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Biomedical subjects

G Gray

Publications and source records attributed to G Gray.

At least 55 records · Page 3Linked to original sources
PubMed1997

Measurement of lactate in cerebrospinal fluid in investigation of inherited metabolic disease.

Measurement of lactate concentrations in cerebrospinal fluid (CSF) has been suggested as part of the investigation of inborn errors of the electron transport chain, but little information exists regarding the reference range in children or the relationship between CSF and plasma concentrations. In 39 children without bacterial meningitis, diabetes, or recent seizures, we determined that the median (range) lactate concentrations in CSF and plasma collected concurrently were 1.4 (0.8-2.2) and 1.5 (0.6-2.3) mmol/L; the regression equation was CSF lactate = (0.38+/-0.06) plasma lactate + 0.83 (r2 = 0.14). In 8 of 11 (73%) children with electron transport chain defects, CSF lactate was > or =3.0 mmol/L; however, 2 of these 8 had a normal plasma lactate concentration. CSF lactate was also increased in 2 children with nonketotic hyperglycinemia. The finding that CSF lactate concentrations may be increased despite a normal plasma lactate value in children with electron transport chain defects is an important clue to the diagnosis of these disorders.

Adolescent↗
PubMed1997

Population screening for the common G985 mutation causing medium-chain acyl-CoA dehydrogenase deficiency with Eu-labeled oligonucleotides and the DELFIA system.

We have screened 10171 neonatal blood spots from the Trent and West Midlands regions of the UK for the common G985 mutation to more accurately establish the incidence of medium-chain acyl coenzyme (Co)A dehydrogenase (MCAD) deficiency. We have used a technique involving PCR and Eu-labeled allele-specific oligonucleotides detected by using time-resolved fluorometry on the dissociation-enhanced fluorescence immunoassay (DELFIA) system for the detection of the G985 mutation. We have also evaluated the feasibility of neonatal screening with this technique. We identified 158 G985 heterozygotes and no G985 homozygotes. The calculated incidence of MCAD deficiency in the population studied (all mutations, assuming 90% of MCAD mutations are G985) is 1 in 13426 (95% confidence limits 1 in 10070-1 in 18791). At the optimum cutoff criteria, the technique has a sensitivity of 97.5%, specificity of 99.6%, and positive predictive value of 80.2%. We conclude that this study confirms that MCAD deficiency is a common inherited metabolic disease and is a candidate for neonatal screening. The methodology used is robust and suitable for large-scale population studies such as this. The technique is also potentially suitable for screening.

Acyl-CoA Dehydrogenase↗
PubMed1996

Health care in North must acknowledge Inuit values, traditional medicine.

Dr. Gail Gray spent a week on Baffin Island in a retreat devoted to discussions about health care delivery in the North. She says it is obvious that traditional medical practices and Inuit cultural values must be part of any new health care initiatives if the initiatives are to be successful.

Delivery of Health Care↗
PubMed1996

Establishing equivalence between scaled measures of quality of life.

In this paper, methodologies which have been used in the pharmaceutical industry to demonstrate the equivalence of drug preparations, are applied to the measurement of quality of life (QOL). This approach is feasible when the generated data are measured on the same scale. Data from the quality of life instruments are transformed into interval scales by means of an appropriate scaling procedure. It is demonstrated that equivalence of QOL instruments is linked by a linear relationship between the QOL instruments Functional Assessment of Cancer Therapy (FACT) and the Functional Living Index-Cancer (FLIC). The linear relationship is derived using orthogonal least squares regression which takes into account that both measures are subject to error.

Activities of Daily Living↗
PubMed1995

Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.

Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.

Abatacept↗
PubMed1995

Comparative study of the immunogenicity and safety of two dosing schedules of hepatitis B vaccine in neonates.

