Search

Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.

Background: We studied long-term right ventricular (RV) pacing threshold (RVPT) behavior in patients consecutively implanted with pacemakers capable of automatic output reprogramming tracked by automatic RV threshold measurement (automatic verification of capture [AVC]). Methods: All the patients had state-of-the art steroid-eluting bipolar pacing leads and were RV-paced by an AVC algorithm from the three American manufacturers. Follow-up occurred twice in the first year after implantation, then yearly until approaching elective replacement indicator. Results: Three hundred and twenty-one patients aged 73 ± 12 years were observed for 49 ± 26 months on average. At implantation, RVPT was 0.54 ± 0.2 V at 0.4 ms at an average 774 ± 217 Ω impedance. Forty-one of the 321 patients (12.8%) had a permanent RVPT increase above 1.5 V at 0.4 ms: RVPT was between 1.6 and 2.5 V in 29 of 321 (9%) patients, whereas it was between 2.6 and 3.5 V in seven of 321 (2.2%) patients, and >3.5 V in five of 321 (1.5%) patients. No exit block occurred because of automatic RV output adjustment by AVC algorithms. No predictor of RVPT increase was found at multivariable analysis. The maximum RVPT increase occurred within 12 months from implantation in 19 of 321 (5.9%) patients, between the first and the second year in 12 of 321 (3.7%), between the second and the sixth year in eight of 321 (2.5%), and after the sixth year in two of 321 (0.6%). Conclusion: Despite technologic improvement in lead manufacturing, long-term increase of the RVPT occurs in about 13% of patients, possibly representing a serious safety issue in 3.7% when 2.5 V at 0.4 ms is exceeded. AVC algorithms can improve patients' safety by automatic tailoring of the pacing output to threshold fluctuations, while maximizing device longevity

Introduction. Little is known about alterations of cyclin dependent kinase inhibitors p15INK4B, p16INK4A and p14ARF due to single nucleotide polymorphisms (SNPs) located within the CDKN2A/B genes and/or neighbouring loci. In order to investigate the potential involvement of such common DNA sequence variants in leukemia susceptibility, an association study was performed. Methods. 23 SNPs spanning the MTAP, CDKN2A/Band CDKN2BAS loci, as well as relative intergenic regions were genotyped in a case-control cohort made up of 149 leukemia patients, including Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples, and 183 healthy controls. 6 SNPs were selected on the basis of their previous association with several diseases, such as coronary artery disease (rs2891168, rs518394, rs564398, rs10757278), type 2 diabetes mellitus (rs564398), frailty (rs2811712). The remaining 17 SNPs were selected to deepen the SNPs coverage for the examined region. Genotyping was performed using iPLEX Gold technology and MassARRAY high-throughput DNA analysis with Matrix-assisted laser desorption/ionization timeof-flight (MALDI-TOF) mass spectrometry (Sequenom, Inc., San Diego, CA). Results. A total of 17 SNPs, spanning the 9p genomic interval that encompasses the MTAP, CDKN2A/B and CDKN2BAS loci, were successfully genotyped and used for investigating their potential associations with the leukemia phenotypes. Five SNPs (rs1012713, rs10965179, rs34011899, rs3731232, rs3218010) with MAF 20% missing call rates, were instead excluded from the association analysis and potential population stratification affecting the control sample was ruled out as its genotypes distribution satisfies the Hardy-Weinberg equilibrium criterion. Among the 17 SNPs, rs564398, mapping to the CDKN2BAS locus that encodes for ANRIL antisense non-coding RNA, showed a statistically significant correlation with the ALL phenotype, with a risk pattern that was compatible with an overdominant model of disease susceptibility and a OR of 2 (95% CI, 1.20 to 3.33; P=7.1¥103). Conclusions. Since a co-ordinated regulation of ANRIL and p14/ARF, p16/CDKN2A, p15/CDKN2B transcription has been already observed in both physiologic and pathologic conditions, we hypothesized that rs564398 association reflects a condition of high linkage disequilibrium between such polymorphism and a causative variant that is able to alter CDKN2A/B expression profiles by changing ANRIL dosage, thus leading to abnormal proliferative boosts and consequent increased ALL susceptibility. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione - Università 2007-2009.

AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P

La terapia di resincronizzazione è una valida opzione nel trattamento dello scompenso cardiaco. Esiste ancora però una percentuale elevata di pazienti che non risponde in termini di rimodellamento ventricolare inverso. Con lo scopo di ridurre il numero di non responder, migliorando la sincronia di contrazione atrio-ventricolare e inter/intraventricolare, negli ultimi anni ha preso piede l’ottimizzazione della programmazione degli intervalli atrio-ventricolare e interventricolare. Facendo una revisione della letteratura si può notare che i contributi sperimentali sull’ottimizzazione dei parametri AV e VV sono diversi, utilizzano svariate tecniche di ottimizzazione e i trial multicentrici condotti fino a oggi portano a conclusioni controverse soprattutto per quel che riguarda l’intervallo VV. Nella seconda parte del lavoro abbiamo confrontato tre metodiche ecocardiografiche per la valutazione dell’intervallo VV ottimale (VTI, Strain circonferenziale e velocità). In primis, abbiamo dimostrato che l’ottimizzazione dell’intervallo VV ha determinato un maggior beneficio dopo impianto di CRT, rispetto alla programmazione standard in termini di rimodellamento ventricolare inverso. Inoltre, c’è una buona correlazione tra le tre metodiche utilizzate per ottimizzare l’intervallo VV; metodiche che non solo valutano la funzione sistolica del ventricolo sinistro ma anche la dissincronia.

Dissection of the interventricular septum (IVS) is a rare condition, which can uncommonly complicate an acute myocardial infarction (AMI). We describe a case of unruptured IVS dissection observed 16 days after 2 close episodes of AMI. The diagnosis was made by transthoracic echocardiography. An echo-free space within the thickness of IVS, extended from the apex to the mid-portion, for a total length of about 30 mm was evident. The careful examination of the left ventricle did not reveal any discontinuity of the myocardial wall. The stable clinical condition, the absence of flow within the dissection, the demonstration of its favourable evolution during the hospitalisation and the characteristics of the underlying coronary disease (left anterior descending artery occlusion without myocardial viability) led to the decision of avoiding surgery. The predischarge contrast echocardiographic examination (Levovist) showed clearly the border of the infarcted zone and demonstrated an area reduction and echogenicity increase of the neocavitation, with partially organised thrombi. The patient recovered uneventfully and was discharged on medical therapy with a clinical and echocardiographic follow-up program. We believe that for IVS hemorrhagic dissection a nonsurgical option can be proposed; surgery should only be considered for myocardial revascularization when indicated. A close echocardiographic follow-up is mandatory.