Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells

Polymorphisms in MHC class II molecules, in particular around β-chain position-57 (β57), afford susceptibility/resistance to multiple autoimmune diseases, including type 1 diabetes, through obscure mechanisms. Here, we show that the antidiabetogenic MHC class II molecule I-A^b affords diabetes resistance by promoting the differentiation of MHC-promiscuous autoreactive CD4⁺ T cells into disease-suppressing natural regulatory T cells, in a β56–67-regulated manner. We compared the tolerogenic and antidiabetogenic properties of CD11c promoter-driven transgenes encoding I-A^b or a form of I-A^b carrying residues 56–67 of I-Aβ^g7 (I-A^b-g7) in wild-type nonobese diabetic (NOD) mice, as well as NOD mice coexpressing a diabetogenic and I-A^g7–restricted, but MHC-promiscuous T-cell receptor (4.1). Both I-A transgenes protected NOD and 4.1-NOD mice from diabetes. However, whereas I-A^b induced 4.1-CD4⁺ thymocyte deletion and 4.1-CD4⁺Foxp3⁺ regulatory T-cell development, I-A^b-g7 promoted 4.1-CD4⁺Foxp3⁺ Treg development without inducing clonal deletion. Furthermore, non–T-cell receptor transgenic NOD.CD11cP-I-A^b and NOD.CD11cP-IA^b-g7 mice both exported regulatory T cells with superior antidiabetogenic properties than wild-type NOD mice. We propose that I-A^b, and possibly other protective MHC class II molecules, afford disease resistance by engaging a naturally occurring constellation of MHC-promiscuous autoreactive T-cell clonotypes, promoting their deviation into autoregulatory T cells.     

Propafenone versus procainamide for conversion of atrial fibrillation to sinus rhythm

Background and hypothesis: Antiarrhythmic drugs are widely used for treatment of atrial fibrillation (AF) and restoration off sinus rhythm. This prospective, randomized, and controlled study compared the efficiency and safety of propafenone versus procainamide for the treatment of acute AF. Methods: In all, 117 patients (55 women, 62 men, mean age 64.2 ± 13 years, median 63 years) who presented with AF were included in the study. Exclusion criteria were signs or symptoms of heart failure on physical examination, recent myocardial infarction or cardiac surgery, cardiogenic shock, or hypotension. Forty-one patients spontaneously recovered sinus rhythm; the remaining 76 patients were randomized to receive propafenone or procainamide. Propafenone was given at a dose of 2 mg/kg body weight intravenously (IV) over 30 min. Patients randomized to receive procainamide received a bolus of 100 mg IV administered every 5 min up to a maximum dose of 1 g. The clinical characteristics of the two groups were comparable. Results: The number of patients who recovered sinus rhythm after the treatment was larger in the procainamide-treated group (Group 1) (69.5%) than in the propafenone-treated group (Group 2) (48.7%); p < 0.05. The time required for cardioversion was significantly lower in Group 1 (mean 4.1 ± 1.3 h). than in Group 2 patients (mean 7.3 ± 2.6 h) (p<0.01). Conclusion: In the present study, procainamide was more effective than propafenone for the treatment of AF of short duration.     

Increased temporal dispersion of myocardial repolarization in myotonic dystrophy type 1: beyond the cardiac conduction system

Objectives

To assess ventricular dysfunction and ventricular interaction after repair of Tetralogy of Fallot (ToF) employing echocardiography speckle-tracking and cardiac magnetic resonance imaging (CMR).

Background

Severe pulmonary regurgitation and right ventricular (RV) dysfunction are common after repair of ToF and may also affect the shape and function of the left ventricle (LV). Recent studies suggest that LV dysfunction may be of particular prognostic value.

Methods and results

Twenty-one consecutive adults with repaired ToF (15 male, mean age 38 ± 11 years, 7 with severe PR) underwent a comprehensive echocardiographic exam including speckle-tracking analysis, CMR and cardiopulmonary exercise testing. Twenty-one subjects without relevant heart disease served as controls. Echocardiographically measured RV diameters correlated with RV volumes obtained from CMR (r = 0.63; p = 0.006). In addition, a close correlation was found between RV and LV function on CMR (r = 0.74, p = 0.002), speckle-tracking LV and RV peak longitudinal 2D strain (r = 0.66, p = 0.003) and mitral and tricuspid annular plain systolic excursion (r = 0.71, p = 0.0003). While LV ejection fraction was normal in the majority of patients and not different from controls, LV longitudinal strain was significantly reduced in ToF patients (− 16.5 ± 3.3 vs. -20.5 ± 2.7%, p = 0.0001).

Conclusion

Left and right ventricular function both by CMR and speckle-tracking is interrelated in adults with repaired ToF. Despite normal LV ejection fraction, 2D longitudinal strain is significantly reduced in ToF patients, suggesting subclinical LV myocardial damage. Considering the potential prognostic value of LV dysfunction in ToF, this measurement may gain importance and should be included in future outcome studies.     

