0.01). In conclusion, intermediate doses of interferon-alpha and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.
PURPOSE: The study objective was to evaluate the effects of long-term methadone use and human T-cell leukemia virus (HTLV) types I and II seropositivity on the distribution of lymphocyte subsets and on lymphocyte function as measured in vitro in intravenous drug users seronegative for human immunodeficiency virus type 1 (HIV-1). PATIENTS AND METHODS: Anti-HIV-1-negative intravenous drug users receiving methadone maintenance therapy (n = 24) were studied in a Veterans Administration drug abuse treatment center. These subjects were compared to 38 age- and sex-matched control subjects who did not abuse drugs. HIV-1 and HTLV serostatus was determined by repetitive enzyme-linked immunosorbent assay and confirmed by immunoblot. Lymphocyte subsets were determined by two-color flow cytometry. Lymphocyte function was measured by proliferative response to plant mitogens and by natural killer (NK) cell-mediated cytotoxicity to a tumor cell target. RESULTS: Significant differences were seen in lymphocyte phenotype in the methadone-treated group, with elevations in the T-cell helper subset CD4+CD26+; in CD8 and CD8+I2+ cells, suppressor/cytotoxic T lymphocytes, and activated suppressor/cytotoxic T cells; and in CD2+CD26+ cells and activated total T lymphocytes. Lymphocyte function was suppressed in the methadone group, with poor responses to pokeweed mitogen and phytohemagglutinin in culture. Moreover, NK-cell cytotoxicity was significantly reduced in the methadone group. None of these immunologic differences were attributable to HTLV serostatus. CONCLUSION: The immune abnormalities seen suggest that a clinically significant degree of immune impairment exists in methadone-treated intravenous drug users. However, these abnormalities could not be explained by the presence of other retroviruses in this HIV-1-negative study group, as there was no significant difference in immune function when HTLV-seropositive patients were compared to HTLV-seronegative subjects treated with methadone.
The Transfusion Safety Study retrospectively screened a repository of serum specimens collected in late 1984-early 1985 to identify blood donors with antibody to human T-cell lymphotropic virus (HTLV) at that time. They and their recipients have been traced for additional HTLV studies. Immunophenotypic analyses of peripheral blood lymphocytes from nine anti-HTLV-positive recipients, assumed to be infected during or since late 1984, showed no significant changes from healthy controls. Evaluation of the immunophenotypes of the 48 donors, however, showed significant elevations in the absolute counts of the T-cell (CD2) and natural killer (CD56) populations, the T helper/inducer and suppressor/inducer subsets (CD4+ CD29+ and CD4+ CD45RA+), and changes in T-cell activation markers. Long-term but not recent HTLV infection appears to alter the T-cell immunophenotypic pattern. Both infection with HTLV and human immunodeficiency virus type 1 are associated with a decreased CD2+ CD26+ count.
Nutritional deficiencies have been documented to affect immune function. The present study indicates that vitamin B6 deficiency is prevalent in CDC stage III HIV-1-infected subjects, despite adequate dietary vitamin B6 intake. As vitamin B6 deficiency has been previously shown to affect immune function, these relatively asymptomatic HIV-1-infected patients were examined for evidence of a relationship between vitamin B6 deficiency and immune dysregulation. Vitamin B6 status in HIV-1-infected subjects was significantly associated with functional parameters of immunity [multivariate F(3,36) = 3.70, p less than or equal to 0.02]. Additional analyses indicated that overtly deficient participants exhibited significantly decreased lymphocyte responsiveness to the mitogens phytohemagglutinin and pokeweed, and reduced natural killer cell cytotoxicity, compared to subjects with clearly adequate vitamin B6 status (chi 2 = 8.78, df = 3, p less than 0.04). Vitamin B6 status was not related to immune cell subpopulations, e.g., CD4, CD8 cell number, or level of serum immunoglobulins. The results of this study indicate that while vitamin B6 status is not a primary etiological factor in HIV-1-related immunological dysregulation, it appears to be an important cofactor of immune function.
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We have recently described the presence of a guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] inhibitor (GCI) in an aqueous extract of the balsam pear (Momordica charantia abbreviata). Because the guanylate cyclase-cyclic GMP system is though to be involved in cell growth, DNA and RNA synthesis, and possible malignant transformation, we examined the effect of the aqueous extract containing GCI on an undifferentiated adenocarcinoma of the rat prostate and concanavalin-A-stimulated [3H]thymidine incorporation into cultured splenic lymphocytes, a process thought to be mediated by cyclic GMP. The results demonstrate that the extract of the balsam pear blocks both the growth of the rat prostatic adencarcinoma in vitro and [3H]thymidine incorporation into DNA. DNA histograms from flow cytometry indicated that the extract containing GCI inhibited in the G2 + M phase of the cell cycle, a presumed locus of cyclic GMP effects. In addition, guanylate cyclase activity was significantly greater in the tumor than normal prostate tissue and was decreased by the extract containing GCI. Cyclic GMP levels in the tumor in culture wer also decreased by addition of the extract. It remains to be determined whether or not the anti-tumor agent and GCI are the same substance.