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Biomedical subjects

A C Tarn

Publications and source records attributed to A C Tarn.

18 recordsLinked to original sources
PubMed1997

Primary hyperoxaluria type 1: diagnostic relevance of mutations and polymorphisms in the alanine:glyoxylate aminotransferase gene (AGXT).

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). The disease shows considerable phenotypic, enzymatic and genetic heterogeneity. To date, 7 polymorphisms and 11 point mutations have been described in the gene encoding AGT. We report on the prevalence of these polymorphisms and mutations in 79 patients with PH1 with the aim of assessing their diagnostic relevance. A strong association of the C154T, intron 1 insertion and C386T polymorphisms is confirmed and this linkage extends to include the type 1 variant of a polymorphic tandem repeat in intron 4. Only 64 of 158 (40%) PH1 alleles have one of the defined mutations, with the G630A mutation accounting for 39 of these and T853C for 14. Overall only 20 (25%) of the patients studied had the genetic basis of their disease fully explained: 7 were homozygous for the G630A mutation, 5 were homozygous for the T853C mutation, 1 was homozygous for the C819T mutation, and 7 had two different mutations identified and were presumed to be compound heterozygotes. Only the two more frequent G630A and T853C mutations are of general diagnostic relevance for mutation screening. It seems likely that there are a significant number of other mutations, perhaps family-specific, still to be described. There was no apparent difference in the types of mutations in patients presenting in the first year of life (36%), suggesting that other factors, such as periods of dehydration or urinary tract infections, might contribute more to the clinical manifestation than genotype.

Adolescent↗
PubMed1996

Case reports.

Explore the source record for details and available documents.

Humans↗
PubMed1996

Phenylketonuria: treatment in adolescence and adult life.

In our clinic the decision on whether to continue with dietary treatment of phenylketonuria or not is left to each adolescent and adult patient after the advantages and disadvantages, as discussed in this paper, of continuing diet have been presented to them. As a result 61 of 132 patients have stopped diet or declined to restart and only 4 of them have phenylalanine values below 1000 mumol/l. Seventy-one patients have remained on diet or started again with phenylalanine values below 1000 mumol/l in 58 of them. This series of 132 excludes women who returned to diet to conceive.

Adolescent↗
PubMed1990

Correlates of blood pressure in young insulin-dependent diabetics and their families.

We compared the correlates of blood pressure in 163 young patients with insulin-dependent diabetes and in 232 of their non-diabetic siblings. A single observer recorded blood pressure in all subjects, plus all their available parents, using a standardized technique. Other variables recorded included age, weight, height, presence of diabetes and urinary albumin. The major factors accounting for over 50% of the variance of systolic blood pressure (SBP) in both groups were age, weight, paternal SBP and sex. In addition, in the diabetic group the logarithm of the random urinary albumin concentration was a significant explanatory variable. For diastolic blood pressure (DBP) approximately 16% of the variance was explained by age, weight and maternal DBP. Parental blood pressure was an important determinant of blood pressure in both the diabetic and non-diabetic sibling groups. The similarity of the correlates of blood pressure in the two groups suggests that the determinants of blood pressure in young insulin-dependent diabetic patients and in the general population are similar.

Adolescent↗
PubMed1989

Persistent reduction of CD4/CD8 lymphocyte ratio and cell activation before the onset of type 1 (insulin-dependent) diabetes.

Over a period of 5 years, lymphocyte subpopulations and their markers of activation were studied prospectively in 56 first degree relatives of Type 1 (insulin-dependent) diabetic probands. Lymphocytes were phenotyped using a panel of monoclonal antibodies which recognise CD3, CD4, CD8 lymphocytes, K/NK cells, HLA Class II products and IL-2 receptors (IL-2r). Twenty-six subjects were negative for islet cell antibody (ICA), 18 had complement fixing ICA (CF-ICA) and 12 only conventional ICA (ICA-IgG). The total number of observations (blood samples collected) was 386. Overall, changes in T cell data were observed in the three groups of first degree relatives compared to 70 normal subjects without a family history of diabetes. Six individuals developed Type 1 diabetes in the course of the study. They all possessed CF-ICA and five out of six showed a persistent reduction (less than 1.5) of the CD4/CD8 lymphocyte ratio before the clinical onset of the disease. Activated lymphocytes were found on two occasions in two of these subjects. We conclude that imbalance of lymphocyte immunoregulatory subsets is present before the onset of Type 1 diabetes in susceptible individuals; the persistence of a reduced CD4/CD8 lymphocyte ratio may reflect the ongoing process leading to B-cell destruction.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Predicting insulin-dependent diabetes.

