Evidence for a Type 1 diabetes‐specific mechanism for the insulin gene‐associated IDDM2 locus rather than a general influence on autoimmunity

Aims The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5′ upstream of the insulin (INS) and insulin‐like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self‐tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes‐specific locus or acting as a general autoimmunity gene. Methods We genotyped the INS‐IGF2 VNTR [using the surrogate INS?23 HphI single nucleotide polymorphism (SNP)] in 823 Graves’ disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. Results We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case–control dataset showed no genotypic or allelic difference between the two populations. Conclusions These data suggest that the INS‐IGF2 VNTR is acting as a Type 1 diabetes‐specific susceptibility gene rather than as an influence on general autoimmunity.     

Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository.

AIMS: Autoimmune disorders co-exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population. METHODS: Between 1989 and 1996, 505 British families with at least two siblings affected by Type 1 diabetes were recruited. Clinical information was collected regarding the presence of autoimmune disease in the parents and the prevalence of disease in the parents was compared with that expected in the general population. RESULTS: The prevalence of autoimmune disease in the parents was significantly higher in the repository compared with that expected in the general population [P-value = 1.98 x 10(-5) (female), P-value = 1.1 x 10(-8) (male)]. Type 1 diabetes was recorded in 63/1010 (6.2%) parents with a marked paternal preponderance (9.5 vs. 3%P = 0.002). Other autoimmune diseases affected 27% of parents with diabetes and 13.2% of parents without diabetes (P < 0.01). CONCLUSION: These data confirm the importance of family history as a significant risk factor for the development of Type 1 diabetes and support the hypothesis that the common autoimmune diseases share at least some aetiological mechanisms.     

Importance of dosimeter calibration method on nebulizer output.

BACKGROUND: We have observed that dosimeter-run nebulizers have a much smaller output when manually activated than when breath activated; however, this has not been adequately investigated. OBJECTIVE: To evaluate the effect of different calibration methods on nebulizer output. METHODS: Six healthy subjects performed all calibrations. The nebulizers were operated by 2 different dosimeters and were calibrated to produce 9 microL per actuation by breath activation followed by exhalation to the room. The nebulizers were then operated at these identical settings, and the output determined in 3 ways: (1) breath activation followed by exhalation to the room, (2) breath activation with exhalation into the nebulizer, and (3) manual activation (with no subject using the nebulizer). These 3 methods were termed regular, rebreathe, and manual, respectively. RESULTS: There was a large and statistically significant difference in nebulizer output among the 3 methods. The measured rebreathe outputs (5.6 and 5.7 microL per actuation) were approximately two thirds and the manual outputs (3.2 and 3.9 microL per actuation) were approximately one third of the regular calibration outputs (8.6 and 8.9 microL per actuation); the 2 values are for the 2 dosimeters. The results were highly statistically significant (P < .001). CONCLUSIONS: The method by which a nebulizer-dosimeter system is calibrated results in different nebulizer outputs. This has a high likelihood of influencing the concentration of methacholine causing a 20% decrease in volume in the first second of forced expiration.     

12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression)

OBJECTIVE: Inpatients with major depressive illness often have coexistent nonaffective psychiatric and/or medical conditions. The authors' objective is to address the following questions: 1) What is the effect of comorbid illness on the severity of major depression and associated psychosocial factors? 2) How does the course of depression differ for patients with and without concurrent illness? 3) Do patients with compound depression differ in rate of recovery and time to recovery from patients with pure depression? METHOD: The subjects were 78 patients with a DSM-III diagnosis of major depression who were consecutively admitted to an acute care university-affiliated psychiatric hospital; 37 of these patients had major depression only and 41 had major depression compounded by a coexisting axis I, II, or III condition. The patients were studied while hospitalized and for 12 months after hospital discharge. Instruments used included the Modified Hamilton Rating Scale for Depression, the Global Assessment Scale, and the Social Readjustment Rating Scale. RESULTS: Patients with compound depression reported significantly poorer functioning over the 12-month follow-up period and had lower recovery rates than the patients with pure depression. There were no differences in recovery rates between men and women with compound depression, but significantly more men than women with pure depression recovered. CONCLUSIONS: Compound depression is a common clinical occurrence, the course of illness is more difficult for patients with compound depression than for patients with pure depression, and the recovery rate of patients with compound depression is lower than that of patients with pure depression.     

The dental management of patients with bipolar disorder

Bipolar disorder (manic depressive disease) affects 1% of the United States population. These persons suffer from prolonged episodes of extreme elation and depression. There is a significant incidence of dental pathosis and a need for dental care among these patients. The medications used for the treatment of this disease, their physiologic effects, and their interactions with the drugs used in dentistry are reviewed.     

Supratentorial hemangioblastoma associated with Von Hippel Lindau disease: case report and review of the literature

Multiple vascular lesions in the brain were identified by angiography in a 45-year-old woman with Von Hippel Lindau disease. One of these lesions was a histologically-proven hemangioblastoma. The occurrence of such lesions in a cerebral hemisphere is exceedingly rare and is usually related to Von Hippel Lindau disease.     

A new approach to chemotherapy based on molecular biology and nucleic acid chemistry: Matagen (masking tape for gene expression)

The nucleotide sequences of genes contain information which can potentially be used to understand gene function and thus the biological properties of living organisms. This information can also be used to develop innovative new strategies for chemotherapy employing sequence-specific non-ionic oligonucleoside methylphosphonates. These oligonucleotide analogs, termed Matagen (an acronym for masking tape for gene expression), have the following properties: (1) the negatively charged phosphodiester linkage normally found in nucleic acids is replaced with a non-charged methylphosphonate group which confers increased lipophilicity to the oligomer; (2) the oligomers form stable hydrogen-bonded complexes with complementary nucleic acid sequences and retain the fidelity of Watson-Crick base pairing; (3) the lipophilic oligomers cross the cell membrane and also enter various organs of the body; and (4) the methylphosphonate backbone is inherently resistant to nuclease hydrolysis and thus oligomers are taken up intact from cell culture media and remain stable within the cellular environment. Two general strategies are used to block gene expression by Matagens at the mRNA level in mammalian cells. In the first approach, Matagens complementary to specific sites such as the initiation codon region are used to block translation of mRNA. Thus Matagens specifically inhibit translation of rabbit globin mRNA in cell-free systems and rabbit reticulocytes, and vesicular stomatitis virus protein synthesis, but not cellular protein synthesis, in virus-infected cells. In the second approach, Matagens complementary to splice junctions of precursor mRNAs are used to inhibit splicing. For example, a Matagen complementary to the donor splice junction of simian virus 40 (SV40) large T-antigen mRNA inhibits T-antigen synthesis in SV40-infected cells, and a Matagen complementary to the acceptor splice junction of herpes simplex virus (HSV) immediate early pre-mRNA 4 + 5 inhibits HSV replication in virus-infected cells. Two new types of Matagen, one derivatized with the photoactivatable cross-linking group psoralen and the other derivatized with a hydroxyl radical-producing group, EDTA-Fe(II), have been designed to improve the efficacy of Matagen and to overcome some of the problems inherent in physical binding of Matagens to complementary nucleic acids. The Matagen approach provides a new way to design antiviral and chemotherapeutic agents in a rational manner. It combines nucleic acid chemistry and chemotherapy to form a common basis for drug development as well as to provide fundamental knowledge about organisms and humans.