Biomedical subjects

B A Millward

Publications and source records attributed to B A Millward.

43 records · Page 3Linked to original sources

PubMed1987

Evidence that the reduced number of natural killer cells in type 1 (insulin-dependent) diabetes may be genetically determined.

Viruses may cause Type 1 (insulin-dependent) diabetes. We wondered whether the number and function of natural killer cells, which are important in anti-viral defense, are disturbed in diabetic patients. We studied 16 recently diagnosed Type 1 diabetic patients, 18 Type 1 diabetic patients diagnosed more than 15 years previously, 18 Type 2 (non-insulin-dependent) diabetic patients and 23 control subjects. We determined the number of natural killer cells (expressed as log10%) using anti-Leu 11 monoclonal antibody and the function (in log10 lytic units) concurrently using a 51Cr release assay with K562 as target cells. We found that the number of natural killer cells was reduced in Type 1 diabetes (1.01 +/- 0.04) as compared with Type 2 diabetic patients (1.16 +/- 0.04, p = 0.004) and normal control subjects (1.16 +/- 0.04, p = 0.006). To establish whether the reduced natural killer cell number is genetically determined we studied 19 identical twin pairs discordant for Type 1 diabetes; we found that even the non-diabetic co-twins had a reduced natural killer cell number (0.93 +/- 0.05, p = 0.0006) as compared with normal control subjects. Natural killer cell function was similar in all groups while natural killer activity per cell was significantly increased in the recently diagnosed diabetic patients (1.63 +/- 0.07) as compared with long-standing diabetic patients (1.26 +/- 0.26, p = 0.03) and controls subjects (1.36 +/- 0.07, p = 0.006). In conclusion the reduced number of natural killer cells in Type 1 diabetes appears to be genetically determined while their activity at diagnosis is increased.

Adolescent↗

PubMed1987

T cell receptor beta chain polymorphisms are associated with insulin-dependent diabetes.

We investigated the T cell receptor constant beta chain (TCR C beta) genes of patients with insulin dependent diabetes mellitus (IDDM) using DNA restriction fragment length polymorphism (RFLP) analysis. Genomic DNA from patients and controls was digested with the restriction endonuclease Bg1 II and transferred to nylon filters using the Southern blot procedure. This enzyme identifies a polymorphic site between the two TCR C beta chain genes. We have found a highly significant increase in the frequency of the 10.0; 9.2 kilobase heterozygous phenotype in patients with IDDM (62.7% versus 42.0% in normal controls; P = 0.0006). In identical twin pairs, this association was most striking in those concordant for IDDM (79.2% versus 42.0% in controls; P = 0.0006).

Adolescent↗

PubMed1986

Immune changes associated with insulin dependent diabetes may remit without causing the disease: a study in identical twins.

Activation of T lymphocytes and islet cell antibodies were studied in two groups of insulin dependent diabetics and their non-diabetic identical cotwins. Group 1 comprised 12 "short term" twin pairs (diabetic twin diagnosed less than five years previously) in whom only a third of the cotwins were likely to develop diabetes; 10 of the 12 non-diabetic cotwins showed increased values of activated T lymphocytes, islet cell antibodies, or both. Group 2 comprised 10 "long term" twin pairs (diabetic twin diagnosed more than 11 years previously) in whom none of the non-diabetic cotwins was likely to develop diabetes; these pairs were selected because all the non-diabetic cotwins had shown islet cell antibodies at some time in the past, but only two still did so (one with an increased value of activated T cells). There was relative glucose intolerance in the cotwins of the short term group but not in those of the long term group. Non-diabetic cotwins of diabetics may show the immune changes associated with insulin dependent diabetes and relative glucose intolerance, but these changes may remit without leading to diabetes.

Adolescent↗

PubMed1983

Value of profiling liver function in the elderly.

The value of measuring three routine tests of liver function was assessed prospectively in 523 geriatric patients. Abnormalities were found in 27% of patients and were clinically helpful in half of these cases. Profiling liver function, without clinical indication, revealed abnormal results in 17% of patients and was important in one-third of these (6% of total). The two most important diagnoses were unsuspected osteomalacia and gall stone disease.

Aged↗

PubMedDate not supplied

Chromosome 7q35 and susceptibility to diabetic microvascular complications.

