Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Abstract The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.</jats:p

Three-dimensional reconstruction of coronary arteries and plaque morphology using CT angiography – comparison and registration with IVUS

BACKGROUND: The aim of this study is to present a new methodology for three-dimensional (3D) reconstruction of coronary arteries and plaque morphology using Computed Tomography Angiography (CTA). METHODS: The methodology is summarized in six stages: 1) pre-processing of the initial raw images, 2) rough estimation of the lumen and outer vessel wall borders and approximation of the vessel’s centerline, 3) manual adaptation of plaque parameters, 4) accurate extraction of the luminal centerline, 5) detection of the lumen - outer vessel wall borders and calcium plaque region, and 6) finally 3D surface construction. RESULTS: The methodology was compared to the estimations of a recently presented Intravascular Ultrasound (IVUS) plaque characterization method. The correlation coefficients for calcium volume, surface area, length and angle vessel were 0.79, 0.86, 0.95 and 0.88, respectively. Additionally, when comparing the inner and outer vessel wall volumes of the reconstructed arteries produced by IVUS and CTA the observed correlation was 0.87 and 0.83, respectively. CONCLUSIONS: The results indicated that the proposed methodology is fast and accurate and thus it is likely in the future to have applications in research and clinical arena

Biomechanical considerations in the pathogenesis of osteoarthritis of the knee

Osteoarthritis is the most common joint disease and a major cause of disability. The knee is the large joint most affected. While chronological age is the single most important risk factor of osteoarthritis, the pathogenesis of knee osteoarthritis in the young patient is predominantly related to an unfavorable biomechanical environment at the joint. This results in mechanical demand that exceeds the ability of a joint to repair and maintain itself, predisposing the articular cartilage to premature degeneration. This review examines the available basic science, preclinical and clinical evidence regarding several such unfavorable biomechanical conditions about the knee: malalignment, loss of meniscal tissue, cartilage defects and joint instability or laxity

Serotypes and antimicrobial susceptibilities of 1033 pneumococci isolated from children in Greece during 2001-2004

Pneumococci (n = 1033) isolated in the major paediatric hospitals of Athens during 2001-2004 from children with invasive infections (n = 186), non-invasive infections (n = 641) and healthy carriers (n = 206) were studied. The most prevalent serotypes were serotypes 14 (44.6%), 19F (43.5%) and 6B (22.8%) in invasive, non-invasive and carriage isolates, respectively. Among invasive isolates, the potential coverage by the seven-valent conjugate vaccine was 75.3%. Resistance rates to penicillin, amoxycillin, cefotaxime, erythromycin, co-trimoxazole, clindamycin, tetracycline and chloramphenicol were 44.6%, 2.7%, 1.2%, 43.6%, 43.5%, 12.4%, 34.7% and 5.9%, respectively. The M-phenotype accounted for 68.0% of the erythromycin-resistant isolates. All isolates were susceptible to ofloxacin