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E A Gale

Publications and source records attributed to E A Gale.

At least 37 records · Page 2Linked to original sources
PubMed1999

Evaluation of a high-throughput second antibody radiobinding assay for measuring IgA antibodies to human tissue transglutaminase.

We describe a novel high-throughput radiobinding assay for IgA antibodies to tissue transglutaminase (TG) which uses second antibody precipitation to isolate immune complexes. Using this assay, 24 of 25 patients with untreated coeliac disease (96%) and nine of 526 healthy blood donors (2%) had TG antibody levels above a threshold defined by the 97.5th centile of 347 schoolchildren. All patients and five of the nine blood donors with transglutaminase antibodies above this threshold were endomysial antibody (EMA) positive. Using this threshold, 410/445 (92%) routine clinical samples were concordant for TG antibodies and EMA, including 72 of 75 with EMA. TG antibodies above the 97.5th centile were found in 32 of 370 EMA negative samples, 15 of whom had anti-gliadin antibodies (AGA), histologically proven coeliac disease or partial villous atrophy. We conclude that this assay achieves a sensitivity and a specificity at least equivalent to those of EMA. It is technically simple and suitable for coeliac disease screening.

Adolescent↗
PubMed1999

Measurement of nicotinamide and N-methyl-2-pyridone-5-carboxamide in plasma by high performance liquid chromatography.

We describe a simple and reproducible method for simultaneous determination of nicotinamide and its major human biological metabolite N-methyl-2-pyridone-5-carboxamide (2pyr). Previous assays for nicotinamide in plasma and in urine have been complicated by the use of tedious extraction procedures or HPLC conditions which, although often allowing simultaneous analysis of several metabolites, add to the difficulties of performing multiple analyses. The procedure we describe is simple, using a rapid column clean-up of samples prior to injection, which can then be done using an autosampler. Both nicotinamide and its major metabolite 2pyr can be assayed rapidly, with good reproducibility, and at the same time.

Calibration↗
PubMed1999

Insulin autoantibodies: more specific than proinsulin autoantibodies for prediction of type 1 diabetes.

Proinsulin autoantibodies (PAA) are a potential alternative to insulin autoantibodies (IAA) for the prediction of type 1 diabetes. We measured the prevalence of PAA and IAA in 179 patients with newly diagnosed type 1 diabetes and 1028 schoolchildren, and compared the potential of these antibodies for disease prediction. Antibodies were measured using a novel microassay in which screening for binding of radio-labelled antigen was followed by competitive displacement. Thresholds for both antigen binding and competitive displacement were selected so that equivalent numbers of patients with type 1 diabetes were identified by the proinsulin and insulin antibody assays. Similar numbers of schoolchildren were found to have insulin and proinsulin binding above the screening threshold but, after competitive displacement, the prevalence of PAA (3.7%) was more than twice that of IAA (1.4%) with 66% sensitivity. Both PAA and IAA were present in 113 (63%) of patients, as against 0.8% of schoolchildren, implying that individuals with both antibodies are at particularly high risk of disease. The majority of samples with IAA or PAA were displaced with both insulin and proinsulin, suggesting that the main epitopes recognized by these antibodies are on the insulin molecule. We conclude that IAA are more specific than PAA for the prediction of type 1 diabetes.

Adolescent↗
PubMed1999

Optimized autoantibody-based risk assessment in family members. Implications for future intervention trials.

