Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis

OBJECTIVES: We sought to determine the prognostic capabilities of exercise thallium (Tl)-201 tomographic imaging performed relatively early (within 2 years) after coronary artery bypass graft surgery (CABG). BACKGROUND: Exercise testing is commonly performed after CABG, but few data exist demonstrating its prognostic value in this setting. METHODS: Four hundred eleven patients were followed up for a median duration of 5.8 years. Eleven prospectively chosen clinical, exercise and Tl-201 variables were tested for their associations with outcome end points by means of proportional hazards regression models. RESULTS: During follow-up there were 60 deaths from any cause, 53 initial cardiac deaths or nonfatal myocardial infarctions (MIs) and 22 late (>3 months after the Tl-201 study) revascularization procedures. The number of abnormal Tl-201 segments on the postexercise image was the only variable in the multivariate analyses to show a significant association with all three outcome end points: chi-square 7.3, p = 0.007 for overall mortality; chi-square 8.1, p = 0.004 for cardiac death or MI; chi-square 7.8, p = 0.005 for any cardiac event. Other independent predictors of outcome were exercise duration (chi-square 10.7, p = 0.001) and age (chi-square 3.9, p = 0.049) for overall mortality and exercise angina score (chi-square 8.7, p = 0.003) for cardiac death or MI. The 5-year survival rate free of cardiac death or MI was 93% for patients without angina and a normal image or small postexercise perfusion defect versus 71% for patients with angina and a medium or large defect. CONCLUSIONS: Exercise Tl-201 imaging performed within 2 years of CABG can stratify patients into low and high risk subgroups.     

Maternal uniparental disomy for chromosome 14

A girl carrying a de novo balanced 13-14 robertsonian translocation showed a clinical phenotype with severe hypotonia, hyperextensible joints, frontal bossing, asymmetric face, no mental retardation, severe scoliosis and motor delay. In situ hybridization analysis on chromosome spreads revealed the presence of the two centromeres in the rearranged chromosomes. Molecular analysis on genomic DNA showed the presence in the proposita of two chromosomes 14 of maternal origin and no chromosome 14 from the father indicating a maternal monocentric uniparental disomy for chromosome 14 (mUPD14). Our patient shows several similarities with other reported cases of mUPD14, suggesting imprinting of a region(s) of chromosome 14 and defining a possible mUPD14 Syndrome.     

Recurrence of insulin-dependent diabetes mellitus after transient neonatal diabetes: a report of two cases

Insulin-dependent diabetes mellitus developed in two patients with transient neonatal diabetes after more than 5 years without insulin therapy. The absence of islet cell antibodies and of the typical HLA types suggests that they may have a nonimmunologic form of diabetes.     

A search for uniparental disomy in carriers of supernumerary marker chromosomes

Dietary supplementation with 4% eicosapentaenoic acid (EPA), a long-chain polyunsaturated fatty acid, suppressed the development of lung metastases in nude mice from MDA-MB-435 human breast cancer cell mammary fat pad solid tumors. Zymography of primary tumor homogenates showed that this inhibition of metastasis was associated with reduced levels of 92-kDa type IV collagenase gelatinolytic activity; this isoform has been previously associated with the metastatic phenotype. The 72-kDa isoform, which was also present, may have arisen from the cancer cells, or tumor-associated host cells. In vitro, the incorporation of EPA, 0.25-1.0 micrograms/ml into the medium caused a concentration-related suppression of cultured MDA-MB-435 cell 92-kDa type IV collagenase mRNA expression.     

Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23

Transient neonatal diabetes mellitus (TNDM) is a rare form of childhood diabetes which usually resolves in the first 6 months of life but which predisposes to type 2 diabetes of adult onset. We recently reported paternal uniparental isodisomy of chromosome 6 (UPD6) in two children with TNDM and proposed that there may be an imprinted gene important in the aetiology of diabetes on chromosome 6. We now describe two unrelated families which independently suggest that the gene is imprinted, is paternally expressed and maps to 6q22-q23. One family has a duplication while the other, with familial TNDM, shows linkage to a marker in this region.     