Aldose reductase (ALR2), the first enzyme of the polyol pathway, may plan an important role in the pathogenesis of diabetic microvascular complications. The gene coding for ALR2 has been localized to chromosome 7q35. Using an ALR2 probe in conjunction with the restriction endonuclease Bam-HI, we have investigated the ALR2 locus of 128 patients with type I diabetes. A significant decrease in the frequency of the 8.2 kilobase (kb) Bam-HI ALR2 genotype and 8.2 kb allele was found in patients with nephropathy (nephropaths) compared to those with retinopathy alone (retinopaths) (p < 0.05 and 0.25, respectively). We have previously shown that an RFLP of the T-cell antigen receptor constant beta-chain (TCRBC) locus, which is also localized to chromosome 7q35, is strongly associated with susceptibility to microvascular complications. The 128 patients were genotyped using the restriction endonuclease Bgl-II and a TCRBC probe. The 10/9.2-8.2 kb TCRBC-ALR2 genotype was significantly decreased in the nephropaths compared to the retinopaths (13.7% versus 43.6%, chi 2 = 10.1, p < 0.0025). The 10/9.2 and 9.2/9.2 kb TCRBC-ALR2 haplotypes were increased in the nephropaths compared to the retinopaths (32.5% versus 8.9% chi 2 = 10.9, p < 0.001). These results suggest that chromosome 7q35 harbors a gene(s) that is involved in the pathogenesis of microvascular complications. Interestingly, the gene coding for endothelial nitric oxide synthase has recently been localized to the same chromosomal region as ALR2.

Adolescent↗

PubMedDate not supplied

The angiotensin I-converting enzyme (ACE) locus is strongly associated with age and duration of diabetes in patients with type I diabetes.

We have investigated the frequency of the angiotensin I-converting enzyme (ACE) insertion/ deletion (I/D) polymorphism in 249 patients with type I diabetes and 162 normal healthy controls. There was no significant difference in the frequency of ACE genotypes between those patients with diabetic nephropathy (n = 72) (nephropaths) compared to those with no proteinuria after 20 years duration of diabetes (n = 86) (normoalbuminurics). There was, however, a significant difference in the frequency of ACE genotypes between the short-duration and long-term normoalbuminuric group (chi = 11.5, p = 0.001). Analysis of the ACE genotypes with respect to age and duration of diabetes showed that homozygosity for the insertion (I/I) genotype was significantly decreased with longer duration of diabetes (r2 = 92.7%, p < 0.009). No association was found with age in the normal controls. In conclusion, these results suggest that the ACE locus may be associated with longevity and survival in patients with type I diabetes rather than diabetic nephropathy or microvascular disease per se.

Adolescent↗

PubMedDate not supplied

A novel polymorphism in the 5' flanking region of the glucose transporter (GLUT1) gene is strongly associated with diabetic nephropathy in patients with Type 1 diabetes mellitus.

Glucose transporter 1 (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. Recent studies have suggested that polymorphisms in the GLUT1 gene are associated with susceptibility to diabetic nephropathy (DN) in patients with diabetes mellitus. In this study, a novel polymorphism (A-2841T) in the 5' flanking region of GLUT1 was examined in 288 patients with Type 1 diabetes mellitus (T1DM) and 101 normal controls. The polymorphisms were amplified and the fragment digested with the enzyme HpyCH4V. There was a highly significant increase in the frequency of the TT-2841 genotype in patients with nephropathy (n=131) compared with those with either no microvascular complications after a 20-year duration of diabetes (uncomplicated; n=72; 54.5% vs. 2.7%, chi=79.4, P<.000001). There was no difference between the uncomplicated group and those who only had retinopathy (n=50; 2.7% vs. 4.0%, respectively). The frequency in recently diagnosed patients was 17.1% and only 2.0% in normal controls. In contrast, the AA genotype was found in 13.6% of the nephropaths, 76.3% of uncomplicated, 48.0% of retinopaths, and 65% of normal controls. These results confirm previous reports of an association between the GLUT1 gene and susceptibility to DN but not retinopathy. The localisation of this polymorphism suggests that it may be involved in the expression of the gene.

5' Untranslated Regions↗