OBJECTIVE: To determine the best autoantibody-based testing strategy for recruiting relatives for future intervention trials and to establish the role of islet cell antibodies (ICAs) within this strategy. RESEARCH DESIGN AND METHODS: ICAs, insulin autoantibodies (IAAs), GAD antibodies, and IA-2 antibodies were determined in serum samples at study entry of 3,655 non-diabetic first-degree relatives of patients with type 1 diabetes who were followed for a median of 5.5 years. The cumulative risk of diabetes associated with single and combined antibody marker levels of > or = 97.5th percentile in schoolchildren was calculated by using life-table analysis. RESULTS: Of the 26 relatives who developed insulin-requiring diabetes during follow-up, 16 were aged < 20 years and 7 were aged 20-39 years at study entry. Of the 23 cases aged < 40 years, 83% had IA-2 and/or GAD antibodies, and 87% had IAA and/or GAD antibodies > or = 97.5th percentile compared with 61% who had ICAs of > or = 5 Juvenile Diabetes Foundation units (JDF U). A two-step strategy with parallel testing for IA-2/GAD antibodies followed by IAA testing identified 50% of cases aged < 20 years and was associated with a 71% risk within 10 years. In subjects aged 20-39 years, this strategy conferred a 51% risk, whereas using ICAs as the second test gave 86% sensitivity and a 74% risk. Primary screening for IA-2 and/or GAD antibodies followed by testing for IAA and/or ICA antibodies achieved the highest sensitivity in both age-groups and conferred a 63% risk. In contrast, ICAs of > or = 20 JDF U (the inclusion criteria for the European Nicotinamide Diabetes Intervention Trial) gave 48% sensitivity and 35% risk. CONCLUSIONS: ICA testing can be replaced as a primary screening measure by IA-2/GAD or IAA/GAD antibody testing. The sensitivity of ICAs (used alone or in combination with IAAs) gives them a useful role in second-line testing. Combination testing could reduce the size of screening populations needed for recruitment in future intervention trials by approximately 50% compared with testing based on ICAs alone.

Adolescent↗
PubMed1999

Progression to diabetes in relatives with islet autoantibodies. Is it inevitable?

OBJECTIVE: A large cohort of family members with islet cell antibodies (ICA) > or = 20 Juvenile Diabetes Foundation units (JDF U) was examined to determine whether there was a subgroup at low risk of progression to diabetes; whether risk of progression changed over time; and whether rate of progression to diabetes varied according to age, islet autoantibodies, and genetic markers of susceptibility. RESEARCH DESIGN AND METHODS: Individuals with ICA > or = 20 JDF U were identified from 4,423 family members recruited to prospective family studies in the U.K. Subjects were followed for up to 18 years. Antibodies to insulin, GAD, and IA-2 were measured in the first sample, and HLA class II typing was performed. RESULTS: Of 147 family members with ICA > or = 20 JDF U on at least one occasion, 29 developed type 1 diabetes after a median of 3.2 years (maximum 18.1). The cumulative risk of developing diabetes within 15 years was 47% (95% CI 28-67) for all family members with ICA > or = 20 JDF U, 2.8% (0-8.2) for those with ICA alone, and 66% (44-87) for those with at least one additional autoantibody marker. There were no differences in age, HLA class II type, or levels of ICA, insulin autoantibodies, or IA-2 antibodies between those who developed diabetes within 5 years of testing and those who developed diabetes after this time. GAD antibody levels we ..., however, higher in those who progressed more slowly. CONCLUSIONS: Family members with ICA alone are at low risk of progression to diabetes. Rapid development of disease after ICA detection could not be distinguished from delayed development on the basis of autoantibodies or markers of genetic susceptibility, and those with multiple antibodies remained at high risk throughout long-term follow-up. This suggests that all family members with multiple islet autoantibodies are destined to develop autoimmune diabetes.

Adolescent↗
PubMed1999

Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group.

