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N Maclaren

Publications and source records attributed to N Maclaren.

At least 37 records · Page 2Linked to original sources
PubMed1991

Insulin dependent diabetes 1991.

Insulin dependent diabetes (IDD) most often results from the autoimmune destruction of pancreatic beta cells. During this process, autoantibodies to islet cell constituents (islet cell cytoplasm, 64KDa protein [GAD]) and to insulin arise and can be used for disease prediction if found before onset or for classification at onset in cases in which type of diabetes is not clear. Approximately 4-5% of immediate family members have at least one of these antibodies. The younger the age and the higher the antibody titer, the greater the chance of IDD developing. Because studies using immunosuppression in newly-diagnosed IDD have shown transient prolongation of beta cell function, efforts to use such therapies prior to diabetes onset may prevent beta cell destruction and clinical disease. A multicenter trial is underway in Florida to screen relatives for diabetes-related antibodies and then to enter those found positive and at increased risk in a study to prevent diabetes. Details of the study and its rationale are presented.

Autoimmune Diseases↗
PubMed1989

Initial pathogenic events in IDDM.

A workshop sponsored by the National Institute of Child Health and Human Development was held in June 1988 to discuss the initial events in the pathogenesis of insulin-dependent diabetes and to make recommendations for future studies. Better definition of immunological markers to reliably predict the disease will enable the detection and study of the earliest pathogenic events involved. The precise autoimmune mechanisms and the role of the environment, both in the initiation of the disease process and precipitation of clinically overt disease, need to be accurately determined to define strategies that might eventually lead to its prevention.

Animals↗
PubMed1989

Genetic conditions among Canadian Mennonites: evidence for a founder effect among the old colony (Chortitza) Mennonites.

Distinctive disease patterns exist among Canadian Old Colony (Chortitza) Mennonites. This religious and genetic isolate is of 16th century Dutch/German ancestry. The group originated in the Netherlands, then settled in the Vistula delta area of western Prussia for 200 years. A small number of founding families later migrated to Chortitza, the "Old Colony", in the Ukraine in the late 18th/early 19th century, where they remained a distinct genetic isolate. This group has come to Canada over the past 100 years. The more conservative Canadian Mennonites of Chortitza descent practice strict endogamy, have a large family size and live predominantly in rural public health subdistricts in the four western provinces, and in southern Ontario. The world's largest reported familial aggregations of insulin-dependent diabetes mellitus, of autoimmune diseases and of Tourette syndrome were initially ascertained in a small northern Alberta public health subdistrict. Clusterings of malformations, inborn errors of metabolism, and other conditions were also found in the subdistrict, and in group descendents living in other provinces. A founder effect, or genetic drift, accounts for the familial aggregations of autosomal recessive and dominant conditions, some diseases of multifactorial determination, and other inherited conditions in Canadian kinships descending from this ancestral group. The medical literature on genetic conditions among Canadian Mennonites is reviewed and re-evaluated in the light of this information. There is biochemical, serologic, and molecular biologic evidence in favour of genetic homogeneity amongst patients with certain inherited conditions in this special population group. This genetic isolate offers potential for the study of the genetic epidemiology and molecular biology of inherited diseases. A computerized genealogic data base on about 1400 group members, as well as a cryopreserved lymphocyte/DNA bank on over 100 individuals with genetic conditions has been established in this special population group.

Alberta↗
PubMed1988

Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus.