Healthy Egyptian neonates born to hepatitis B surface antigen (HBsAg)-seronegative mothers were randomly enrolled in one of three vaccination schedules. A dose of 2.5 micrograms of recombinant HB vaccine was given at birth, two, and six months of age (group A) or two, four, and nine months of age (group B). These two groups and a third control group (group C) also were given the other routine childhood vaccines (BCG, DPT, polio, and measles). Blood samples were taken one month after the third vaccine dose in groups A (seven months of age) and B (10 months of age), and a second follow-up blood sample was taken at the age of 18 months for all three groups. Sera were tested for HBsAg and antibody to hepatitis B core antigen, and quantitatively for antibody to hepatitis B surface antigen (anti-HBs) using commercial enzyme immunoassay kits. The vaccine was well tolerated and side effects were limited to local soreness, redness, or temporary swelling. Among 590 infants who were followed-up, good (51-300 mIU anti-HBs/ml) or excellent (> 300 mIU/ml) immune responses occurred in 85% of the infants in group A and in 96% in group B. Geometric mean titers of anti-HBs at the first and second follow-up were 306 and 55 mIU/ml in group A, and 1,492 and 147 mIU/ml in group B. The recombinant HB vaccine is safe and immunogenic when given in three doses of 2.5 micrograms in either regimen, but delay of the booster dose of the vaccine until nine months after birth produced a higher immune response.

Female↗
PubMed1994

Differential up-regulation of the B7-1 and B7-2 costimulatory molecules after Ig receptor engagement by antigen.

Ag-pulsed B cells are potent APCs, in part, because of the ability of the Ig receptor to mediate rapid and specific Ag uptake. However, it is also known that full T cell activation requires signals delivered by costimulatory molecules, which naive B cells seem to lack. This study examines the effect Ig receptor engagement has on the expression and function of a new CD28 counter-receptor, B7-2. Unlike B7-1 (B7), B7-2 was rapidly induced on the cell surface of B cells after engagement of the Ig receptor by either anti-Ig mAbs or hen egg lysozyme (HEL) on normal and HEL-specific B cell receptor transgenic B cells, respectively. Furthermore, B7-2 expression was up-regulated on tolerant B cells isolated from HEL/anti-HEL double transgenic mice after Ag stimulation, although at lower levels than on nontolerant transgenic B cells. No significant cell surface levels of B7-1(B7) were observed under these conditions. Finally, the B7-2 molecules induced by Ig cross-linking costimulated T cell proliferation in a CD28-dependent manner, independent of B7-1(B7) expression. Thus, the effectiveness of Ag-specific B cells as APCs depends on both their enhanced Ag uptake, mediated by the B cell receptor, and immediate up-regulation of a potent costimulatory molecule, B7-2.

Animals↗
PubMed1994

Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1.

In six unrelated patients with hereditary tyrosinemia type 1 (HT1), three different disease-causing mutations were found by DNA sequencing. Two Pakistani patients, with acute and intermediate forms of HT1, were homozygous for a G192-->T mutation in the last nucleotide of exon 2. This caused aberrant splicing with partial intron 2 retention and premature termination. Three Turkish patients with chronic and intermediate forms of HT1 were homozygous for an A698-->T mutation substituting aspartic acid 233 with valine. A Norwegian patient with an intermediate clinical phenotype was heterozygous for G786-->A, introducing a TGA stop codon for Trp262 (W262X). Site-directed mutagenesis and expression in a rabbit reticulocyte lysate system demonstrated that the nonsense and missense mutations abolished fumarylacetoacetase activity and gave reduced amounts of a truncated and a full-length protein, respectively. Simple tests were established to identify the three mutations by restriction digestion of PCR-amplified genomic DNA. Among 30 additional HT1 patients investigated, 2 were found to be homozygous and 1 heterozygous for G192-->T. Two other patients were homozygous and one was heterozygous for W262X.

Alternative Splicing↗
PubMed1994

Balloon electric shock ablation. A surgical technique for treatment of ventricular tachycardia: influence of endocardial scar on depth of ablation achieved.

