A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type 1 diabetes on intensified insulin therapy. The UK Trial Group.

Aims: Despite considerable experience with insulin lispro, few blinded comparisons with soluble insulin are available. This study compared insulin lispro with human soluble insulin in patients with Type 1 diabetes mellitus on multiple injection therapy who inject shortly before meals.

Methods: Glucose control, frequency of hypoglycaemia and patient preference were examined in the course of a prospective, randomized, double-blind, crossover comparison, with a 6-week run-in period and 12 weeks on each therapy.

Abnormalities of somite development in the absence of retinoic acid.

We describe the effects of an absence of retinoic acid (RA) on the development of somites in the quail embryo. RA was removed by generating vitamin A deficient quail embryos whereupon the resulting defects in the embryos can be analysed. The effect on the somites is threefold.

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

We have previously described a simple and reproducible method for the measurement of nicotinamide and its major metabolite N-methyl-2-pyridone-5-carboxamide (2-pyr) in human plasma. We now describe a low-cost high-throughput method for measurement of urinary 2-pyr, and demonstrate that Isolute C18 bulk can replace use of the column to clean up the samples prior to injection into the HPLC apparatus. Using a standard curve together with an internal standard for each sample, with mean recovery of 2-pyr greater than 95%, the assay has proved reproducible, with considerable savings in cost and time.

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.

Hindbrain respecification in the retinoid-deficient quail.

We report here the development and rescue of the truncated hindbrain of retinoid-deprived quail embryos. The embryo is completely rescued by an injection of retinol into the egg; this confirms retinol, or a related retinoid, as a required molecule in hindbrain development. Staging the retinoid replacement enabled us to determine that the 3-4 somite stage is the period when retinoids are required for normal development.

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.

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.

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.

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.

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).

Stress in dentistry.

Dentists believe their profession is stressful. Research has indicated this belief is generally based upon patient behaviors and economic pressures. A discussion of stress and adaptation is presented.

Psychophysiological assessment of stress in chronic pain: comparisons of stressful stimuli and of response systems.

Due to disparate findings across the published studies, the stress-hyperactivity hypothesis has never been fully accepted as a causal mechanism for chronic muscle pain. Two recent comprehensive reviews of the psychophysiological studies of chronic pain came to opposite conclusions about the viability of the hypothesis, which stemmed from differing importance placed on the experimental methodology: the adequacy of stress manipulation. The present study tested the hypotheses that the adequacy of stress manipulation is influenced by stress stimuli type, degree of personal relevance, and selection of criterion for verification of stress experience, and that these factors have a measurable impact on the related physiological responses in a manner that is consistent with a theory of stress applicable to clinical stress disorders.

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.

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 distribution of endogenous retinoic acid in the chick embryo: implications for developmental mechanisms.

The aim of these experiments was to determine the endogenous distribution of retinoic acid (RA) across a wide range of embryonic stages in the chick embryo. By high pressure liquid chromatography, it was revealed that didehydroRA is the most prevalent retinoic acid in the chick embryo and that the tissues of the stage 24 embryo differed widely in their total RA content (didehydroRA + all-trans-RA). Some tissues such as the heart had very little RA and some such as the neural tube had very high levels, the total variation between these two being 29-fold.

The role of vitamin A in the development of the central nervous system.

We describe here the defects that arise in the central nervous system (CNS) of quail embryos when they develop in the absence of vitamin A. It has been assumed that because of the effects of excess vitamin A and its metabolites, particularly retinoic acid (RA), on the CNS they are involved in various aspects of CNS development. We show that this is indeed the case, because these deficient quail embryos have three defects in their CNS.

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.

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.

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.

Positional apoptosis during vertebrate CNS development in the absence of endogenous retinoids.

We have previously shown that quail embryos that develop in the absence of vitamin A have severe defects in their central nervous system. One defect is a completely missing posterior hindbrain. Here we have studied how this comes about by examining cell death using a wholemount technique.

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.