MEF2C deletions and mutations versus duplications: A clinical comparison

5q14.3 deletions including the MEF2C gene have been identified to date using genomic arrays in patients with severe developmental delay or intellectual disability, stereotypic behavior, epilepsy, cerebral malformations and a facial gestalt not really distinctive though characterized by broad and/or high, bulging forehead, upslanting palpebral fissures, flat nasal root and bridge, small, upturned nose, hypotonic small mouth resulting in cupid bow/tented upper lip. MEF2C mutations have been also identified in patients with overlapping phenotype so that it is considered the gene responsible for the 5q14.3 deletion syndrome. To date, one single duplication including MEF2C has been reported in a patient with intellectual disability but its clinical significance remains uncertain also because of the large size of the imbalance. Here we present two further patients with 5q14.3 duplications including MEF2C. Their phenotype indeed suggest the pathogenic effect of the MEF2C duplication although other duplicated genes also brain expressed might contribute to the clinical features. In none of them a clear-cut syndrome can be identified. A comparison between MEF2C deleted/mutated and duplicated patients is also presented.     

Pharmacologic Preconditioning Therapy Prior to Atrial Septal Defect Closure in Patients at High Risk for Acute Pulmonary Edema

Objectives: The aim of this study was to assess whether transient atrial septal defect (ASD) occlusion and, if required, vasodilator therapy would improve the safety of percutaneous ASD closure in high-risk subsets. Background: While percutaneous ASD closure is generally considered a low risk intervention, hypertensive and elderly patients may develop pulmonary edema following the procedure because of underlying left ventricular (LV) diastolic dysfunction. Methods: Fifty-two consecutive patients who underwent successful percutaneous ASD closures were enrolled into a single-center prospective registry. Patients with arterial hypertension and/or >60 years of age (n = 15) were considered at risk for periprocedural pulmonary edema. Those patients were tested for an increase of LV filling pressures during transient ASD occlusion and, if this was the case, treated according to a prespecified algorithm. Clinical and echocardiography data were collected in-hospital and at 6 months follow-up. Results: Shunt size was comparable in high and standard-risk patients (Qp:Qs 2.1 ± 0.8 vs. 2.1 ± 0.7, P = 0.82). High-risk patients had more often pulmonary hypertension (58% vs. 14%, P < 0.05) and were more frequently symptomatic. Among them, 4/15 (27%) demonstrated a significant rise of left-sided filling pressures during transient ASD balloon occlusion and underwent pharmacologic preconditioning prior to ASD closure. None of them developed periprocedural pulmonary edema. At follow-up, patients were less symptomatic (Pre: NYHA II n = 15, NYHA III n = 9; Post: NYHA II n = 15, NYHA III n = 0; P = 0.02) and right ventricular size decreased from 23 ± 5 cm(2) to 17 ± 5 cm(2) , P < 0.05. Conclusion: Transient ASD occlusion and, if required, pharmacologic preconditioning prior to percutaneous closure may prevent periprocedural pulmonary edema in high-risk patients. (J Interven Cardiol 2012;25:505-512).     

Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis

Background: The systemic use of combined amoxicillin and metronidazole (AMX/MET) as an adjunctive treatment to full‐mouth scaling and root planing (FMSRP) has been proposed for the treatment of generalized aggressive periodontitis; however, its effectiveness and clinical safety remain to be defined. The purpose of the present meta‐analysis is to assess the effectiveness of FMSRP + AMX/MET compared to FMSRP alone. Methods: An electronic search of eight databases and a hand‐search of 10 international dental journals were conducted through September 11, 2011. Gain in clinical attachment level (CAL), reduction in probing depth (PD), secondary outcomes, and adverse events were analyzed. A random‐effect model was used to pool the extracted data. The weighted mean difference (MD) with 95% confidence interval (CI) was calculated for continuous outcomes, whereas risk difference (RD) with 95% CI was used for dichotomous data; heterogeneity was assessed with the χ²‐based Cochran Q test and I² statistic. The level of significance was set at P <0.05. Results: After the selection process, six randomized clinical trials were included. Results of the meta‐analysis showed significant CAL gain (MD, 0.42; 95% CI, 0.23 to 0.61; P <0.05) and PD reduction (MD, 0.58; 95% CI, 0.39 to 0.77; P <0.05) in favor of FMSRP + AMX/MET; moreover, no significant RD was found in the occurrence of adverse events (RD, 0.01; 95% CI, ?0.02 to 0.04; P >0.05). Conclusion: The findings of the meta‐analysis seem to support the effectiveness and the clinical safety of FMSRP + AMX/MET; however, future studies are needed to confirm these results.     

Parkin-Knockout Mice did not Display Increased Vulnerability to Intranasal Administration of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The loss of nigral dopaminergic neurons in Parkinson’s disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, the hybrid 129Sv-C57BL/6 parkin-deficient mice did not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to neurotoxicity induced by 6-hydroxydopamine (6-OHDA) or intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We aimed to re-evaluate the role of parkin in a pure C57BL/6 background after an acute intranasal (i.n.) MPTP administration, a new route of toxin delivery to the brain that mimics environmental exposure to neurotoxins. We found that the deficiency of parkin gene modifies the d-amphetamine-induced locomotion in saline-treated animals. Intranasal MPTP induced Parkinsonism in parkin^+/+ mice, through depletion of striatal dopamine, decreased number of dopaminergic neurons in the substantia nigra, and decreased d-amphetamine-induced hyperlocomotion. Additionally, the deletion of the parkin gene in a pure C57BL/6 background did not lead to increased vulnerability to i.n. MPTP-induced neurotoxicity. Moreover, the i.n. MPTP induced nigral astrogliosis predominantly in the pars reticulata in wild type and parkin^?/? mice. Taken together, these results showed that the absence of parkin did not modify the vulnerability of nigrostriatal dopaminergic pathway after i.n. MPTP intoxication, suggesting that independently of mouse strain, the endogenous parkin is not required for protection of this system. These findings also suggest that the development of familial parkin-linked PD is not associated with exposure to environmental factors that specifically affects the dopaminergic system.     

Antiproliferative effects of chalcones on T cell acute lymphoblastic leukemia-derived cells: Role of PKCβ

In this study, a series of 20 chalcone derivatives was synthesized, and their antiproliferative activity was tested against the human T cell acute lymphoblastic leukemia-derived cell line, CCRF-CEM. On the basis of the structural features of the most active compounds, a new library of chalcone derivatives, according to the structure–activity relationship design, was synthesized, and their antiproliferative activity was tested against the same cancer cell line. Furthermore, four of these derivatives (compounds 3 , 4 , 8 , 28 ), based on lower IC₅₀ values (between 6.1 and 8.9 μM), were selected for further investigation regarding the modulation of the protein expression of RACK1 (receptor for activated C kinase), protein kinase C (PKC)α and PKCβ, and their action on the cell cycle level. The cell cycle analysis indicated a block in the G0/G1 phase for all four compounds, with a statistically significant decrease in the percentage of cells in the S phase, with no indication of apoptosis (sub-G0/G1 phase). Compounds 4 and 8 showed a statistically significant reduction in the expression of PKCα and an increase in PKCβ, which together with the demonstration of an antiproliferative role of PKCβ, as assessed by treating cells with a selective PKCβ activator, indicated that the observed antiproliferative effect is likely to be mediated through PKCβ induction.