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Biomedical subjects

M D Grant

Publications and source records attributed to M D Grant.

At least 37 records · Page 2Linked to original sources
PubMed1993

Changes in the cytotoxic T-cell repertoire of HIV-1-infected individuals: relationship to disease progression.

The repertoire of antigen-specific receptors expressed on T lymphocytes is shaped by fixed genetic and variable environmental selective pressures. Recent technological advances have enabled the analysis of T-cell receptor (TCR) expression in the context of selective pressures arising through normal immune system development and also through pathological features of disease. The pathological features of acquired immune deficiency syndrome (AIDS) are reflected by selective depletion of particular T lymphocyte subsets and expansion of others. An important question concerning the immunopathogenesis of AIDS is whether or not the perturbation of the CD4+ and CD8+ T-cell subsets following infection with human immunodeficiency virus (HIV) is selective based on TCR variable (V) region gene expression. To address this question, we have functionally analyzed TCR V gene expression on CD8+ cytotoxic T lymphocytes from HIV-1-infected individuals. This was done using monoclonal antibodies against individual TCR V regions to trigger redirected cytolysis in 51Cr release assays. The percent specific lysis induced by each antibody functionally measures the representation of the TCR V region gene product it is specific for. Relative to non-HIV-infected controls and asymptomatic HIV-infected individuals with only moderate CD4 lymphocyte depletion, HIV-infected individuals with low CD4 lymphocyte counts exhibited skewed patterns of TCR V region representation. Therefore, the perturbation within the CD8+ cytotoxic T lymphocyte repertoire in HIV infection appears to be selective based on TCR V region usage, increasingly so as disease progresses. The TCR V genes affected varied between different HIV-infected individuals and skewing detected in functional assays was not always apparent by flow cytometric analysis. These results suggest that HIV infection causes generalized effects on the T-cell repertoire, which are reflected in the relative TCR V gene representation of the CD8+ cytotoxic T lymphocyte population in peripheral blood.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Lysis of CD4+ lymphocytes by non-HLA-restricted cytotoxic T lymphocytes from HIV-infected individuals.

Individuals infected with HIV have elevated numbers of total and activated CD8+ lymphocytes in peripheral blood. CD8+ lymphocytes from HIV-infected individuals have been shown to mediate non-human histocompatibility-linked antigen (HLA)-restricted suppression of viral replication, HLA-restricted killing of cells expressing HIV antigens, and killing of uninfected lymphocytes. We studied CD8+ T lymphocytes that lysed autologous CD4+ lymphocytes. heterologous CD4+ lymphocytes from HIV-infected individuals and uninfected CD4+ lymphocytes. Killing in all cases required T cell receptor (TCR)-mediated recognition or triggering. However, these CD8+ cytotoxic T lymphocytes (CTL) killed HLA class I mismatched CD4+ lymphocytes and CD4+ lymphocytes treated with a MoAb against HLA-A, B and C antigens (PA2.6) which blocks HLA class I-restricted killing. HLA class II-negative CD4+ T lymphoma cells (CEM.NKR) were also killed by anti-CD3 inhibited CTL. Stimulation of peripheral blood lymphocytes (PBL) from HIV-infected individuals, but not uninfected controls, with concanavalin A (Con A) and IL-2, induced non-HLA-restricted TCR alpha beta+, CD8+ CTL which lysed CD4+ lymphocytes. Activation of CD4+ lymphocytes increased their susceptibility to CD8+ CTL-mediated lysis. In HIV infection, a population of non-HLA-restricted CTL which lyse activated CD4+ lymphocytes is expanded. The expansion of CTL with unusual characteristics is interesting, because the stimulus for this expansion is unknown. CTL which recognize activated CD4+ cells could play a role in immune regulation and the pathogenesis of AIDS.

CD4-Positive T-Lymphocytes↗
PubMed1992

Hormone levels in vegetarian and nonvegetarian teenage girls: potential implications for breast cancer risk.

