Polymorphims in the Interferon-y/Interleukin 26 Gene Region Contribute to Sex Bias in Susceptibility to Rheumatoid Arthritis

Objective:

To determine whether polymorphisms in the interferon-? (IFN?)/interleukin-26 (IL-26; formerly, AK155) gene cluster contribute to sex-based differential susceptibility to rheumatoid arthritis (RA).

Methods:

Four microsatellite markers, located in a 118-kb interval that contains both the IFN? and IL-26 genes on chromosome 12q15, were typed in 251 patients with RA and 198 unrelated healthy controls (all of whom lived in Northern Ireland) by means of polymerase chain reaction–based fragment analysis.

Results:

Marker D12S2510, which is located 3 kb 3' from the IL-26 gene, was significantly associated with RA in women (corrected P [Pcorr] = 0.008, 2 degrees of freedom [2 df]) but not in men (P = 0.99, 2 df). A 3-marker haplotype, IFNGCA*13;D12S2510*8;D12S2511*9, was inferred that showed significant underrepresentation in women with RA (odds ratio 0.50, 95% confidence interval 0.32–0.78; P = 0.002, Pcorr = 0.03) but not in men with RA.

Conclusion:

Our results demonstrate that common polymorphisms in the IFN?/IL-26 gene region may contribute to sex bias in susceptibility to RA, by distorting the propensity of female carriers versus male carriers to contract this disease. These results conform to our recent observations of a role for this gene cluster in sex-based differential susceptibility to another Th1-type inflammatory disease, multiple sclerosis.

Prediction and Verification of miRNA Expression in Human and Rat Retinas.

PURPOSE: MicroRNAs (miRNAs) play a global role in regulating gene expression and have important tissue-specific functions. Little is known about their role in the retina. The purpose of this study was to establish the retinal expression of those miRNAs predicted to target genes involved in vision. METHODS: miRNAs potentially targeting important "retinal" genes, as defined by expression pattern and implication in disease, were predicted using a published algorithm (TargetScan; Envisioneering Medical Technologies, St. Louis, MO). The presence of candidate miRNAs in human and rat retinal RNA was assessed by RT-PCR. cDNA levels for each miRNA were determined by quantitative PCR. The ability to discriminate between miRNAs varying by a single nucleotide was assessed. The activity of miR-124 and miR-29 against predicted target sites in Rdh10 and Impdh1 was tested by cotransfection of miRNA mimics and luciferase reporter plasmids. RESULTS: Sixty-seven miRNAs were predicted to target one or more of the 320 retinal genes listed herein. All 11 candidate miRNAs tested were expressed in the retina, including miR-7, miR-124, miR135a, and miR135b. Relative levels of individual miRNAs were similar between rats and humans. The Rdh10 3'UTR, which contains a predicted miR-124 target site, mediated the inhibition of luciferase activity by miR-124 mimics in cell culture. CONCLUSIONS: Many miRNAs likely to regulate genes important for retinal function are present in the retina. Conservation of miRNA retinal expression patterns from rats to humans supports evidence from other tissues that disruption of miRNAs is a likely cause of a range of visual abnormalities.

Unlinked vital events in census-based longitudinal studies can bias subsequent analysis

Objective: To examine the potential biases arising from the nonlinkage of census records and vital events in longitudinal studies.
Study Design and Setting: A total of 56,396 deaths of residents of Northern Ireland in the 4 years after the 2001 Census were linked to the 2001 Census records. The characteristics of matched and nonmatched death records were compared using multivariate logistic regression. Subject attributes were as recorded on the death certificate.
Results: In total, 3,392 (6.0%) deaths could not be linked to a census record. Linkage rates were lowest in young adults, males, the unmarried, people living in communal establishments, or living in areas that were more deprived or had recorded low census enumeration. For those aged less than 65 years at census, this linkage would exclude from analysis 20.2% of suicides and 19.7% of deaths by external causes.
Conclusion: The nonlinkage of census and death records is a combination of nonenumeration at census and deficient information about the deceased recorded at the time of death. Unmatched individuals may have been more disadvantaged or socially isolated, and analysis based on the linked data set may therefore show some bias and perhaps understate true social gradients.

Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (30 untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 30-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.

Cytotoxic alkaloids motuporamines A-C: Synthesis and structural verification

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Investigating the Interhemisphere 14C Offset in the 1st Millennium AD and Assessment of Laboratory Bias and Calibration Errors

Past measurements of the radiocarbon interhemispheric offset have been restricted to relatively young samples because of a lack of older dendrochronologically secure Southern Hemisphere tree-ring chronologies. The Southern Hemisphere calibration data set SHCal04 earlier than AD 950 utilizes a variable interhemispheric offset derived from measured 2nd millennium AD Southern Hemisphere/Northern Hemisphere sample pairs with the assumption of stable Holocene ocean/ atmosphere interactions. This study extends the range of measured interhemispheric offset values with 20 decadal New Zealand kauri and Irish oak sample pairs from 3 selected time intervals in the 1st millennium AD and is part of a larger program to obtain high-precision Southern Hemisphere 14C data continuously back to 200 BC. We found an average interhemispheric offset of 35 ± 6 yr, which although consistent with previously published 2nd millennium AD measurements, is lower than the offset of 55–58 yr utilized in SHCal04. We concur with McCormac et al. (2008) that the IntCal04 measurement for AD 775 may indeed be slightly too old but also suggest the McCormac results appear excessively young for the interval AD 755–785. In addition, we raise the issue of laboratory bias and calibration errors, and encourage all laboratories to check their consistency with appropriate calibration curves and invest more effort into improving the accuracy of those curves.