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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

The optimal management of chronic ischemic mitral regurgitation (CIMR) remains controversial. Herein, the authors reviewed the past 10 years of their experience to compare the long-term results of mitral valve repair with prosthetic replacement.Between January 1993 and January 2003, 102 patients (mean age 67.8 years; range: 51-80 years) with a preoperative diagnosis of CIMR, underwent mitral valve repair (n = 61; 59.8%) or prosthetic replacement (n = 41; 40.2%), along with myocardial revascularization (2.5 +/- 1.0 distal anastomoses per patients, internal thoracic artery used in 78.5%). A Carpentier Classic ring was always used in the repair procedures. The two groups were homogeneous for preoperative characteristics and comorbidities.Total operative mortality was 7.8% (repair 8.2%; prosthesis 7.3%; p = NS). The five-year actuarial survival (operative mortality included) was 66.6 +/- 7.4% for repair and 73.4 +/- 8.7% for prosthesis (p = NS). Cox multivariate analysis showed as independent risk factor for late survival a preoperative left ventricular ejection fraction (LVEF)or = 30% (RR 3.91; 95% CI = 1.47-10.38) and a preoperative pulmonary artery pressure (PAP)or = 35 mumHg (RR 2.74; 95% CI = 1.07-7.02), while the type of mitral procedure was not significant. Patients with annular dilation as a mechanism of regurgitation were significant more likely to undergo repair rather than receive a prosthesis. Their preoperative LVEF and PAP were significantly worse than patients who had altered leaflet motion as a regurgitation mechanism.Prosthetic mitral replacement and valve repair offer very similar results for CIMR. When a perfect repair is not easily feasible, cardiac surgeons should not hesitate to perform mitral valve replacement, as it is an excellent alternative therapy, though long-term outcome is mainly dependent on preoperative condition.

To evaluate the distribution of the MHC class I chain related gene A transmembrane (MICA-TM) alleles in Italian patients with Behçet's disease (BD), and to investigate the relative contribution of MICA alleles and HLA-B51 in the susceptibility and specific clinical features of BD.A total of 69 consecutive Italian patients who satisfied the International Study Group criteria for BD were followed at rheumatology, ophthalmology, and neurology units during a 3 year period (1997-99). We selected 130 healthy subjects from the same geographic areas as controls. All patients and controls were examined for MICA microsatellite polymorphisms using polymerase chain reaction. Serological HLA class B51 typing was performed by a standard microlymphocytotoxicity technique.A strong association with HLA-B51 was observed in patients with BD (OR 5.7, 95% CI 2.8-11.3). The MICA-TM allele A6, in linkage disequilibrium with HLA-B51, was only slightly increased in patients compared to controls (60.9% vs 50.8%; p = NS). No significant associations between HLA-B51 or MICA-TM alleles and clinical subgroups, particularly central nervous system or eye involvement, were found.HLA-B51 is the most important susceptibility gene in BD. Association with MICA-A6, when it exists, is secondary to the strong linkage disequilibrium with HLA-B51.

To evaluate by molecular typing the possible associations of HLA-DRB1, DQA1, and DQB1 alleles with biopsy proven giant cell arteritis (GCA) in a Mediterranean country, and to examine possible relationships between these alleles and GCA clinical subsets.Thirty-nine patients from the Reggio Emilia area diagnosed over a 12 year period with biopsy proven GCA were studied. The clinical findings at diagnosis and during the followup were evaluated through interviews and by reviewing the medical records. HLA-DRB1, DQA1, and DQB1 alleles were determined in the 39 patients and in 250 healthy controls from the same geographic area by polymerase chain reaction amplification using sequence-specific primers.No associations were found between GCA and the shared epitope, the DRYF epitope, or the DRB1*04 or DQA1 alleles. The only significant association was with DQB1*0302 allele (p = 0.03, RR = 2.2). However, the association was weak and the significance was lost when corrected for the number of antigens tested. The frequencies of DQB1*0301 and 0302 in DR4 patients were not significantly different from those observed in DR4 positive controls. Significant associations were found between DRB1*04 allele and the presence of systemic signs and/or symptoms (p = 0.04, RR = 1.5) and between DRB1*07 allele and the male patients (p = 0.04, RR = 2.6).Our data showed no associations of biopsy proven GCA with HLA-DRB1*04 and HLA-DRB1*01 alleles, rheumatoid epitope, or DRYF epitope. Discrepancies with other studies may be related to the different ethnic backgrounds of the populations studied and to differences in the referral patterns of patients with GCA.