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Biomedical subjects

R McHugh

Publications and source records attributed to R McHugh.

At least 19 recordsLinked to original sources
PubMed2000

Inhibition of hippocampal kindling by metabotropic glutamate receptor antisense oligonucleotides.

Recent work has shown that metabotropic glutamate receptors (mGluRs) increase in response to seizure activity and can contribute significantly to the expression and progression of partial seizures. Using the kindling model of temporal lobe seizures, we evaluated the ability of local hippocampal injections of mGluR1 antisense or mGluR3 antisense oligonucleotides to suppress receptor expression and alter hippocampal kindling. Daily antisense injections in the hippocampus resulted in a significant decrease in mGluR1 or mGluR2/3 immunoreactivity. Rats injected with mGluR3 antisense showed a brief suppression of afterdischarge duration when compared to matched rats injected with a nonsense-oligonucleotide. Rats injected with a mGluR1 antisense oligonucleotide had a dramatic suppression of the rate of seizure progression with no significant effect on afterdischarge duration. Suppression of mGluR1 synthesis by local antisense inhibition may provide a new therapeutic approach for the control of epileptogenesis.

Animals↗
PubMed1999

Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase-reactive T cells.

Thymectomy at day 3 of life (d3Tx) results in the development of organ-specific autoimmunity. We have recently shown that d3Tx BALB/c mice which develop autoimmune gastritis contain CD4+ T cells specific for the gastric parietal cell proton pump, H/K ATPase. Here, we demonstrate that freshly explanted gastric lymph node (LN) cells from d3Tx mice react significantly to the H/K ATPase alpha chain, but only marginally to the beta chain. Two H/K ATPase-reactive T cell lines were derived from the gastric LN of d3Tx mice. Both are CD4+, TCR alpha/beta-, and I-Ad restricted, and recognize distinct peptides from the H/K ATPase alpha chain. One cell line secretes Th1 and the other Th2 cytokines, but both are equally potent in inducing gastritis with distinct profiles of cellular infiltration in nu/nu recipient animals. Neither of the cell lines induced disease in normal BALB/c recipients and transfer of disease to nu/nu recipients was blocked by co-transfer of normal BALB/c spleen cells containing CD4+ CD25+ cells. Although CD4+ CD25+ T cells are thought to emigrate from the thymus after day 3 of life, they could be identified in LN of 2-day-old animals. The capacity of CD4+ CD25+ T cells to abrogate the pathogenic activity in vivo of both activated Th1/Th2 lines strongly suggests that this suppressor T cell population may have a therapeutic role in other models of established autoimmunity. The availability of well-characterized lines of autoantigen-specific T cells should greatly facilitate the analysis of the mechanism of action and target of the CD4+ CD25+ immunoregulatory cells.

Animals↗
PubMed1996

Induction of autologous tumor-specific cytotoxic T-lymphocyte activity against a human renal carcinoma cell line by B7-1 (CD8O) costimulation.

Recently mouse models have shown that expression of costimulatory molecules such as B7-1 on tumor cells can induce tumor-specific immunity, suggesting that tumor cells modified to express costimulatory molecules can be a potential tumor vaccine. To investigate the importance of B7-1 co-stimulation in induction of autologous tumor immunity in humans, we established a renal carcinoma cell line, RCC-1, from a tumor resection and studied the patient's antitumor immune responses in vitro. The RCC-1 cell line constitutively expressed major histocompatibility complex (MHC) class I, intercellular adhesion molecule (ICAM)-1, and leukocyte function-associated antigen (LFA)-3 molecules, and MHC class II molecules were induced by interferon-gamma (IFN-gamma) treatment in vitro. However, neither RCC-1- nor IFN-gamma-treated RCC-1 cells expressed B7-1, and both failed to induce T-cell proliferative responses in mixed lymphocyte and tumor cell reaction (MLTR) assays, suggesting that the costimulatory signals provided by cell adhesion molecules such as ICAM-1 and LFA-3 were not sufficient to elicit an antitumor immune response. However, on transfection of the human B7-1 into RCC-1, these cells were able to induce a significant T-cell proliferation in MLTR assays. This T-cell response could be blocked by anti-B7 mAb treatment of the tumor cells. RCC-1B7 cells also induced the generation of tumor-specific cytolytic T lymphocytes to the parent RCC-1 cells in vitro, with little nonspecific cytolysis of an unrelated RCC line, A498, or autologous phytohemagglutinin (PHA) blasts. This specific cytotoxicity could be abrogated by anti-CD8 mAb and complement treatment. In summary, our study indicates that B7-1-CD28 interaction plays a critical role in induction of autologous tumor-specific cytotoxic T lymphocytes (CTLs) in humans, suggesting that the costimulatory molecule transfected tumor cells could be useful in expanding tumor-specific autologous CTL in vitro for adoptive tumor immunotherapy.

Antigens, Neoplasm↗
PubMed1995

Expression of heat-stable antigen on tumor cells provides co-stimulation for tumor-specific T cell proliferation and cytotoxicity in mice.