OBJECTIVE: The predictive value of microalbuminuria (MA) in children with type 1 diabetes has not been defined. We describe the natural history of MA in a large cohort of children recruited at diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1985 and 1996, 514 children (279 male) who developed type 1 diabetes before the age of 16 years (91% of those eligible from a region where ascertainment of new cases is 95%) were recruited for a longitudinal study with central annual assessment of HbAlc and albumin excretion (three urine samples). Dropout rates have been < 1% per year, and 287 children have been followed for > 4.5 years. RESULTS: MA (defined as albumin-to-creatinine ratio > or = 3.5 and > or = 4.0 mg/mmol in boys and girls, respectively) developed in 63 (12.8%) and was persistent in 22 (4.8%) of the subjects. The cumulative probability (based on the Kaplan-Meier method) for developing MA was 40% after 11 years. HbAlc was worse in those who developed MA than in others (mean difference +/- SEM: 1.1% +/- 0.2, P < 0.001). In subjects who had been 5-11 years of age when their diabetes was diagnosed, the appearance of MA was delayed until puberty, whereas of those whose age was < 5 years at diagnosis of diabetes, 5 of 11 (45%) developed MA before puberty. The adjusted proportional probability (Cox model) of MA was greater for female subjects (200%), after pubertal onset (310%), and with greater HbAlc (36% increase for every 1% increase in HbAlc). Despite earlier differences based on age at diagnosis of diabetes (< 5, 5-11, and > 11 years), the overall cumulative risks in these groups were similar (38 vs. 29 vs. 39%, respectively) after 10 years' duration of diabetes. CONCLUSIONS: Prepubertal duration of diabetes and prepubertal hyperglycemia contribute to the risk of postpubertal MA. The differences in rates of development of MA relating to HbAlc, sex, and age at diagnosis relative to puberty may have long-term consequences for the risk of subsequent nephropathy and for cardiovascular risk.

Adolescent↗
PubMed1998

Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse.

As many as half of all schizophrenic patients have abused alcohol or illicit drugs. This study determines the extent of substance abuse in a treatment-resistant population and assesses the response of this population to olanzapine treatment. Sixty patients with a DSM-III-R diagnosis of schizophrenia were included in an open 7-week trial of up to 25 mg/day of olanzapine. A history of substance abuse was present in 23 (38%) of the patients. At baseline evaluation, patients with a history of substance abuse had lower CGI scores and less negative symptomatology while having a higher rate of tardive dyskinesia. The overall group improved significantly over time. There were no differences in response between the substance-abusing (SA) and non-substance-abusing (NSA) patients as measured by the total BPRS, GGI and SANS ratings. The NSA group had significantly greater improvement in negative symptoms as measured by the BPRS negative symptom factor. Sixty-nine per cent (16/23) of the SA group and 60% (22/37) of the NSA were considered olanzapine responders by a priori criteria (p = NS). Extrapyramidal symptoms declined significantly in the overall group, but did not significantly differ between the SA and NSA groups. Treatment-refractory patients with prior substance abuse had a comparable outcome on olanzapine therapy to those with no history of abuse, as well as no increase in adverse effects. This suggests that olanzapine may be of benefit to SA patients who have a greater tendency for antipsychotic side effects and tardive dyskinesia.

Adult↗
PubMed1998

Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes.

OBJECTIVE: A precise time-action profile of insulin lispro (Humalog) at mealtime may reduce the incidence of severe hypoglycemia. Because it is a rare complication, we performed a cumulative meta-analysis to compare the frequency of severe hypoglycemia during insulin lispro and human regular insulin therapy in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: The analysis included eight large multi-center clinical trials, three with parallel and five with crossover designs. The studies included 2,576 type 1 diabetic patients in total, with 2,327 receiving insulin lispro and 2,339 receiving regular human insulin, representing > 1,400 patient-years of insulin therapy Severe hypoglycemia was defined as coma or requiring glucagon or intravenous glucose. The patients received either NPH or ultralente as their basal insulin and insulin lispro or regular human insulin before each meal. RESULTS: Seventy-two patients (3.1%) had a total of 102 severe hypoglycemic episodes during insulin lispro therapy compared with 102 patients (4.4%) with a total of 131 episodes during regular human insulin therapy (P=0.024). CONCLUSIONS: The results of this meta-analysis demonstrate that in type 1 diabetic patients, the frequency of severe hypoglycemia can be reduced by taking insulin lispro as compared with regular human insulin therapy.

Clinical Trials as Topic↗
PubMed1997

Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart's-Oxford Study Group.