Gestational diabetes mellitus and subsequent development of overt diabetes mellitus

GDM develops in 1-3% of all pregnancies. Women with GDM are characterized by a relatively diminished insulin secretion coupled with a pregnancy-induced insulin resistance primary located in skeletal muscle tissue. The cellular background for this insulin resistance is not known. The binding of insulin to its receptor and the subsequent activation of the insulin receptor tyrosine kinase have significant importance for the cellular effect of insulin. Thus, the pathogenesis to the insulin resistance was studied by investigating insulin receptor binding and tyrosine kinase activity in skeletal muscle biopsies from women with GDM and pregnant controls. No major abnormalities were found in GDM wherefore it is likely that the insulin resistance is caused by intracellular defects distal to the activation of the tyrosine kinase. Glucose tolerance returns to normal postpartum in the majority of women with GDM. However, previous studies, in populations quite different from a Danish population, have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Hence, we aimed to investigate the prognosis of women with previous GDM with respect to subsequent development of diabetes and also to identify predictive factors for the development of overt diabets in these women. A follow-up study of diet treated GDM women diagnosed during 1978 to 1985 at the Rigshospital, Copenhagen was performed. Glucose tolerance was evaluated in 241 women (81% of the GDM population) 2-11 years after pregnancy. Abnormal glucose tolerance was found in 34.4% of the women (3.7% IDDM, 13.7% NIDDM, 17% IGT) in contrast to a control group where none had diabetes and 5.3% had IGT. Logistic regression analysis identified the following independent risk factors for later development of diabetes: a high fasting glucose level at diagnosis of GDM, a delivery more than 3 weeks before term, and an abnormal OGTT 2 months postpartum. Low insulin secretion at diagnosis of GDM was also an independent risk factor. The presence of ICA and GAD-autoantibodies in pregnancy was associated with later development of IDDM. In another study the following techniques: hyperinsulinaemic euglycaemic clamp, indirect calorimetry and tritiated glucose infusion were used to evaluate insulin sensitivity in glucose tolerant nonobese women with previous GDM and controls. A decreased insulin sensitivity due to a decreased non-oxidative glucose metabolism in skeletal muscle was found in women with previous GDM. Hence, the activity of three key enzymes in intracellular glucose metabolism (GS, HK and PFK) was studied in skeletal muscle biopsies obtained in the basal state and after 3 h hyperinsulinaemia, with the aim to identify the cellular defects causing the decreased insulin sensitivity. However, no abnormalities in enzyme activity was found. The same group of previous GDM women had a relatively reduced insulin secretion evaluated by the IVGTT. A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. Thus the present review has shown that even nonobese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. Hence, the combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy. The first OGTT should be performed around 2 months postpartum in order to diagnose women already diabetic and to identify women with the highest risk for later development of overt diabetes. Women with previous GDM comprise a target group for future intervention trials with the aim to prevent or delay development of NIDDM and IDDM.     

Meningiomas with disomy of chromosome 22: study of 9 cases

BACKGROUND: Cytogenetic studies of meningiomas suggest that loss of (or parts of) chromosome 22 is a primary event in the development of these tumors; later on, other chromosomal changes would occur in the caryotypes. All these secondary changes are observed mainly in cases with high clinical aggressivity. However, in a few cases of meningiomas disomy 22 coexists, but with other chromosomic anomalies. We present clinical, histopathological and cytogenetic findings in a group of meningiomas with disomy of chromosome 22. PATIENTS AND METHODS: We collected 10 meningiomas from nine patients which ages ranged between 28-70 years. Fresh tumoral specimens were divided for histologic examination and cytogenetic study, performed after short-term culture. RESULTS: At microscopic examination 5 tumors were classified as benign meningiomas, four as atypical and one as malignant meningioma. Four cases were recurrent tumors. The cytogenetic studies showed that all tumors presented two chromosomes 22 and other chromosome abnormalities. Losses in chromosomes 4, 7, 10, 14, 16, 17 and 20 were frequent; cytogenetics rearrangements of chromosomes 1, 4, 5, 7, 14, 19 and 22 were frequently involved. CONCLUSIONS: In karyotypic evolution of meningiomas, secondary anomalies of chromosomes 1p, 10 and 14 are the most common and appear to be associated with a more aggressive clinical course. In this group of meningiomas with disomy 22, these anomalies were also frequently found, and were related in 50% of cases with atypical or malignant morphologies and of them with recurrent tumors in the 40%.     

