Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3ß inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper- to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3ß, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.

The prevalence and clinical significance of premature ventricular beats in the athlete.

Adolescents and adults with cardiovascular disease who are engaged in sports activity have an increased risk of sudden cardiac death (SCD) that is three times greater than that of their non-athletic counterparts. Sport acts as a trigger for cardiac arrest in the presence of underlying cardiovascular diseases predisposing to life-threatening ventricular arrhythmias. Frequent and complex premature ventricular beats (PVBs) detected during the cardiovascular screening of the athletic population may be a sign of an underlying cardiovascular disease at risk of SCD, but are also often recorded in trained athletes without cardiovascular abnormalities. Thus, the interpretation of PVBs could represent a clinical dilemma, particularly in the athlete. However, while some characteristics of PVBs can be considered common and benign, others occur uncommonly in the athletic population and raise the suspicion of an underlying cardiovascular disease. This review discusses the prevalence and clinical significance of PVBs in the athlete, with a focus on exercise-induced PVBs, on the analysis of PVB's morphology at 12-lead ECG, and on the morphological substrates identified by imaging techniques. The implications on eligibility for competitive sports participation are also discussed, according to the relevance of PVB detection for disqualifying athletes from competitions.

Evaluation of Right Ventricular Function in the Management of Patients Referred for Left Ventricular Assist Device Therapy.

BACKGROUND: Speckle tracking echocardiography analysis (STE) has recently allowed an in-depth analysis of right ventricular (RV) performance. The aim of the study was to observe RV function by STE in patients with advanced heart failure before and after left ventricular assist device (LVAD) implantation. METHODS: A transthoracic echocardiogram was performed in 19 patients referred for LVAD implant at baseline and with serial echocardiograms after LVAD implantation (Jarvik 2000). All echocardiographic images were analyzed off line by an independent operator to calculate with STE the RV free wall longitudinal strain (RVLS). RESULTS: All the patients, except 4, showed a progressive increase of RVLS after LVAD implant. However, 4 patients, who presented the lowest RVLS values at baseline, presented a further RV failure in the postoperative. The value of -11% represented the empirical preoperative cutoff able to identify patients at greater risk of postimplant RV failure. CONCLUSIONS: RV myocardial deformation may have important clinical implications for the selection and management of LVAD patients. It can be used to evaluate RV function before LVAD implantation, to drive decisional strategy regarding the management of this type of patients, and after LVAD implant for the follow-up.

Phenotypic and genotypic alterations characterize patients bearing plasma cell dyscrasias with a high M-component.

As at present only a long-term follow-up can fully determine whether monoclonal gammapathies of undetermined significance (MGUS) will evolve into multiple myeloma (MM), this study attempted to identify other variables connected with the amount of monoclonal component (MC), generally considered as the most reliable marker of malignant evolution. Thirty-four MGUS subjects showing a high MC (> or = 15.0 g/l) but without clinical evidence of MM (MGUS group b), were characterized for their phenotypic and genotypic profile by comparing them either with 40 MM patients or with 24 subjects affected by a benign form of monoclonal gammapathy (MGUS group a) according to the standard criteria. In addition to the usual laboratory markers, the levels of expression of a panel of CD membrane subsets were measured on B and T lymphocytes. Also, the serum level of the p53 mutant protein and the structural alterations of the c-myc oncogene were evaluated. The results show that for MGUS group b patients, an increased M-protein was accompanied by significantly increased levels of peripheral blood CD3+ T cells and oncogenetic aberrations in c-myc. Since a high serum MC level seems to indicate a greater likelihood of malignant transformation for MGUS patients, these findings suggest that this relationship may be a result of the concomitant alterations observed at a phenotypic and genotypic level. Such alterations may be potentially useful as surrogate markers for the transition of benign to malignant (MM) plasma cell dyscrasia.