OBJECTIVES: To monitor incidence of insulin dependent diabetes in children in Oxford health region since 1985, and to look for any evidence of disproportionate increase in children aged under 5. DESIGN: Primary ascertainment of cases of childhood diabetes was by prospective registration of all patients with insulin dependent diabetes diagnosed before age 15 years between 1985 and 1996 and resident in Oxford region at time of diagnosis. This was supplemented by examination of centralised hospital discharge records and death certificates. Secondary case ascertainment was by postal surveys of general practitioners in 1987 and 1996. SETTING: Area formerly administered by Oxford Regional Health Authority. SUBJECTS: 1037 children presenting with insulin dependent diabetes under age of 15 years. MAIN OUTCOME MEASURES: Incidence of insulin dependent diabetes in children aged 0-4, 5-9, and 10-14 years during 1985-95. RESULTS: Overall incidence of diabetes in children aged 0-15 was 18.6 cases/100000/year and showed an annual increase of 4% from 1985 to 1996. This was mainly due to a rapid increase in children aged 0-4 years, in whom there was an annual increase of 11% (95% confidence interval 6% to 15%, P < 0.0001), while the annual increase in those aged 5-9 was 4% (0 to 7%, P = 0.05) and in those aged 10-14 was 1% (-2% to 4%, P = 0.55). CONCLUSIONS: Incidence of insulin dependent diabetes in children aged under 5 years has risen markedly in the Oxford region over the past decade. The cause of the increase is unknown, but environmental influences encountered before birth or in early postnatal life are likely to be responsible.

Adolescent↗
PubMed1997

Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus.

OBJECTIVE: To study the comparative importance of environment and genes in the development of islet cell autoimmunity associated with insulin dependent diabetes mellitus. DESIGN: Population based study of diabetic twins. SETTING: Danish population. SUBJECTS: 18 monozygotic and 36 dizygotic twin pairs with one or both partners having insulin dependent diabetes. MAIN OUTCOME MEASURES: Presence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase (GAD65) in serum samples from twin pairs 10 years (range 0-30 years) and 9.5 years (2-30 years) after onset of disease. RESULTS: In those with diabetes the prevalence of islet cell antibodies, insulin autoantibodies, and autoantibodies to glutamic acid decarboxylase in the 26 monozygotic twins was 38%, 85%, and 92%, respectively, and in the dizygotic twins was 57%, 70%, and 57%, respectively. In those without diabetes the proportions were 20%, 50%, and 40% in the 10 monozygotic twins and 26%, 49%, and 40% in the 35 dizygotic twins. CONCLUSION: There is no difference between the prevalence of islet cell autoantibodies in dizygotic and monozygotic twins without diabetes, suggesting that islet cell autoimmunity is environmentally rather than genetically determined. Furthermore, the prevalence of islet cell antibodies was higher in the non-diabetic twins than in other first degree relatives of patients with insulin dependent diabetes. This implies that the prenatal or early postnatal period during which twins are exposed to the same environment, in contrast with that experienced by first degree relatives, is of aetiological importance.

Adolescent↗
PubMed1997

A novel micro-assay for insulin autoantibodies.

Insulin autoantibodies (IAA) are established markers of Type 1 diabetes and are widely used for the prediction of this disease. Standard assays require relatively large serum volumes for reliable measurement of IAA, limiting their use in young children. We have developed a novel small volume assay which is suitable for screening large numbers of samples. For reasons of economy we have adopted a two-stage strategy in which all samples are screened for insulin binding and those with raised levels are quantified in an assay using competitive displacement. Using this assay 126 out of 241 (52%) newly diagnosed IDDM patients (median age 10.2, range 1.3-20.7 years) had IAA levels above the 99th centile of 2860 schoolchildren (median age 11.3, range 9.0-13.8 years), including 81 out of 117 (69%) patients below the age of 10 years. The assay compared well overall when measuring IAA in direct comparison with a conventional assay. We conclude that reliable measurement of IAA is possible on less than 50 microl of serum using this novel assay and that this should facilitate large scale screening, particularly in young children.

Adolescent↗
PubMed1997

Insulin lispro: a new quick-acting insulin analogue.