Between September 1984 and June 1985, a total of 75 adolescent girls, 35 vegetarians residing in a Seventh-Day Adventist school and 40 nonvegetarians residing in a private non-Adventist boarding school, underwent measurement of their plasma hormone levels in the follicular and luteal phase of their menstrual cycles as well as dietary intake measured by 3-day food records, medical history, height, and weight. There were no significant differences between vegetarians and nonvegetarians in average age of the girls, weight, body mass index, age at menarche, years since the onset of menstruation, or percentage of girls with ovulatory cycles. Vegetarian girls had significantly higher levels of log follicular estradiol [2.00 +/- 0.27 (SD) versus 1.85 +/- 0.27 pg/ml, P less than or equal to 0.05] and luteal dehydroepiandrosterone sulfate (DHS) (1.88 +/- 0.71 versus 1.45 +/- 0.80 microgram/ml, P less than or equal to 0.05) than nonvegetarian girls. Follicular DHS was higher in vegetarians than in nonvegetarians (1.72 +/- 0.79 versus 1.45 +/- 0.95 microgram/ml), but the difference was not significant. The differences in follicular and luteal DHS, but not the difference in log estradiol, were significant (P less than or equal to 0.05) after controlling for ovulation, smoking, and alcohol intake with multivariable regression analysis. There were no significant differences in testosterone or in percentage free estradiol levels between vegetarians and nonvegetarians. Smoking was significantly associated with follicular and luteal DHS and with percentage free follicular estradiol, while alcohol use was significantly and inversely associated with percentage free follicular estradiol after controlling for other variables. The implications for breast cancer risk are discussed.

Adolescent↗
PubMed1992

The influence of lymphocyte counts and disease progression on circulating and inducible anti-HIV-1 cytotoxic T-cell activity in HIV-1-infected subjects.

OBJECTIVE: To evaluate specific anti-HIV cytotoxic T-lymphocyte (CTL) activity in relation to basic clinical and laboratory parameters used to follow HIV infection. METHODS: Lymphocytes from HIV-1-infected subjects with different clinical and immunologic features of HIV infection were tested for circulating and inducible anti-HIV CTL activity using autologous B-lymphoblastoid cells infected with recombinant vaccinia viruses expressing the HIV gag, pol and env genes as targets. Anti-HIV CTL were induced by stimulation with HIV-infected autologous lymphoblasts in vitro. RESULTS: We detected circulating anti-HIV CTL in asymptomatic subjects exclusively and found a significant association (P < 0.01) between CD8+ lymphocyte counts > or = 900/microliters blood and detectable levels of circulating anti-HIV CTL. Subjects with circulating anti-HIV CTL also had a higher mean CD8+ lymphocyte count than those without detectable circulating activity (P < 0.001), but there was no significant difference in mean CD4+ lymphocyte count. CD8+ human histocompatibility leukocyte antigen (HLA) class I-restricted anti-HIV CTL were induced in all HIV-infected subjects tested following stimulation with HIV-infected autologous lymphoblasts in vitro. In subjects without detectable circulating anti-HIV CTL, circulating HLA-DR+ cells contributed to anti-HIV CTL activity induced by stimulation with HIV or concanavalin A in vitro. CONCLUSIONS: Circulating anti-HIV CTL activity is associated with CD8+ lymphocyte counts > or = 900/microliters. Anti-HIV CTL retain proliferative and functional capacity following in vitro stimulation with HIV and interleukin-2 through all stages of HIV infection. Persistent inducible anti-HIV CTL activity in subjects with advanced HIV disease and without circulating CTL suggests impaired activation and/or proliferation of the CTL in vivo.

CD4-Positive T-Lymphocytes↗
PubMed1992

Single dose cephalosporin prophylaxis in high-risk patients undergoing surgical treatment of the biliary tract.

During June 1985 through October 1986, 292 patients considered to be at high risk for having postoperative complications develop underwent cholecystectomy and were evaluated in a multicenter, randomized, prospective, double-blind study. Risk factors included age greater than 70 years, acute cholecystitis within the previous six months, obstructive jaundice, obesity and diabetes mellitus. One gram of cefamandole was administered intravenously to 144 patients and 148 patients received 1 gram of cefotaxime intravenously 30 minutes prior to skin incision. Culture-proved bactibilia was found in 55 patients and 11 of the patients had choledocholithiasis. Of the risk factors considered to place patients at high risk for postoperative infectious complications, obesity and acute cholecystitis proved to be the more common. However, age greater than 70 years, diabetes mellitus and obstructive jaundice were more significant risk factors predisposing to bactibilia. The most common organisms isolated from the bile and gallbladder intraoperatively were Staphylococcus, Streptococcus and Klebsiella species along with enterococcus, Escherichia coli and diphtheroids. Clinically significant postoperative infections occurred in eight patients, including six patients in the cefamandole group and two patients in the cefotaxime group. Antibiotic concentrations were measured in the serum, muscle, subcutaneous fat, gallbladder and bile, with cefamandole showing statistically significant greater concentrations in bile, gallbladder and muscle tissue. There was no statistical significance between the postoperative infection rates, total period of hospitalization or total hospital charges for each group. Therefore, there is no significant advantage between a single prophylactic dose of cefamandole versus cefotaxime for high-risk patients undergoing biliary tract operation.