Balloon electric shock ablation is a surgical technique that has been used for treatment of ventricular tachycardia. However, little is known about the energy requirements and precise electrode array best suited to achieve effective ablation of the target area while limiting injury to the surrounding myocardium. This study was designed to determine the effects of endocardial scar (often present at the "site of origin" of clinical ventricular tachycardia) on depth of ablation resulting from balloon electric shock ablation. A chronic canine model of endocardial scar (3.9 +/- 0.6 mm thick) was developed with the use of balloon electric shock ablation techniques. We compared depth of ablation achieved with balloon electric shock ablation with low-energy shocks (22 J per bead) in normal dogs versus those with chronic endocardial scar. No difference was found in depth of ablation in normal dogs and in the scar model (7.2 +/- 1.2 mm versus 6.2 +/- 1.0 mm). Depth of injury expressed as a percentage of wall thickness was not different in the two groups (61% +/- 11% versus 57% +/- 3%). We conclude that the presence of endocardial scar does not influence depth of injury resulting from balloon electric shock ablation. This data provides guidance for clinical application of the technique as a "closed heart" surgical approach for control of ventricular tachycardia. The data are also discussed in relation to energy levels currently used for direct current catheter ablation in patients with ventricular tachycardia.

Animals↗
PubMed1994

"Bunt bradycardia": two cases of slowing of heart rate inflight during negative Gz.

Two cases are presented of Canadian Forces pilots who experienced inflight bradycardia during 15 s of -1 Gz acceleration. The bradycardia was characterized by rapid cardio-deceleration, stable bradycardia, then cardio-acceleration during recovery following the -Gz exposure that was slower than the cardio-deceleration. Vagally mediated bradycardia in humans subjected to -Gz acceleration stress has been previously documented in laboratory studies. This bradycardia may be operationally significant since it signifies the presence of other physiological effects that predispose aviators to reduced subsequent +Gz tolerance. Research to investigate the implications of reduced +Gz tolerance following -Gz acceleration is warranted.

Aerospace Medicine↗
PubMed1994

Bias in misspecified mixtures.

A finite mixture is a distribution where a given observation can come from any of a finite set of components. That is, the density of the random variable X is of the form f(x) = pi 1f1(x) + pi 2f2(x) + ... + pi kfk(x), where the pi i are the mixing proportions and the fi are the component densities. Mixture models are common in many areas of biology; the most commonly applied is a mixture of normal densities. Many of the problems with inference in the mixture setting are well known. Not so well documented, however, are the extreme biases that can occur in the maximum likelihood estimators (MLEs) when there is model misspecification. This paper shows that even the seemingly innocuous assumption of equal variances for the components of the mixture can lead to surprisingly large asymptotic biases in the MLEs of the parameters. Assuming normality when the underlying distributions are skewed can also lead to strong biases. We explicitly calculate the asymptotic biases when maximum likelihood is carried out assuming normality for several types of true underlying distribution. If the true distribution is a mixture of skewed components, then an application of the Box-Cox power transformation can reduce the asymptotic bias substantially. The power lambda in the Box-Cox transformation is in this case treated as an additional parameter to be estimated. In many cases the bias can be reduced to acceptable levels, thus leading to meaningful inference. A modest Monte Carlo study gives an indication of the small-sample performance of inference procedures (including the power and level of likelihood ratio tests) based on a likelihood that incorporates estimation of lambda. A real data example illustrates the method.

Animals↗
PubMed1993

Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation.

Signaling via the T-cell receptor complex is necessary but not sufficient to induce antigen-specific T lymphocytes to expand clonally. To proliferate, T cells must receive one or more costimulatory signals provided by antigen presenting cells (APCs). One such critical costimulatory signal is delivered by the CD28/CTLA-4 counterreceptor, B7, expressed on APCs. B7 costimulation induces CD28 signaling, resulting in interleukin 2 (IL-2) secretion, and T-cell proliferation. Conversely, T-cell receptor signaling in the absence of B7 costimulation results in induction of antigen-specific tolerance. Here, we show that activated human B lymphocytes express two additional CTLA-4 counterreceptors also capable of providing T-cell costimulation. At 24 hr postactivation, B cells express a CTLA-4 counterreceptor not recognized by anti-B7 or -BB-1 monoclonal antibodies (mAbs), which induces detectable IL-2 secretion and T-cell proliferation. At 48 and 72 hr postactivation, B cells express both B7 and a third CTLA-4 counterreceptor identified by the anti-BB-1 mAb. BB-1 appears to be a molecule distinct from B7 by its expression on B7- cells and its capacity to induce T cells to proliferate without significant accumulation of IL-2. As observed for B7, costimulatory signals mediated by these alternative CTLA-4/CD28 counterreceptors are likely to be essential for generation of an immune response and their absence may result in antigen-specific tolerance. We propose the following terminology for these CTLA-4 counterreceptors: (i) B7, B7-1; (ii) early CTLA-4 binding counterreceptor, B7-2; and (iii) BB-1, B7-3.

