Methotrexate and bone formation and turnover in rheumatoid arthritis

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Prevalence and associations of gout and hyperuricaemia: results from an Australian population-based study

Despite gout and hyperuricaemia being major comorbid health issues worldwide, there is a knowledge gap regarding their impact in the Australian community.To determine the prevalence and associations of self-reported medically diagnosed gout and hyperuricaemia in an Australian population-based cohort.The North West Adelaide Health Study is a longitudinal cohort study consisting of three stages of data collection. Each stage comprised a self-complete questionnaire, clinic assessment and computer-assisted telephone interview. In Stage 3 (2008-2010), participants were asked if a doctor had ever diagnosed them with gout. Additional data included demographics, comorbidities, laboratory data and Short Form 36 (SF-36). Participants were defined as having gout if they had self-reported medically diagnosed gout or were taking any gout-specific medication (allopurinol, colchicine, probenecid). Hyperuricaemia was defined as a serum uric acid (SUA) level >0.42 mmol/L in men and >0.34 mmol/L in women.The overall prevalence of gout was 5.2%. Males were significantly more likely to have gout than females (8.5 vs 2.1%, P < 0.001). The overall prevalence of hyperuricaemia was 16.6%, with being male again identified as a significant risk factor (17.8 vs 15.4%, P < 0.01). Both gout and hyperuricaemia were associated with male sex, body mass index and renal disease after multivariable adjustment. There was no significant difference reported in quality of life (mean SF-36) scores in participants with gout compared to unaffected individuals.The prevalence of gout and hyperuricaemia is high in the South Australian population. This study emphasises the need for optimal diagnosis and management of gout in Australia.K. Ting, T. K. Gill, H. Keen, G. R. Tucker, and C. L. Hil

Toward the effective surveillance of hypospadias.

Concern about apparent increases in the prevalence of hypospadias--a congenital male reproductive-tract abnormality--in the 1960s to 1980s and the possible connection to increasing exposures to endocrine-disrupting chemicals have underlined the importance of effective surveillance of hypospadias prevalence in the population. We report here the prevalence of hypospadias from 1980 to 1999 in 20 regions of Europe with EUROCAT (European Surveillance of Congenital Anomalies) population-based congenital anomaly registers, 14 of which implemented a guideline to exclude glanular hypospadias. We also report data from the England and Wales National Congenital Anomaly System (NCAS). Our results do not suggest a continuation of rising trends of hypospadias prevalence in Europe. However, a survey of the registers and a special validation study conducted for the years 1994-1996 in nine EUROCAT registers as well as NCAS identified a clear need for a change in the guidelines for registration of hypospadias. We recommend that all hypospadias be included in surveillance, but that information from surgeons be obtained to verify location of the meatus, and whether surgery was performed, in order to interpret trends. Investing resources in repeated special surveys may be more cost-effective than continuous population surveillance. We conclude that it is doubtful whether we have had the systems in place worldwide for the effective surveillance of hypospadias in relation to exposure to potential endocrine-disrupting chemicals

Translation and cross-cultural adaptation with preliminary validation of GCOS-24 for use in Spain

The aim in this study was to translate and cross-culturally adapt the Genetic Counseling Outcome Scale (GCOS-24) for use in Spain and to carry out a preliminary psychometric validation in a sample of Spanish patients. With oversight by an expert panel, forward and backward translations were conducted to create the draft Spanish GCOS-24. Fourteen patients were recruited from a clinical genetics service in Madrid, Spain to participate in cognitive interviews designed to explore readability and interpretability of the draft. Following qualitative analysis of interview transcripts, a final version of the Spanish GCOS-24 was agreed with the expert panel. No significant cross-cultural differences were identified. The Spanish GCOS-24 was then completed prior to and 2-4 weeks after genetic counseling by 59 patients attending the service, and data were analysed using analysis of variance. Preliminary psychometric validation of the Spanish GCOS-24 showed significantly higher GCOS-24 scores after genetic counseling (p<0.0001), with good internal consistency (α=0.84) and sensitivity to change over time, with a medium-to-large size effect (Cohen ́s d=0.70). This compares well with the original English language GCOS-24. Findings demonstrate that the Spanish GCOS-24 has potential for use in evaluating clinical genetics services in Spain, but would benefit from assessment of test-retest reliability as well as structural and construct validity

A randomised controlled trial of a psychoeducational intervention for women at increased risk of breast cancer

This study aimed to compare the impact of two versions of a psychoeducational written intervention on cancer worry and objective knowledge of breast cancer risk-related topics in women who had been living with an increased risk of familial breast cancer for several years. Participants were randomised to three conditions: scientific and psychosocial information pack (Group 1), scientific information pack only (Group 2) or standard care control (Group 3). They completed postal questionnaires at baseline (n¼163) and\ud 4 weeks (n¼151). As predicted, there was a significant decrease in cancer worry for Group 1, but not Group 2. Objective\ud knowledge significantly improved for both Group 1 and Group 2 as expected, but not Group 3. However, there was an unpredicted\ud decline in cancer worry for Group 3. This study supports the value of a scientific and psychosocial information pack in providing up-to-date information related to familial risk of breast cancer for long-term attendees of a familial breast cancer clinic. Further research is warranted to determine how the information pack could be incorporated into the existing clinical service, thus providing these\ud women with the type of ongoing psychosocial support that many familial breast cancer clinics are currently lacking

De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern