Ia-Type alloantigens and humoral autoimmune responsiveness in insulin-dependent diabetes mellitus.

In the search for markers either closely linked to or identical with the hypothetical "diabetogenic major histocompatibility gene," immune region-associated alloantigens were defined in 80 patients with insulin-dependent diabetes and in 107 controls. A close association between the Ia-type alloantigen DRw3 and DRw4 and insulin-dependent diabetes was obtained. DRw3 was found in 36% and DRw4 in 32% of the patients compared to 11% and 16%, respectively, of the controls. In addition, a significant influence of DRw3 and humoral anti-islet-cell autoimmunity could be observed, which was found to be due to a high incidence of DRw3 in those patients with islet cell antibody persistence. Islet-cell antibodies (ICA) were observed in 60% of the DRw3-positive patients compared to only 9% of the DRw3-negatives with longstanding disease (greater than 5 yr). These data show a significant association between insulin-dependent diabetes and the Ia-type alloantigens DRw3 (p uncorr. less than 0.0005) and DRw4 (p uncorr. less than 0.025). Furthermore, they provide direct evidence of an association between an Ia-type alloantigen and persisting humoral autoimmune responsiveness in man.     

Development of insulin-dependent diabetes mellitus in a patient with chronic hepatitis C during therapy with interferon-alpha

Interferon (IFN)-alpha is used for the treatment of chronic viral hepatitis. It has been associated with various forms of autoimmune disease, e.g. autoimmune hepatitis, Hashimoto thyroiditis and insulin-dependent diabetes mellitus. Further, an increase of insulin resistance and development of non-insulin-dependent diabetes mellitus has been described after treatment with IFN-alpha. Several studies have investigated the induction of different autoimmune markers by IFN-alpha, but only few specified patients who developed insulin-dependent diabetes mellitus. We report the case of a 37-year-old man with chronic hepatitis C who was treated with IFN-alpha plus ribavirin. Thirty weeks after the start of treatment, the patient developed insulin-dependent diabetes mellitus and therapy was withdrawn. HLA typing showed an HLA-DR1,3 phenotype. At manifestation of diabetes mellitus, the C-peptide level was 0.37 ng/ml (normal range 0.5-3 ng/ml). The patient had a positive family history for type 2 diabetes. Several autoimmune markers were investigated before, during and 6 months after withdrawal of antiviral treatment. High titres of glutamic acid decarboxylase (GAD) antibodies were present before therapy. A significant increase in titres of islet cell antibodies, parietal cell antibodies and sperm antibodies was present after 14 weeks of IFN-alpha treatment. Six months after withdrawal of IFN-alpha therapy, these antibodies had significantly decreased whereas GAD antibodies remained unchanged. There was no clinical sign of any other autoimmune disease. Our data show that, in patients with a predisposition to insulin-dependent diabetes mellitus, the disease may become manifest as a side-effect during therapy with IFN-alpha. Several pathogenetic factors may be involved in this process, and, in addition to IFN-alpha, hepatitis C itself may induce autoimmune mechanisms. We conclude that screening for autoantibodies specific for type 1 diabetes should be performed before the start of IFN-alpha treatment. In patients found to be at increased risk of developing diabetes mellitus type 1, monitoring of titres of these antibodies during therapy could help to assess the individual risk-benefit ratio of IFN-alpha treatment.     

Immunoglobulin allotype markers and HLA DR genes in type I diabetes mellitus

Although it is now well established that insulin-dependent (type I) diabetes mellitus is closely associated with genes of the HLA-DR locus, the genetics of the disease remains an area of controversy. It is generally believed that the HLA-linked diabetes genes provide the majority of disease susceptibility to type I diabetes, however, there is some evidence for the existence of other non-HLA-linked genetic loci predisposing to this disorder. Therefore, allotypes of the Gm (immunoglobulin heavy chain) locus on chromosome 14 and of Km (immunoglobulin light chain) locus on chromosome 2 were studied in 180 caucasoid type I diabetic patients. No association between immunoglobulin allotype markers and the whole group of type I diabetes could be observed. However, a particular immunoglobulin allotype, G1m(a), and a particular Gm immunoglobulin phenotype (a-x-f+b+) showed a significant heterogeneity within the diabetics subdivided by HLA-DR type. The data of this study support the concept that (1) the genes in the HLA region provide the majority of, but not the only, genetic susceptibility to type I diabetes mellitus and (2) Gm-associated genes could interact with these susceptibility genes at least in the DR3+4 heterozygote type I diabetics. Further studies should be undertaken in order to elucidate a possible role of these factors in the humoral immune response of type I diabetics and their families.     

Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.     

Left ventricular hypertrophy and diastolic dysfunction in healthy pregnant women

OBJECTIVE: The purpose of this study was to examine which hemodynamic parameters change under the natural volume overload of pregnancy. STUDY DESIGN: 46 healthy pregnant women were echocardiographically examined during the course of pregnancy. To evaluate left ventricular diastolic function, mitral inflow and pulmonary venous flow profiles were used. Fractional shortening and left ventricular muscle mass were calculated. RESULTS: In the course of pregnancy the left ventricular muscle mass index increased (from 66 +/- 6 to 96 +/- 9 g/m(2)), fractional shortening decreased (from 38 +/- 4 to 32 +/- 6%) and a disturbed diastolic relaxation pattern was documented. Eight weeks after delivery, all left ventricular systolic and diastolic functional parameters returned to normal values. CONCLUSION: The natural volume overload in pregnancy leads to a reversible 'physiological' left ventricular hypertrophy, a short-term decrease in systolic function and a significant change in left ventricular diastolic function.     

The impact of risk factors and more stringent diagnostic criteria of gestational diabetes on outcomes in central European women

OBJECTIVES: In the face of the ongoing discussion on the criteria for the diagnosis of gestational diabetes (GDM), we aimed to examine whether the criteria of the Fourth International Workshop Conference of GDM (WC) select women and children at risk better than the World Health Organization (WHO) criteria. DESIGN AND SETTING: This was a prospective longitudinal open study in five tertiary care centers in Austria. PATIENTS AND OUTCOME MEASURES: The impact of risk factors, different thresholds (WC vs. WHO), and numbers of abnormal glucose values (WC) during the 2-h, 75-g oral glucose tolerance test on fetal/neonatal complications and maternal postpartum glucose tolerance was studied in 1466 pregnant women. Women were treated if at least one value according to the WC (GDM-WC1) was met or exceeded. RESULTS: Forty-six percent of all women had GDM-WC1, whereas 29% had GDM-WHO, and 21% of all women had two or three abnormal values according to WC criteria (GDM-WC2). Eighty-five percent of the GDM-WHO were also identified by GDM-WC1. Previous GDM [odds ratio (OR) 2.9], glucosuria (OR 2.4), preconceptual overweight/obesity (OR 2.3), age 30 yr or older (OR 1.9), and large-for-gestational age (LGA) fetus (OR 1.8) were the best independent predictors of the occurrence of GDM. Previous GDM (OR 4.4) and overweight/obesity (OR 4.0) also independently predicted diabetes postpartum. GDM-WC1 had a higher rate of obstetrical complications (LGA neonates, neonatal hypoglycemia, cesarean sections; P < 0.001) and impaired postpartum glucose tolerance (P < 0.0001) than GDM-WHO. CONCLUSION: These results suggest the use of more stringent WC criteria for the diagnosis of GDM with the initiation of therapy in case of one fasting or stimulated abnormal glucose value because these criteria detected more LGA neonates with hypoglycemia and mothers with impaired postpartum glucose metabolism than the WHO criteria.     

Titanium orthodontic brackets: structure, composition, hardness and ionic release.

OBJECTIVES: The aim of the present study was to investigate the composition, morphology, bulk structure and ionic release of two brands of titanium orthodontic brackets: Orthos2 (Ormco, USA) and Rematitan (Dentaurum, Germany). METHODS: Five specimens of each group were examined with computerized X-ray microtomography, to reveal the morphology and structure of brackets, whilst resin-embedded and metallographically polished specimens were subjected to SEM/EDS analysis and Vickers microhardness measurements. Brackets were also maintained in 0.9% saline for 2 months and the ionic release in the immersion medium was determined with Inductively Coupled Plasma Atomic Emission Spectroscopy. The results of the hardness and ionic release measurements were statistically analyzed with two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: Orthos2 brackets consisted of two parts, the base (commercially pure Ti grade II) and the wing (Ti-6Al-4V alloy), joined together by laser welding, producing large gaps along the base-wing interface. The base was of lower hardness (Hv = 145), than the wing (Hv = 392) and incorporated a standard foil base-mesh pad. Rematitan brackets consisted of commercially pure Ti grade IV, with a single-piece manufacturing pattern of virtually identical hardness (p > 0.05) at the base and wings, featuring a laser-etched base-mesh pad. The hardness of the Rematitan brackets was significantly lower than the hardness of the Orthos2 wings, but double the hardness of the Orthos2 base. Released Ti levels were below the threshold level (1 ng/ml) of analysis for both materials, whilst traces of Al (3 ppm) and V (2 ppm) were found in the immersion media for Ti-6Al-4V alloy. SIGNIFICANCE: The structural and hardness differences found may influence the torque transfer characteristics from activated archwires to the brackets and the crevice corrosion potential at the base-wing interface (Orthos2). The detection of Al and V in the immersion medium (Orthos2) may imply a different biological response from the two types of Ti brackets.     

