Social anxiety and autism spectrum traits among adult FMR1 premutation carriers

Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using the Social Phobia Inventory (SPIN) and the Autism‐Spectrum Quotient (AQ) questionnaires. Fifty‐nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that fragile X‐associated tremor/ataxia syndrome (FXTAS) patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no‐FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results, a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation.     

Outcome of pharmacological rhythm control for new-onset persistent atrial fibrillation in patients with systolic heart failure: a comparison with patients with normal left ventricular function.

AIMS: To compare outcome of a serial cardioversion strategy in atrial fibrillation (AF) patients with and without systolic heart failure (HF). METHODS AND RESULTS: In patients with new-onset persistent AF and systolic HF [left ventricular ejection fraction (LVEF) <0.40] outcome of a serial electrical cardioversion (ECV) and serial antiarrhythmic drug strategy was compared with a control group of patients without HF. Follow-up was 18 months. Sixty-four consecutive patients with systolic HF (mean age 64 +/- 12 years, 50% coronary artery disease, LVEF 0.30 +/- 0.07) were enrolled and compared with 48 consecutive patients without HF (mean age 66 +/- 8 years, all LVEF >0.50, 40% lone AF). Success of ECV and occurrence of subacute and late recurrences in patients with and without HF were comparable. After the first relapse, AF was accepted in significantly more HF patients (23 vs. 4%, P < 0.01). Significantly less HF patients underwent serial ECV and antiarrhythmic drug approach (42 vs. 71%, respectively, P < 0.001). At the end of follow-up more HF patients were in permanent AF (45 vs. 29%, P = 0.03). CONCLUSION: Recurrence pattern after ECV is comparable between patients with and without systolic HF, but outcome of a serial cardioversion strategy is worse in HF patients, possibly related to a less stringent use of this approach.     

Exercise-induced ventricular tachycardia: A rare manifestation of digitalis toxicity

Digitalis intoxication is one of the most common adverse drug reactions. Although some arrhythmias are seen more frequently than others, virtually any rhythm disturbance, including ventricular tachycardia, may occur. However, to our knowledge, exercise-induced ventricular tachycardia as a complication of digitalis therapy has never been described before. This case presents a patient with a digitalis-induced ventricular tachycardia occurring exclusively during exercise.     

Septicemia and meningitis caused by Fusobacterium aquatile.

A case of septicemia and meningitis caused by Fusobacterium aquatile is described. The insidious onset of the megningitis and occurrence of multiple cranial nerve affections were outstanding features. In spite of adequate antibiotic treatment the course was protracted, and the outcome was permanent damage to 3 of the affected cranial nerves.     

Efficient presentation of naturally processed HLA class I peptides by artificial antigen-presenting cells for the generation of effective antitumor responses.

Appropriate presentation of tumor-associated antigens (TAA) by antigen-presenting cells (APC) is required for the development of clinically relevant antitumor T-cell responses. One common approach, which uses APC pulsed with synthetic peptides, can sometimes generate ineffective immune responses. This failure may, in part, be attributed to the formation of HLA/synthetic pulsed peptide complexes that possess different conformations compared with those of endogenously presented peptides. In addition, endogenous peptides may undergo post-translational modifications, which do not occur with synthetic peptides. Because our goal is to induce immunity that can recognize TAA that are endogenously presented by tumors, we designed an APC that would not only express the required immunoaccessory molecules but also naturally process and present target antigenic peptides. In this study, we generated an artificial APC (aAPC) that can endogenously present any chosen HLA-A*0201 (A2)-restricted peptide by processing a fusion protein that contains a unique "LTK" sequence linked to the antigenic peptide. Proteasome-dependent processing is so effective that the presented peptide can be directly eluted from the cell surface and identified by biochemical methods. Furthermore, we found that aAPC, engineered to endogenously present peptide derived from the melanoma antigen MART1, can be used to prime and expand antitumor CTL that target MART1-expressing tumor cells in a HLA-A2-restricted manner. Our engineered aAPC could serve as an "off-the-shelf" APC designed to constitutively express class I-restricted TAA peptides and could be used to generate effective T-cell responses to treat human disease.     

Methicillin-resistant Staphylococcus aureus in Dutch soccer team

An outbreak of community-acquired methicillin-resistant Staphylococcus aureus occurred among members and close contacts of a soccer team. Typing of the isolates showed the outbreak was caused by the well-known European ST80-IV strain. To our knowledge, this is the first report of an outbreak of this strain among members of a sports team.     

Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2

In the present study, the effects of a large series of flavonoids on multidrug resistance proteins (MRPs) were studied in MRP1 and MRP2 transfected MDCKII cells. The results were used to define the structural requirements of flavonoids necessary for potent inhibition of MRP1- and MRP2-mediated calcein transport in a cellular model. Several of the methoxylated flavonoids are among the best MRP1 inhibitors (IC(50) values, ranging between 2.7 and 14.3 microM) followed by robinetin, myricetin and quercetin (IC(50) values ranging between 13.6 and 21.8 microM). Regarding inhibition of MRP2 activity especially robinetin and myricetin appeared to be good inhibitors (IC(50) values of 15.0 and 22.2 microM, respectively). Kinetic characterization revealed that the two transporters differ marginally in the apparent K(m) for the substrate calcein. For one flavonoid, robinetin, the kinetics of inhibition were studied in more detail and revealed competitive inhibition with respect to calcein, with apparent inhibition constants of 5.0 microM for MRP1 and 8.5 microM for MRP2. For inhibition of MRP1, a quantitative structure activity relationship (QSAR) was obtained that indicates three structural characteristics to be of major importance for MRP1 inhibition by flavonoids: the total number of methoxylated moieties, the total number of hydroxyl groups and the dihedral angle between the B- and C-ring. Regarding MRP2 mediated calcein efflux inhibition, only the presence of a flavonol B-ring pyrogallol group seems to be an important structural characteristic. Overall, this study provides insight in the structural characteristics involved in MRP inhibition and explores the differences between inhibitors of these two transporters, MRP1 and MRP2. Ultimately, MRP2 displays higher selectivity for flavonoid type inhibition than MRP1.