Utility of Diabetes Type–Specific Genetic Risk Scores for the Classification of Diabetes Type Among Multiethnic Youth

OBJECTIVEGenetic risk scores (GRS) aid classification of diabetes type in White European adult populations. We aimed to assess the utility of GRS in the classification of diabetes type among racially/ethnically diverse youth in the U.S.RESEARCH DESIGN AND METHODSWe generated type 1 diabetes (T1D)- and type 2 diabetes (T2D)-specific GRS in 2,045 individuals from the SEARCH for Diabetes in Youth study. We assessed the distribution of genetic risk stratified by diabetes autoantibody positive or negative (DAA^+/−) and insulin sensitivity (IS) or insulin resistance (IR) and self-reported race/ethnicity (White, Black, Hispanic, and other).RESULTST1D and T2D GRS were strong independent predictors of etiologic type. The T1D GRS was highest in the DAA⁺/IS group and lowest in the DAA⁻/IR group, with the inverse relationship observed with the T2D GRS. Discrimination was similar across all racial/ethnic groups but showed differences in score distribution. Clustering by combined genetic risk showed DAA⁺/IR and DAA⁻/IS individuals had a greater probability of T1D than T2D. In DAA⁻ individuals, genetic probability of T1D identified individuals most likely to progress to absolute insulin deficiency.CONCLUSIONSDiabetes type–specific GRS are consistent predictors of diabetes type across racial/ethnic groups in a U.S. youth cohort, but future work needs to account for differences in GRS distribution by ancestry. T1D and T2D GRS may have particular utility for classification of DAA⁻ children.     

Predictors of cognitive improvement after reality orientation in Alzheimer's disease

BACKGROUND: there is increasing evidence to support the efficacy of reality orientation in cognitive deficits in patients with Alzheimer's disease. The clinical characteristics of patients who respond to reality orientation are poorly understood; this knowledge could be important, given that the provision of reality orientation therapy is labour-intensive and may provoke emotional distress. AIM: to evaluate retrospectively which demographic and clinical characteristics of Alzheimer's patients predict cognitive outcomes. METHOD: we analysed 38 mild-to-moderately demented outpatients who regularly attended a one-month formal reality orientation programme. The mini mental state examination score changes from baseline-and immediately after-reality orientation were correlated with demographic and pre-treatment clinical characteristics by a linear regression analysis. RESULTS: short-term responsiveness to reality orientation was significantly predicted by a lower level of cognitive functioning (as measured by the mini mental state examination) at baseline and by the absence of euphoria, accounting together for 57.6% of variance. CONCLUSION: a lower mini mental state examination and the absence of euphoric behaviour in patients with mild-to-moderate Alzheimer's disease may predict a good cognitive outcome of reality orientation therapy.     

Segmental dyskinesia in Wolff-Parkinson-White syndrome: a possible cause of dilatative cardiomyopathy

Wolff-Parkinson-White (WPW) is a syndrome characterized by the presence of an accessory pathway that skipping A-V node may lead the electrical stimulus from the atrium directly to the ventricle. Some studies reported the finding of myocardial dyskinesia in the segments precociously activated by the accessory pathway, at echocardiogram and at nuclear cardiac study. Soria et al. reported, in 1985, an increased incidence of dilative cardiomyopathy in patients with WPW. The pathophysiological pathway that leads to ventricular dilation may be due to the increase of end-diastolic pressure secondary to a tachycardia-induced cardiomyopathy. Tachycardia-induced cardiomyopathy is usually secondary to frequent and prolonged tachycardia episodes. In this paper we report the cases of three patients affected by WPW who developed dilative cardiomyopathy during the follow-up. Particularly dyskinetic segments, working such as a functional aneurysm, could induce deep modifications of intraventricular haemodynamics, leading to remodelling and progressive ventricular dilation. This hypothesis could have important empirical consequences because it could imply the necessity of a precocious ablative therapy in this kind of patients.     

A novel silent beta-thalassemia mutation in the distal CACCC box affects the binding and responsiveness to EKLF

The silent beta-thalassemia mutation, beta(+)-101C-->T, is the only mutation currently described in the distal beta-globin CACCC box. We present a novel mutation, a C-->G transversion, in the same position. Expression analysis in heterozygous subjects demonstrated that the mutation determines a 20% reduction in the output of the beta-globin gene. DNA-protein interaction and transactivation analysis correlated the decrease in the beta-globin synthesis with the reduced binding and transactivation of EKLF to the mutant promoter. These data predict that the beta-101C-->G mutation will display a silent thalassemia phenotype similar to that of the beta-101C-->T mutation.     

Trajectories in estimated glomerular filtration rate in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study

AimsWe sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes.MethodsWe assessed the direction of eGFR change at two visits (mean 6.6 years apart) in SEARCH, a longitudinal cohort study of youth-onset type 1 and type 2 diabetes. We used the CKiD_Cr-CysC equation to estimate GFR and categorized ‘rising’ and ‘declining’ eGFR as an annual change of ≥3 ml/min/1.73 m² in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR.ResultsEstimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index.ConclusionsOver the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.