Insulin lispro (Humalog) is a biosynthetic insulin analogue in which the positions of proline and lysine are reversed in the C-terminal portion of the B chain. Human insulin readily self-associates into hexamers, which dissociate relatively slowly following subcutaneous injection. In consequence, there is a clinically important delay between the subcutaneous injection of soluble insulin and its maximal pharmacodynamic effect. The clinical development of lispro has been based on minor and elegant manipulation of the amino acid sequence to create an insulin which self associates poorly, and is therefore absorbed more rapidly into the circulation. By virtue of this characteristic, it has a more rapid onset of action than soluble insulin preparations, and a shorter duration of action. Potential clinical benefits include better matching of peak insulin action to food absorption following meals, and better glycaemic control in the immediate post-prandial period together with less risk of hypoglycaemia in the period before the next meal is due. An important practical advantage for patients is that the insulin injection does not have to be taken 30 min before meals, as recommended for soluble insulin, but can instead be given almost immediately before meals.

Journal Article↗
PubMed1997

Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers.

Strategies for assessing risk of progression to IDDM, based on single and combined autoantibody measurement, were evaluated in 2,855 schoolchildren (median age 11.4 years) and 256 children with newly diagnosed IDDM (median age 10.2 years), recruited to a population-based study in the Oxford region. In 256 children with IDDM, levels of antibodies > or =97.5th centile of the schoolchild population were found in 225 (88%) for islet cell antibodies (ICAs), in 190 (74%) for antibodies to GAD, in 193 (75%) for antibodies to protein tyrosine phosphatase IA-2 (IA-2), and in 177 (69%) for autoantibodies to insulin (IAAs). Estimates of risk of progression to IDDM within 10 years, derived by comparing the distribution of antibody markers in the two populations (schoolchildren and children with IDDM), were 6.7% (ICAs), 6.6% (GAD antibodies), 5.6% (IA-2 antibodies), and 4.8% (IAAs) for schoolchildren with levels above the 97.5th centile, increasing to 20, 23, 24, and 11%, respectively, for antibody levels >99.5th centile. Most children with IDDM had multiple antibody markers, and 89% of those diagnosed over age 10 years had > or =2 antibodies above the 97.5th centile, as compared against 0.7% of schoolchildren, in whom this combination gave a 27% 10-year estimated risk of IDDM. Risk increased but sensitivity fell as combined antibody thresholds were raised, or the number of antibodies above the threshold was increased. Strategies based on detection of > or =2 antibodies with primary testing for GAD and IA-2 antibodies and second line testing for ICAs and/or IAAs were evaluated. Detection of at least two markers selected from GAD antibodies > or =97.5th centile and/or IA-2 antibodies > or =99.5th centile and/or ICAs > or =97.5th centile identified 0.25% of schoolchildren and 83% of children with newly diagnosed IDDM, with an estimated risk of 71% (95% CI 57-91). Although confirmation from prospective studies is still needed, this analysis suggests that antibody combinations can predict diabetes in the general population.

Adolescent↗
PubMed1996

Molecular mechanisms of beta-cell destruction in IDDM: the role of nicotinamide.

Autoimmune processes are involved in pancreatic beta-cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against the 37/ 40 K antigen appear in the circulation years before clinical onset and permit increasingly precise disease prediction. A cellular immune response causes pancreatic infiltration, while macrophages and Th-cells appear to be implicated-via local release of cytokines-in beta-cell destruction. Generation of free radicals, DNA strand breaks, activation of the enzyme poly (ADP-ribose) polymerase (PARP), and depletion of intracellular nicotinamide adenine dinucleotide (NAD) appear to be common factors in beta-cell death, whether mediated by oxygen radicals, nitric oxide, or streptozotocin. Nicotinamide, a soluble B group vitamin which offers protection against these toxic stimuli, is at high doses a free radical scavenger, a potent inhibitor of PARP, and protects against depletion of intracellular NAD. A sound scientific rationale therefore exists for its use in human prediabetes, and promising pilot studies have been performed in ICA-positive first-degree relatives and school children. No serious side effects have been reported from its use at the doses proposed in man or other species. There is therefore a sound case for submitting this agent to a controlled clinical trial.

Diabetes Mellitus, Type 1↗