Heat-stable antigen (HSA/J11d/possibly homologous to CD24), a cell adhesion molecule capable of providing a co-stimulatory signal for T cell proliferation, is expressed on B cells, activated T cells, monocytes, granulocytes, Langerhans cells and thymocytes. Recent studies have demonstrated that co-stimulatory signals provided by cell adhesion molecules such as B7-1 play an essential role in generation of an anti-tumor immune response. To examine whether the co-stimulatory signal provided by HSA can induce an anti-tumor immune response, we have transfected HSA cDNA into the murine melanoma cell line K1735M2, and examined the ability of this transfected cell line to induce tumor-specific T cell responses. The results demonstrate that spleen cells from mice immunized with HSA-transfected K1735M2 cells showed enhanced T cell proliferation in a mixed lymphocyte tumor reaction (MLTR) assay and also demonstrated a significant anti-tumor cytotoxicity to the parent tumor cell (K1735M2). This anti-tumor cytolytic activity could be abrogated by pretreatment of effector cells with anti-mouse CD8 monoclonal antibody and complement. Under similar conditions, spleen cells from C3H mice immunized with vector-transfected K1735M2 cells neither actively proliferate in an MLTR assay, nor did they exert significant cytolytic activity against the respective tumor cells. In summary, our study demonstrated that HSA can provide a co-stimulatory signal for the T cell immune response against tumor cells in a murine model.

Animals↗
PubMed1987

Randomization and efficiency in Zelen's single-consent design.

The "single-consent design" was devised by Zelen to circumvent the reluctance of some patients and physicians to participate in certain types of randomized clinical trials. Crucial to the validity of Zelen's design is randomized allocation of patients. Randomization theory is therefore the key theoretical base of the approach taken in this paper to an examination of the efficiency of this design.

Analysis of Variance↗
PubMed1983

Post-stratification in the randomized clinical trial.

A topic of current biometric discussion is whether stratification should be used in randomized clinical trials and, if so, which kind. An approach based upon randomization theory is used to evaluate pre- versus post-stratification. The results obtained relate specifically to the effect of the size of the clinical trial on the bias and precision of estimated treatment contrasts.

Biometry↗
PubMed1982

Estimation of the efficacy of thermal microbial disinfection.

A new biometric model is presented for the rate of thermal disinfection of a microbial population. Unlike the usual approach, this model incorporates random errors arising at two stages into exponential kinetics. The first such stage is a result of sampling at the initial time of deposition of the microorganisms. The second stage corresponds to the variation arising from the subsequent experimentation. Maximum likelihood estimation of the 'decimal reduction time' parameter, tau, is described together with a numerical application and simulation study of the efficiency of estimation of tau under the usual model and the new model.

Bacteria↗
PubMed1981

The importance of osmolality fall and ultrafiltration rate on hemodialysis side effects. Influence of intravenous mannitol.

The decreases in serum osmolality as well as the rate of ultrafiltration during hemodialysis and the influence of each upon the side effects of this treatment were studied in 13 chronic stable dialysis patients. Mannitol (9 mosm/kg water) was infused in two out of four dialyses, in a double blind fashion. A solution of 5% glucose in water was used as control. 1 week after the treatment, there was no residual mannitol in the patients' serum (p less than 0.0005). The decrease in osmolality during dialysis was lower when the patients received treatment with mannitol than with placebo: 14.7 versus 25.0 mosm/kg water (p less than 0.001). The symptoms during dialysis were much less severe when the patients received mannitol (p less than 0.05). Analyzed separately, ultrafiltration rate had no effect on severity of symptoms during dialysis (p greater than 0.1). Decrease in serum osmolality during dialysis seems to be the most important factor in the genesis of dialysis symptoms in chronic stable dialysis patients and are counteracted by the infusion of an osmotically active substance such as mannitol, 1 g/kg/dialysis; this results in a slight increase in body weight between dialyses, and cannot be used routinely because of slow accumulation.

Adult↗
PubMed1980

The earlier detection of colorectal cancers: a preliminary report of the results of the Occult Blood Study.

A long-term clinical study is underway to evaluate the merit of occult stool blood testing in the earlier detection of colorectal cancers; 48,000 participants have been enrolled. Thus far, 873 patients with occult stool blood have been examined, and 77 gastrointestinal cancers have been found in 74 patients. Although data from the control group are not yet available for comparison, most of the cancers found appear to be relatively early in their development. Conventional barium-enema examinations were noted to have "missed" one third of the colon cancers and two-thirds of the colon polyps which were found on colonoscopy. Preliminary results of the study appear encouraging. Definitive analysis will await the availability of additional pertinent data.

Barium Sulfate↗
PubMed1980

Detection of HLA haplotype associations with disease.

In a recent paper, Thomson & Bodmer (1979) explored several conceptual and analytic issues involved in studying the association of HLA haplotypes with disease. One key problem they emphasized was the assessment of the statistical significance of the third order linkage disequilibrium between two HLA genes and a disease susceptibility gene. We have formulated an approach to this problem and illustrate this approach by deriving such statistical tests of true haplotype associations for two models of disease susceptibility previously studied by Terasaki & Mickey (1975) and by Thomson & Bodmer (1977). A numerical example using actual phenotypic data is then presented to demonstrate the practicality of the methods.

Alleles↗
PubMed1980

The parameterization of predictive value for multisite screening.

In the design of a medical screening program, it is standard practice to employ the parameters of sensitivity and specificity of the test, together with the population disease prevalence, in order to obtain the predictive values of the test. Multiphasic screening, i.e. the use of two or more tests on the same occasion to screen for more than a single disease, has stimulated the need for a formulation of the joint predictive value of these tests employed in combination. In this communication a parameterization of joint predictive value is presented in the context of multisite cancer screening. The resulting parameters are related to the separate disease prevalences, as well as to the sensitivities and specificities of the separate tests, under the assumption of statistical independence among cancer screens.

Humans↗