Stellenwert der nichtinvasiven kardialen Diagnostik bei Frauen mit Verdacht auf koronare Herzkrankheit

Zusammenfassung. Hintergrund und Fragestellung: Die koronare Herzkrankheit (KHK) ist die führende Todesursache bei Frauen in den Industrieländern. Unglücklicherweise sind die in der Routine eingesetzten nichtinvasiven Screeningverfahren für das Vorhandensein einer KHK nicht sehr sensitiv und eher unspezifisch für Frauen. Ziel dieser Studie war zu analysieren, inwieweit geschlechtsspezifische Unterschiede bei der nichtinvasiven Vorfelddiagnostik bestehen, welche Vorfelddiagnostik bei Frauen im klinischen Alltag empfohlen werden kann und ob der nichtinvasiven Bestimmung der diastolischen Funktionsparameter eine relevante Bedeutung im Rahmen der Vorfelddiagnostik zukommt. Patienten und Methodik: Insgesamt wurden 180 konsekutive Patienten mit klinischem Verdacht auf eine KHK im Rahmen der Vorfelddiagnostik mit einem Ruhe- und Belastungs-EKG, einer Echokardiographie mit Bestimmung der linksventrikulären systolischen und diastolischen Funktionsparameter, einer Dobutamin-Stressechokardiographie sowie einer Thallium-Myokardszintigraphie vor der Herzkatheteruntersuchung untersucht. Ergebnisse: Angiographisch wurde bei 104 Patienten (58%) eine KHK nachgewiesen. Gegenüber Männern wiesen Angina pectoris, Ruhe-EKG und Ergometrie bei Frauen eine geringere Sensitivität und Spezifität sowie einen geringeren prädiktiven Wert bezüglich der Diagnose KHK auf. Myokardszintigraphie, Dobutamin-Stressechokardiographie sowie die Bestimmung der linksventrikulären diastolischen Füllungsmuster zeigten keine geschlechtsspezifischen Unterschiede und hatten einen deutlich höheren Vorhersagewert als Klinik und elektrokardiographische Untersuchungen. Schlussfolgerung: Bei Frauen mit Verdacht auf eine KHK, sollte als Vorfelddiagnostik eine Stressechokardiographie oder Myokardszintigraphie durchgeführt werde. Als Screeningmethode eignet sich auch die Bestimmung von linksventrikulären diastolischen Funktionsparametern. Alle drei Verfahren können jedoch nicht zwischen einer koronaren Makro- und Mikroangiopathie diskriminieren. Abstract. Background and Objective: Coronary arterty diasese is the leading cause of mortality among women in the industrial countries. Unfortunately, the routinely available noninvasive tests used to screen the presence of coronary artery disease have been relatively insensitive and nonspecific for women. The aim of this study was to evaluate the importance of pretest coronary artery disease probability and to determine whether the evaluation of left ventricular diastolic parameters is a relevant diagnostic tool in women with suspected coronary artery disease. Patients and Methods: Electrocardiography at rest and during exercise, echocardiography at rest with evaluation of systolic and diastolic functional parameters, dobutamine stress echocardiography, exercise thallium myocardial scintigraphy, and coronary angiography were performed in 180 consecutive patients with suspected coronary artery disease. Results: Coronary angiography revealed significant coronary artery disease in 104 patients. Angina pectoris, resting and exercise electrocardiography had a very low pretest probability in women. Dobutamine stress echocardiography, myocardial scintigraphy and the evaluation of left ventricular diastolic function showed less relevant gender-related differences and had a significantly better pretest probability. Conclusion: Dobutamine stress echocardiotraphy and exercise thallium myocardial scintigraphy are reliable methods of diagnosing coronary artery disease in women. Echocardiographic assessment of diastolic left ventricular function represents another screening test for the evaluation of suspected coronary artery disease in women. All three methods, however, are not able to discriminate between coronary macro- or microangiopathy.