We randomly assigned 46 patients (mean age, 11.7 years; range, 4.5 to 32.8) with newly diagnosed insulin-dependent diabetes mellitus within two weeks of beginning insulin to receive either corticosteroids for 10 weeks plus daily azathioprine for one year or no immunosuppressive therapy. Half the 20 immunosuppressed patients completing the one-year trial had satisfactory metabolic outcomes (hemoglobin A1c less than 6.8 percent; stimulated peak C peptide greater than 0.5 nmol per liter; insulin dose less than 0.4 U per kilogram of body weight per day) as compared with only 15 percent of the controls. Three of 20 immunosuppressed patients, but no controls, were insulin independent at one year. Two of these continue to receive azathioprine without insulin after more than 27 months of follow-up. The response to immunosuppression correlated with older age, better initial metabolic status, and lymphopenia (less than 1800 lymphocytes per cubic millimeter) resulting from immunosuppression. The side effects of azathioprine included vomiting in one patient and mild hair loss in several others. Prednisone use resulted in a transient cushingoid appearance, weight gain, and hyperglycemia. The growth rate remained normal in all patients. We conclude that early immunosuppression with short-term use of corticosteroids plus daily azathioprine can improve metabolic control in some patients with insulin-dependent diabetes mellitus, but results from this unblinded study are preliminary and require further confirmation and long-term follow-up.

Adolescent↗
PubMed1988

Inherited susceptibility to insulin-dependent diabetes is associated with HLA-DR1, while DR5 is protective.

Of the HLA allelic associations with insulin-dependent diabetes (IDD) reported to date. DR3 and DR4 have been the most positive and DR2 the most negative. In 952 Caucasian proband patients reported here, only 57 or 6% had no DR3 or DR4 alleles. When these 57 patients were compared to 249 Caucasian controls similarly lacking DR3 and DR4 antigens, there were excesses of DR1 (P = 0.13) and DRW8 (P = 0.01) and deficiencies of DR2 (P = 0.03) and DR5 (P = 0.03) in the patient group. The most common phenotype in this group of patients was DR1/DR7 (12.3%). Only four DR-homozygous patients involving alleles other than DR3 and DR4 were found by genotyping, and all were DR1 homozygotes. Among 506 patients wuth DR3/DRX or DR4/DRX phenotypes, DR1 was more frequent (P = 0.001; Bonferronni P = 0.006), and DR2 (P = 0.001) and DR5 (P = 0.001) less frequent than 243 HLA-matched controls. Of 187 patients with a single DR3 and no DR4, DR1 was more frequent (P = 0.02), with DR2 (P = 0.001) and DR5 (P = 0.02) less frequent than 94 HLA DR-compatible controls. Among 319 patients with a single DR4 but no DR3, DR1 was again more frequent (P = 0.01) and DR2 (P = 0.001) and DR5 (P = 0.001) less frequent than 149 HLA-matched controls. We conclude that DR1 is an additional risk DR allele for IDD to that of DR3 and DR4, and DR5 an additional protective DR allele to that of DR2.

Adolescent↗
PubMed1987

Polymorphisms of DQ beta genes in HLA-DR4 haplotypes from healthy and diabetic individuals.

The restriction fragment length polymorphism (RFLP) of DQ beta was assessed in a panel of control and insulin-dependent diabetes (IDD) patients who were serologically typed as HLA-DR4 homozygotes or HLA-DR3, DR4 heterozygotes. Digestions of genomic DNA with Bam HI, Bgl II, Pst I, Xba I, and Hind III revealed a total of 15 RFLPs in the panel of 71 HLA-DR4 chromosomes. These RFLPs were organized into six allelic groups on the basis of segregation analysis in families. Complete RFLP haplotypes for the 5 restriction enzymes could be constructed for 42 of the HLA-DR4 chromosomes. This analysis revealed 18 RFLP haplotypes of DQ beta associated with the DR4 chromosomes tested. Two of these haplotypes, designated DQ3.DR4. a and DQ3.DR4.b, accounted for over 50% of the DR4 chromosomes analyzed. These two haplotypes were antithetical for the RFLPs detected by all five enzymes, indicating that they represent very distinct forms of DQ beta. The remaining 16 haplotypes were infrequent or unique and were closely related to either a DQ3.DR4.a or DQ3.DR4.b. Two of the RFLPs detected, a 5.8 kb Bgl II fragment and a 10.5 kb Bam HI fragment, had increased frequencies in disease-associated chromosomes. However, none of the RFLPs we detected exhibited a statistically significant increase in IDD or control populations. In contrast, the DQ3.DR4.b DQ beta haplotype was significantly decreased in IDD-associated DR4 chromosomes (P = 0.04). These results suggest that the DQ3.DR4.b DQ beta allele may be protective for the development of IDD.