Abatacept↗
PubMed1993

Evidence for an additional ligand, distinct from B7, for the CTLA-4 receptor.

Activation of T lymphocytes requires the recognition of peptide-major histocompatibility complex complexes and costimulatory signals provided by antigen-presenting cells (APCs). The best-characterized costimulatory molecule to date is the B7 antigen, a member of the immunoglobulin family that binds two receptors, CD28 and CTLA-4, expressed on the T-cell surface. Using the anti-mouse B7 (mB7) monoclonal antibody (mAb) 16-10A1, which we recently developed, we found that mB7 is indeed an important costimulatory ligand for the antigen-specific activation of murine T cells by B lymphocytes. Three lines of evidence suggest, however, the existence of at least one additional ligand for the CTLA-4 receptor. First, a soluble fusion protein of human CTLA-4 and the IgG1 Fc region, termed CTLA4Ig, blocks better than the anti-mB7 mAb the allogeneic stimulation of T cells by unfractionated splenic APCs. Second, saturating amounts of anti-mB7 mAb do not significantly block binding of fluorescein isothiocyanate-conjugated CTLA4Ig to activated splenic APCs. Furthermore, CTLA4Ig but not the anti-mB7 mAb reacts with the M12 and M12.C3 cell lines. The identification of an additional ligand for CTLA-4 may have applications to the treatment of autoimmune disease and transplant-associated disorders.

Abatacept↗
PubMed1993

B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance.

Presentation of antigen by the major histocompatibility complex to T lymphocytes without the requisite costimulatory signals does not induce an immune response but rather results in a state of antigen-specific unresponsiveness, termed anergy. To determine which costimulatory signals are critical for the T cell commitment to activation or anergy, we developed an in vitro model system that isolated the contributions of alloantigen and each candidate costimulatory molecule. Here, we show that transfectants expressing HLA-DR7 and either B7 or intercellular adhesion molecule 1 (ICAM-1) deliver independent costimulatory signals resulting in alloantigen-induced proliferation of CD4-positive T lymphocytes. Although equivalent in their ability to costimulate maximal proliferation of alloreactive T cells, B7 but not ICAM-1 induced detectable interleukin 2 secretion and prevented the induction of alloantigen-specific anergy. These results are consistent with the hypothesis that blockade of the ICAM-1:lymphocyte function-associated 1 pathway results in immunosuppression, whereas blockade of the B7:CD28/CTLA4 pathway results in alloantigen-specific anergy. This approach, using this model system, should facilitate the identification of critical costimulatory pathways which must be inhibited in order to induce alloantigen-specific tolerance before human organ transplantation.

3T3 Cells↗
PubMed1993

Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation.

The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex class II molecule as well as the delivery of one or more costimulatory signals provided by the antigen-presenting cell (APC). Although a number of candidate molecules have been identified that are capable of delivering a costimulatory signal, increasing evidence suggests that one such critical pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7, expressed on APCs. In view of the number of potential costimulatory molecules that might be expressed on the cell surface of APCs, artificial APCs were constructed by stable transfection of NIH 3T3 cells with HLA-DR7, B7, or both. Here, we show that in a human antigen-specific model system, when tetanus toxoid peptide antigen is presented by cells cotransfected with HLA-DR7 and B7, optimal T-cell proliferation and interleukin 2 production result. In contrast, antigen presentation, in the absence of B7 costimulation, results in T-cell clonal anergy. These results demonstrate that it is possible to induce antigen-specific clonal tolerance in human T cells that have been previously sensitized to antigen. The artificial antigen-presenting system provides a useful model for the investigation of the biochemical events involved in the generation of tolerance and for the study of signals necessary to overcome tolerance.

Amino Acid Sequence↗