Adolescent↗
PubMed1991

An idiotypic network model of AIDS immunopathogenesis.

Considerations from a network theory of the immune system suggest that human immunodeficiency virus and allogeneic stimuli may act synergistically to cause AIDS. The immune responses to these stimuli include two components that are directed against each other. In some AIDS risk groups other antigens that mimic major histocompatibility complex antigens may substitute for allogeneic stimuli. Implications for the prevention of AIDS are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Distribution of antibodies against denatured collagen in AIDS risk groups and homosexual AIDS patients suggests a link between autoimmunity and the immunopathogenesis of AIDS.

Autoimmunity often precedes the onset of AIDS-related complex or AIDS, and a number of autoantibodies have been described in AIDS patients and persons at risk for AIDS. The presence of such antibodies provokes speculation that autoimmunity is a component of AIDS pathogenesis. We report evidence of an autoantibody (anticollagen) common to all homosexual AIDS patients studied. High titer serum reactivity against collagen was detected in all homosexual AIDS patients, and in HIV+ homosexuals (66%), HIV+ i.v. drug users (38%) HIV- homosexuals (32%), HIV+ transfusion recipients (22%), and HIV+ hemophiliacs (13%), but not in HIV- i.v. drug users, HIV- transfusion recipients, HIV- hemophiliacs, rheumatoid arthritis patients, or controls. Anticollagen reactivity does not correlate with serum IgG levels, so it is not merely a reflection of polyclonal B-cell activation. Titration of anticollagen positive sera typically revealed anticollagen antibody titers 100 times those of normal sera. Affinity purification and immunoblot analysis confirmed the antibody nature of the anticollagen reactivity. The anticollagen antibodies react preferentially with primary determinants of types I and III collagen revealed after heat denaturation. Similar antibodies occur infrequently in rheumatoid arthritis patients, more often on SLE, and frequently in graft vs host disease and lepromatous leprosy. Levels of anticollagen activity in HIV+ i.v. drug users and transfusion recipients correlate with serum beta 2-microglobulin levels, suggesting that those persons with anticollagen antibodies are at greater risk of developing AIDS. This correlation, the fact that anticollagen antibodies occurred in all homosexual AIDS patients tested, and the occurrence of antibodies against denatured collagen in immune disorders with features similar to AIDS suggest these antibodies may be related to disease progression. The association of anticollagen autoantibodies with AIDS and certain other infections and immune disorders may reflect common immunopathogenic features in the etiology of these disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Cartilage proteoglycan changes in experimental canine osteoarthritis.

Articular cartilage contains at least 2 proteoglycans (PGs) which aggregate with hyaluronate: one larger, richer in chondroitin sulphate (CSRPG); the other smaller, relatively richer in keratan sulphate (KSRPG). With maturation the ratio of CSRPG/KSRPG decreases. In order to test the hypothesis that osteoarthritic cartilage contains an increased amount of proteoglycans characteristic of immature cartilage, experimental osteoarthritis (OA) was induced in 11 dogs by transection of the anterior cruciate ligament. Proteoglycan populations were assessed by composite agarose polyacrylamide gel electrophoresis (CAPAGE). The OA cartilage had more proteoglycan and an increased proportion of the slower migrating band on CAPAGE, which corresponds to the CSRPG, supporting the hypothesis that OA cartilage contains an increased amount of proteoglycans characteristic of immature cartilage.

Animals↗
PubMed1978

Natural rates of teacher approval and disapproval in grade-7 classrooms.

The natural rates of teacher verbal approval and disapproval in ten grade-seven classrooms were determined and compared with those described by White (1975). Although there were differences in the observation techniques used and the behavioral, cultural, and ethnic groups sampled, the results were similar. The majority of the teachers displayed individual rates of disapproval that were higher than their individual approval rates. The correlations between levels of on-task behavior and approval and disapproval rates were low. The issues raised by these findings are discussed in terms of directions for further research.

Journal Article↗