719 first-degree relatives of diabetic children were followed up to assess the value of HLA haplotype sharing and of islet-cell antibodies (ICA) for prediction of insulin-dependent diabetes (IDDM). Within a maximum of 8 years' follow-up (3384 patient-years of observation) 16 unaffected relatives (5 parents and 11 siblings) became insulin dependent. The cumulative risk of becoming insulin dependent by age 25 was 16% for siblings sharing two HLA haplotypes with the proband, 9% for those sharing one haplotype, and zero for those sharing none. 13 of 24 (54%) subjects positive for complement-fixing ICA on three or more occasions became insulin dependent, as against 1 of 30 (3%) with noncomplement-fixing ICA alone and 2 of 665 (0.3%) ICA-negative subjects; by life-table analysis the risks after 8 years of known ICA status are 76%, 3%, and 0.6%, respectively. In terms of total time at risk ICA-positive family members had a relative risk of 75.2 compared with ICA-negative individuals. With positivity for complement-fixing ICA the relative risk was 188.5.

Actuarial Analysis↗
PubMed1988

Between and within subject variation of the first phase insulin response to intravenous glucose.

Eight normal subjects underwent two intravenous glucose tolerance tests to determine the between and within subject variation of the first phase insulin response. Variability was represented by the coefficient of variation. The between subject variation for the incremental 0-10 min insulin area was 58%, and the within subject variation was 22% (median value), range 3-55%. The variation of the first phase response expressed in four different ways was compared. The total and incremental (above fasting levels) 0-10 min areas provided less variable results (variation 52 and 58%) than the 1 + 3 min insulin levels (variation 72%) or mean of the incremental 3-5 min insulin levels (variation 66%). The ratio of the incremental 0-10 min insulin to glucose areas was as variable (variation 53%) as the insulin responses alone. The variability of insulin responses to intravenous glucose severely limits their value as early predictors of B-cell failure.

Adult↗
PubMed1988

Basal and stimulated insulin levels rise with advancing puberty.

We studied the effect of pubertal development on insulin secretion. Intravenous glucose tolerance tests were performed on 47 islet-cell antibody negative siblings of diabetic children and on 16 normal adults. Puberty was staged using Tanner's criteria and subjects were grouped as follows: I, stage 1 (n = 16); II, stages 2 and 3 (n = 15); III, stages 4 and 5 (n = 16); IV, adults (n = 16). Fasting insulin increased with advancing puberty (p = 0.59, P less than 0.001). The stimulated insulin response also rose with increasing pubertal development: for the 0-10 min insulin area, p = 0.46, P less than 0.001 and for the 10-60 min area, p = 0.68, P less than 0.001. There was a low positive correlation between insulin and age to 16 years but multiple regression analysis showed that this could be accounted for by puberty alone. Indeed prepubertal children and adults did not differ. There was no correlation between glucose (fasting and 0-60 min area) and puberty or age. These findings suggest that insulin resistance increases during puberty, and this may contribute to the frequency of presentation or worsening control of insulin dependent diabetes at this time.

Adolescent↗
PubMed1987

Type I (insulin dependent) diabetes: a disease of slow clinical onset?

Type I (insulin dependent) diabetes is usually believed to present acutely and it is assumed that metabolic decompensation is sudden. In a prospective family study, however, 10 of 13 subjects developing the disease showed progressive or intermittent development of hyperglycaemia over many months and the others had non-specific symptoms over a long period. All were first degree relatives of a child with type I diabetes; 10 were siblings (aged 5-24) and three were parents (aged 45-58). All possessed HLA-DR4 or DR3, or both, and all but two had been positive for islet cell antibodies for six to 86 months before diagnosis. Ten had non-specific symptoms for two to 14 months before the onset of thirst and polyuria; one remained asymptomatic even when insulin became necessary. Six subjects had an oral glucose tolerance test before clinical onset, of whom five were diabetic by World Health Organisation criteria four, four, six, seven, and 21 months before insulin was needed. Nine showed random blood glucose concentrations above the 97.5th centile (6.3 mmol/l) six to 34 months (median 12) before diagnosis. Two others had a glucose tolerance test result compatible with diabetes but had not reached the stage of needing insulin. Hyperglycaemia is often of insidious onset in type I diabetes, even in children and young adults. Diagnosis will inevitably be late if considered only when acute symptoms of thirst and polyuria develop.

Adolescent↗
PubMed1986

A DR3-related DX alpha gene polymorphism strongly associates with insulin-dependent diabetes mellitus.

HLA-DQ alpha and HLA-DX alpha gene polymorphisms were analyzed by Southern blot techniques in 78 Caucasoid insulin-dependent diabetes mellitus (IDDM) subjects and 55 control subjects. Five restriction fragment length polymorphisms of the HLA-DQ alpha gene correlated with HLA-DR typing. Two allelic DX alpha-related gene fragments, of 2.1 kb (U) and 1.9 kb (L) in size were identified. Genotype frequencies in the IDDM group for UU, UL, and LL were 54%, 38.5%, and 7.5%, respectively, whereas the corresponding frequencies in the control group were 24%, 40%, and 36% (P less than 0.00005 for differences in genotype frequencies). The U allele was associated particularly with IDDM patients who were DR3, with healthy controls who were DR3, as well as with IDDM patients who were not DR3. Thus, if this DX alpha U allele is not the DR3-associated IDDM susceptibility gene, it is the closest marker hitherto studied.

