62 research outputs found
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
No full textMultiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis
Association of Variants of the Interleukin-23 Receptor Gene With Susceptibility to Pediatric Crohn’s Disease
No full textGenomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism
No full textCopy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population
Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions
No full textWhat are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis
Erratum: A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.
No full textpeer reviewedA correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper
An evaluation of a noninvasive cardiac output measurement using partial carbon dioxide rebreathing in children.
No full textCardiac output (CO) is an important hemodynamic measure that helps to guide the therapy of critically ill patients. Invasive CO assessment in infants and children is often avoided because of the inherent risks. A noninvasive CO monitor that uses partial rebreathing has been recently developed to determine CO via the Fick principle for carbon dioxide. There have been no clinical studies confirming its accuracy in pediatric patients. This is a prospective observational study of 37 childrenleak, we made multiple CO measurements using thermodilution and compared them with noninvasively determined CO measurements. Paired measurements were analyzed for bias, precision, and correlation via Bland-Altman plot and linear regression. Noninvasive measurements showed a linear correlation with thermodilution CO assessment with an r value of 0.83 (P \u3c 0.03). Bland-Altman analysis yielded a bias of -0.27 L/min and a precision +/-1.49 L/min. Cardiac index measurements demonstrated a decreased r value of 0.67 (P = 0.15) and a bias of -0.18 L . min(-1) . m(-2) and precision of +/-2.13 L . min(-1) . m(-2). Differences between partial rebreathing measurements and thermodilution measurements were largest in children with a body surface area of 0.6 m(2) body surface area and \u3e300 mL tidal volume
Integrative genomics identifies LMO1 as a neuroblastoma oncogene
No full textNeuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2×10 -16, odds ratio of risk allele = 1.34 (95% confidence interval 1.25g-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P<0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression. © 2011 Macmillan Publishers Limited. All rights reserved
An Evaluation of a Noninvasive Cardiac Output Measurement Using Partial Carbon Dioxide Rebreathing in Children
No full text- …