Interleukin-1 beta induced transient diabetes mellitus in rats. A model of the initial events in the pathogenesis of insulin-dependent diabetes mellitus?

When aiming at preventing IDDM in man, knowledge of the molecular mechanisms leading to beta cell destruction may facilitate identification of new possible intervention modalities. A model of IDDM pathogenesis in man suggests that cytokines, and IL-1 in particular, are of major importance in the initial events (Nerup et al 1994) (Fig. 1). In vitro rat experiments demonstrated that rhIL-1 beta inhibits beta cell function and induces beta cell death both in isolated islets of Langerhans and in the isolated perfused pancreatic gland. With the long term goal of identifying new modalities capable of preventing IDDM in man, the aim af this review was to investigate the effects of rhIL-1 beta on beta-cell function and viability in normal rats. This review discussed 1) the pharmacokinetics of IL-1 beta in rats as the basis for choice of route of administration and dose of rhIL-1 beta, 2) the effects and molecular mechanisms of IL-1 beta on temperature and food intake used as control parameters for successful injection of rhIL-1 beta in rats, 3) the effects of one or more injection of IL-1 beta on rat beta cell function, 4) the molecular mechanisms leading to IL-1 beta induced beta cell inhibition in vivo, and some possible intervention modalities based on the molecular mechanisms, 5) the effects of IL-1 beta on spontaneous diabetes mellitus in DP BB rats, and 6) the effects and molecular mechanisms of IL-1 beta induced inhibition of thyroid epithelial cell function and aggravated thyroiditis in DP BB rats, compared to the effects of IL-1 beta on rat beta cell function. Finally, this review discussed the effects of IL-1 beta on human beta cells in vitro, and the clinical relevance of these experiments, with special reference to a clinical trial with the aim of preventing IDDM in man. The pharmacokinetic studies suggested that IL-1 beta is distributed according to a two-compartment model with a first-order elimination. Interleukin-1 beta reached all the investigated organs in the rats, was accumulated in kidneys and was excreted in the urine. The data suggested that IL-1 beta also accumulated in the islets of Langerhans. After injection of 4.0 micrograms/kg pathophysiologically relevant concentrations of rhIL-1 beta were reached and intact rhIL-1 beta persisted for up to 5 hrs in plasma. Peripheral injections of IL-1 beta dose-dependently induced fever and anorexia in rats, probably via induction of PGE2 in the brain or in peripheral tissues thereafter passing the blood-brain barrier. Nitric oxide produced by cNOS seems to be a molecular mediator of IL-1 beta induced fever but not of anorexia. Fever and anorexia are well described effects of IL-1 beta in rats, and are as such usefull control parameters of the absorption and biological activity of IL-1 beta after peripheral injection. Injections of rhIL-1 beta to normal, non-diabetes prone rats induced initial beta cell stimulation followed by inhibition, in accordance with in vitro data. Furthermore, induction of peripheral insulin resistance coincided with beta cell inhibition after one daily injection for 5 days, leading to a transient diabetes mellitus-like state, characterized by hyperglycemia and hypoinsulinemia. At this time point, electron-microscopy did not demonstrate beta cell destruction. However, IL-1 beta induced intercellularly edema and microvillous processes on the beta cells, which might be early evidence of apoptosis. The diabetes mellitus-like state was not aggravated if the daily injections were continued beyond 5 days. Daily injections of rhIL-1 beta for 2 to 4 weeks induced formation of blocking IL-1 beta-antibodies in normal rats. Hence, injections exceeding 2 weeks should only be performed using species homologous IL-1 beta. The molecular mechanism of IL-1 beta induced beta cell inhibition in rats in vivo as in vitro, are likely to involve binding of IL-1 beta to the IL-1RtI, since the IL-1RtII is considered to be a decoy receptor. (ABSTRACT TRUNCATED)     

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.     