Chromosome Mapping↗
PubMed1986

Blood pressure in children, adolescents and young adults with type 1 (insulin-dependent) diabetes.

Blood pressure has been measured by a single observer using a standardised technique in 163 Type 1 (insulin-dependent) diabetic patients aged 4 to 32 years, 232 of their non-diabetic siblings in the same age range and in 292 of their natural parents. Results for each sex were examined separately by analysis of variance. Systolic pressures were not significantly different overall nor in any single 4-year age band. In contrast, phase IV diastolic pressure was slightly but significantly higher in the diabetic males than in their sibling group overall (increment = +2.8 mmHg; p less than 0.03), a difference also shown individually within the 16-20 year age band (81.3 versus 76.5 mmHg, p less than 0.025). There were no significant differences in diastolic pressure between the female groups, and no effect of duration of diabetes on blood pressure was shown in either sex. Eighteen of 97 male diabetic patients (19%) had mean blood pressures above the 90th centile for age, derived from the sibling data, compared with 12 of 137 siblings (9%, p = 0.05). The higher blood pressures among the diabetic males could not be explained solely by early nephropathy; familial factors appeared to be important in the determination of elevated blood pressure in this group as well as in the siblings. Alone, these small differences in blood pressure are unlikely to make a major contribution to the incidence of diabetic vascular disease, but the isolated increase in diastolic pressure may indicate altered vascular regulation in Type 1 diabetes.

Adolescent↗
PubMed1986

Insulin autoantibodies in the pre-diabetic period: correlation with islet cell antibodies and development of diabetes.

IgG and IgM class insulin autoantibodies were measured by an enzyme-linked immunosorbent assay in sera from members of the Barts-Windsor-Middlesex prospective family study for Type 1 (insulin-dependent) diabetes. One hundred and twelve individuals from 28 families were selected for study on the basis of a clearly defined islet cell antibody status. IgG insulin autoantibodies were found to be significantly associated with islet cell antibody positive (n = 30) versus islet cell antibody negative (n = 57) first degree family relatives (p = 0.002), with increased significance (p = 0.0003) if complement-fixing (CF)-islet cell antibody individuals (n = 20) only were considered. In addition, a significant association of IgG insulin autoantibodies with subsequent development of diabetes was observed within the CF-islet cell antibody positive group (p less than 0.0003). No such associations were found for IgM insulin autoantibodies, but a higher prevalence of these autoantibodies was observed in islet cell antibody negative first degree relatives (n = 57) compared with a control group of 73 Blood Bank donors (p = 0.00007), and they were significantly associated with siblings (n = 48) rather than parents (n = 39), (p = 0.001). We conclude that the presence of IgG insulin autoantibodies and CF-islet cell antibodies confer more risk for future development of diabetes than the presence of either marker alone.

Autoantibodies↗
PubMed1985

Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11.

A polymorphic DNA sequence in the 5'-flanking region of the human insulin gene was studied in relation to Type 1 (insulin-dependent) diabetes. In 141 Caucasoid subjects analysed by Southern blot hybridisation techniques, two major DNA insertions were observed: a Class 1 allele or a Class 3 allele. The Class 2 allele was not observed in this group of subjects. Genotype frequencies in a control population (n = 88) were: homozygous 1/1, 42%; heterozygous 1/3, 50%; and homozygous 3/3, 8%. Corresponding genotype frequencies in 53 Type 1 diabetic patients were 79%, 21% and 0%, respectively (p less than 0.0005 from chi 2 test). This confirms prevalence data reported by Bell et al. [16]. There appeared to be no coinheritance with HLA-DR3/DR4 related antigens, nor with autoimmune features. Analysis of 17 Type 1 diabetic pedigrees including 34 diabetic and 69 non-diabetic subjects did not demonstrate genetic linkage of these DNA inserts with diabetes, using an autosomal recessive, single locus model of inheritance.

Alleles↗
PubMed1985

Are the WHO criteria for hypertension appropriate in young insulin-dependent diabetics?

Normal adult blood pressure is arbitrarily defined as a systolic pressure equal to or below 140 mmHg together with a diastolic (5th phase) equal to or below 90 mmHg. Hypertension in adults is arbitrarily defined as a systolic pressure equal to or greater than 160 mmHg and/or diastolic (5th phase) equal to or greater than 95 mmHg. The term 'borderline hypertension' is used to denote blood pressure values between the normal and the hypertensive ranges as described above. The blood pressure levels at which hypertension can be defined for children vary with age, but precise levels are under review. Clearly values that would be regarded as hypertensive are lower in children than in adults.

Age Factors↗