Alleles↗
PubMed1986

Molecular genetics of insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus is an autoimmune disease the development of which is influenced by genetic factors (Cahill & McDevitt, 1981). As concordance for IDD is less than 50% in identical twins, environmental factors are also required for the development of IDD. Although viral agents have been implicated in the past, the specific environmental components leading to IDD remain unknown. This paper reviews current research focused on the genetic factors that influence susceptibility to IDD.

Autoantibodies↗
PubMed1982

Gastric parietal cell and other autoantibodies in the BB rat.

A longitudinal study of circulating autoantibodies in the sera of 48 BB rats was performed by indirect immunofluorescence. No pancreatic islet cell, adrenocortical, or thyroid microsomal autoantibodies were found. However, autoantibodies reactive to gastric parietal cells (PCA), smooth muscle, and thyroid colloidal antigens were identified, PCA were not detected in Wistar-Furth or BB x Wistar-Furth F1 hybrid rats. The range of ages at the time of first appearance of PCA was the same as that of onset of insulin-dependent diabetes (IDD) in the BB rats, suggesting that the processes leading to PCA and IDD were occurring at the same time of life in these animals. The presence of PCA was associated with degrees of lymphocytic gastritis and with squamous metaplasia of the gastric mucosa in the oldest BB rats (9 mo of age). Levels of serum iron and vitamin B12 did not differ between PCA-positive and PCA-negative BB rats, nor was achiorhydria found in any rat studied. The identification of PCA (and chronic gastritis) and other autoantibodies in the BB rat suggests that these animals have an underlying autoimmune diathesis. These findings thus provide indirect support for an autoimmune pathogenesis for IDD in the BB rat.

Achlorhydria↗
PubMed1981

Gonadal autoantibodies in patients with hypogonadism and/or Addison's disease.

The sera from 325 normal individuals, 21 patients with Turner's syndrome, 505 patients with insulin-dependent diabetes mellitus, 15 patients with unexplained ovarian insufficiency, and 37 patients with Addison's disease or serological evidence of adrenal autoimmunity were examined for the presence of gonadal autoantibodies by an indirect immunofluorescent technique using sections of human testis. All 12 patients found to have gonadal autoantibodies also had adrenocortical autoantibodies. These autoantibodies were completely absorbed with powdered adrenal cortex and thus were "steroidal cell" antibodies (SCA), cross-reactive with a cytosolic antigen in the steroid-producing cells of adrenal cortex, placental syncytiotrophoblast, Leydig areas of testis, and theca interna/granulosa layer of ovarian follicles. Sera with SCA had reduced titers of adrenal antibodies after repeated absorptions with gonadal or placental tissues, suggesting that adrenal-specific autoantibodies were also present. Sera from patients with only adrenal antibodies had no significant changes in antibody titers after repeated absorptions with gonadal or placental tissues. In conclusion, all gonadal autoantibodies found were SCA. SCA were only found in patients with adrenal autoimmunity, many of whom had hypogonadism. In other patients or in normal individuals, the existence of SCA or gonadal autoimmunity in the absence of adrenocortical autoantibodies must be rare.

Addison Disease↗
PubMed1977

Abnormalities in growth hormone and insulin release in short but otherwise normal patients. The arginine-insulin-glucose (AIGT) stimulation and suppression test.

Arginine-insulin stimulation and IV glucose suppression (AIGT) tests were used to evaluate release of insulin and growth hormone. Adult patients responded normally. Hypopituitary patients showed no hGH response. One third of short normal patients showed abnormal hGH responses to glucose suppression. Two thirds of the short normal patients showed poor insulin responses to either amino acid or glucose stimulation. Such patients might have abnormalities in release mechanisms for insulin and suppression mechanisms for hGH and this might contribute to their growth failure.

Adolescent↗