Zinc and diabetes mellitus

In patients with type 1 and 2 diabetes was frequently found: low blood zinc levels, high zincuria, severe and ubiquitous cellular depletion of zinc, increased basal and after loading blood mineral clearance, and hyperglycaemia due to the reduction of pancreatic insulin secretion and to the reduced biological action of the hormone on liver, as a consequence of chronic zinc deficit. Strong endocellular zinc depletion in diabetics; low insulin secretion; insulin biological action decrease for zinc deficit; IG-I concentration decrease, that happens in this condition; insulin and IGF-I resistance; insulin and IGF-I receptors depletion in diabetics: are strong arguments for zinc pharmacological supplementation, in gastric protective formulation, to avoid gastroenteric problems.     

Diuretics and diabetes mellitus

The term "diuretics" describes a concerning pharmacological action and side effects heterogeneous class of drugs. The special advantage of using diuretics includes reducing edema and expanded plasma volume often associated with hypertension and cardiovascular disease. Diuretics are one of the 5 major classes of antihypertensive agents recommended for the initial drug therapy of hypertension. However, currently treatment of hypertension with diuretics is controversial, because of potentially adverse effects on the cardiovascular risk profile, including deterioration in glucose control especially in patients with impaired glucose tolerance. Additionally there is concern about excess mortality associated with diuretic therapy and diabetes mellitus. The metabolic side effects on glucose metabolism and lipid profile are related to the type of diuretic and its dosage. The adverse effects of thiazides on insulin action, glycemia and lipid profile are dose dependent and can be minimized by using low doses. In contrast, indapamide seems not to alter glucose metabolism and lipid profile. The choice of diuretic depends on concomitant disease. In patients with nephropathy potassium sparing agents should not be used, however furosemid can be used even in high doses. Beside focus on indication of diuretics in patients with diabetes and their metabolic side effects treatment of therapy resistant hypertension in these patients are discussed in this review.     

Smoking and diabetes mellitus

Diabetic patients die mostly from chronic vascular complications, in particular ischaemic heart disease (specially type II diabetics) and renal failure associated with diabetic nephropathy (in particular type I diabetics). Smoking--one of the basic risk factors of atherosclerosis and its complications--accelerates in diabetics the atherosclerotic process and enhances the risk of cardiovascular complications. Smoking causes endothelial dysfunction, as well as deterioration of diabetic nephropathy and retinopathy. Smoking accelerates by various mechanisms the coagulation process and causes thus deterioration of the hypercoagulation state in diabetics. Anti-smoking intervention should be along with a diabetic diet the basic step in non-pharmacological treatment of diabetics.     

Uroradiology of diabetes mellitus

Diabetes mellitus is a prevalent disorder, well controlled in many persons with prolongation of life. Several radiologic manifestations are sufficiently specific to suggest a diagnosis in the unidentified patient, but even more important is an awareness of the sometimes life-threatening complications of diabetes which can be diagnosed from uroradiologic studies. We review the following urinary tract manifestations and complications of diabetes: pyelonephritis, perinephric abscess, renal papillary necrosis, emphysematous pyelonephritis, emphysematous cystitis, fungus infections, calcification of the vas deferens, seminal vesicle, and intrarenal branches of the renal artery, neuropathic bladder, and renal failure.     

Vitiligo and juvenile diabetes mellitus

Five juvenile diabetics had vitiligo. In two children, the vitiligo preceded the onset of diabetes. Four of the five patients had thyroid, adrenal, or gastric antibodies or a combination of these. In three children HLA-B8 antigens were detected, and one additional patient had HLA-Bw15. Of eight nondiabetic children with vitiligo, one had abnormal glucose tolerance. To the evidence supporting an autoimmune form of diabetes mellitus we add another observation: the association of insulin-dependent diabetes and childhood vitiligo.