Prevalence of diabetes in Catalonia (Spain): an oral glucose tolerance test-based population study

The goal of this study was to investigate the prevalence of diabetes mellitus and impaired glucose tolerance in the adult population of Catalonia and study their association with obesity, central obesity, hypertension and smoking habit. A random sample of 3839 subjects aged 30-89 years participated in this cross-sectional study: 2214 subjects underwent a health examination with oral glucose tolerance test (OGTT) and 1625 were interviewed by phone. Diabetes prevalence (known and unknown) in the 30-89-year-old population was 10.3%, (95% CI: 9.1-11.6). In this age group, the prevalence rates of known diabetes, unknown diabetes and impaired glucose tolerance were 6.4, 3.9 and 11.9% in men and 6.9, 3.4 and 11.9% in women. The age adjusted prevalence to the world population for the 30-64-year-old age group was 6.1% (7.1% in men and 5.2% in women).The factors significantly associated with diabetes were age, obesity, hypertension and family history of diabetes. The high ratio of previously known diabetic cases to newly discovered ones, specially in the oldest age group, suggests good levels of awareness and medical services. The prevalence in Catalonia is similar to that observed in other Mediterranean countries.     

EGFR and KRAS mutational profiling in fresh non-small cell lung cancer (NSCLC) cells

Purpose

Knowledge of tumor mutational status has become a priority for effective NSCLC-tailored treatment. NSCLC diagnosis is more often reached through biopsy; thus, there is a clear need to implement for routine tumor molecular profiling on small cytological samples. This work aims to screen and compare the EGFR and KRAS mutational prevalence in fresh tumor cells and in corresponding routinely processed samples derived from trans-thoracic fine-needle aspiration. The latter currently represents the most appropriate diagnostic procedure in case of peripheral lesions, such as adenocarcinomas, which account for almost 40 % of all NSCLCs and for the highest EGFR mutational rates.

Methods

Two hundred and forty-four patients carrying peripheral lung masses underwent CT-guided aspiration. The obtained material was split, and a part was addressed to conventional histopathological analysis while the remaining one was stored at ?20 °C. In case of confirmation of adenocarcinoma, tumor genomic DNA was extracted from both fresh and fixed material, and EGFR and KRAS sequencing was performed.

Results

We identified 136 adenocarcinomas; from 134, we could recover enough material for the study. A full match was demonstrated between EGFR/KRAS mutational prevalences through the two approaches tested. We found EGFR mutations in 13 patients (9.7 %); 7 were females and 11 never or former smokers. KRAS mutations occurred in 20 (14.9 %) patients. EGFR and KRAS mutations were mutually exclusive.

Conclusions

Mutational screening on fresh cancer cells is an achievable, safe and cost-effective procedure which might allow routinely tumor molecular profiling as powerful integration of conventional histopathological analysis.     

Clinical significance of abdominal lymphadenopathy in chronic liver disease

The possibility of assessing the relationship of ultrasound (US)-detected abdominal lymphadenopathy with etiology, biochemical findings, and histologic data in patients with chronic liver disease was evaluated. US examination of the upper abdomen was performed in 321 consecutive patients with various chronic liver disorders and 56 control patients. The prevalence of lymphadenopathy in chronic liver disease was 38%. This prevalence varied according to etiology of liver disease, from 50% in chronic hepatitis C virus (HCV) to less than 10% in alcoholic cirrhosis and hepatitis B-virus (HBV)-related chronic liver disease. Patients with lymphadenopathy showed significantly higher serum levels of AST and ALT, as well as greater histopathological severity on liver biopsy specimens. In anti-HCV positive patients, there were no differences in the prevalence of lymphadenopathy according to HCV genotypes, whereas lymphadenopathy occurred less frequently in responders to interferon therapy than in nonresponders.     

Preclinical dementia: an Italian multicentre study on amnestic mild cognitive impairment

BACKGROUND: Different rates and cognitive predictors of conversion to dementia have been reported in subjects with different kinds of mild cognitive impairment (MCI). METHODS: A prospective, 24-month follow-up study, involving 269 subjects who strictly fulfilled criteria for the amnestic MCI. RESULTS: Conversion rate to dementia was 21.4% per year. Seventy-nine out of the 83 individuals who developed dementia were affected by probable Alzheimer's disease (AD). Among others, at the 24-month follow-up 24.1% were still affected by amnestic MCI, 13.3% had changed their neuropsychological profile of impairment and 17.2% were cognitively normalised. Compared to subjects who did not convert to AD, those who did convert showed poorer immediate and delayed recall and recognition of verbal and visual material at baseline as well as reduced executive abilities. A combination of age, Clinical Dementia Rating boxes and scores on delayed recall and recognition of verbal and visual material accurately identified 86% of the subjects who developed AD. CONCLUSIONS: Elderly subjects affected by an isolated memory disorder have a high probability of developing AD. The ability of verbal and visual measures to predict incipient dementia of memory impairment may be increased by the simultaneous assessment of individual features, such as age or rate of functional impairment.     

Chronic endophthalmitis in pseudophakic patients caused by bacillus subtilis

OBJECTIVE/METHODS: We present two cases of patients with chronic endophthalmitis. The treatment included intraocular lens exchange, total capsulectomy and posterior vitrectomy through the limbus. In both cases, samples of the vitreous were taken and sent to the laboratory together with the intraocular lens and remmants of posterior capsule for culture and antibiogram. RESULTS/CONCLUSIONS: Microbiologic examination and culture were positive in two cases for Bacillus subtilis, which is not actually identified in literature as an etiologic agent for chronic endophthalmitis.