Background
Between 1988 and 2012, prevalence of antinuclear antibodies (ANA) increased in the U.S., especially in adolescents and non-Hispanic Whites. Female predominance of ANA suggests a role for ...hormonal factors, including xenobiotic exposures that may disrupt endocrine signaling. Benzophenone-3 (BP-3) is one such chemical with increasing exposure through sunscreen use. We investigated whether urinary BP-3 levels were related to ANA in adolescents and young adults.
Methods
In a sample of 1,785 individuals ages 12-39 years in the National Health and Nutrition Examination Survey (NHANES; 2003-4, 2011-12), we examined cross-sectional associations of ANA (N=192; 3+ or 4+ at the 1:80 dilution, measured by HEp-2 immunofluorescence) with urinary BP-3, and other phenols bisphenol-A, triclosan, and parabens. Adjusted prevalence odds ratios (POR) were calculated in season-stratified models winter (November-April) and summer (May-October), given differences in sunscreen use and BP-3 concentrations.
Results
BP-3 concentrations (detected in >98.5% of individuals) did not differ by ANA positivity in the summer (geometric mean, GM 30.6 ng/ml ANA-positive vs. 35.3 ANA-negative; GM ratio 1.15), but in winter were higher among ANA-positives (50.2 vs. 20.1 ANA-negative; GM ratio 2.50). ANA was associated with log
10
BP-3 in winter (POR 1.57; 95%CI 1.07-2.30 per unit increase) but not summer (0.94; 0.61, 1.44; interaction p=0.09). Triclosan, parabens, and bisphenol-A levels were unrelated to ANA overall or by season (ORs 0.64 to 1.33).
Conclusions
The association of urinary BP-3 with ANA in the winter may reflect different exposure patterns or unmeasured confounders. Findings warrant replication in prospective studies and including past and year-round exposures.
Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and ...C4B, in genetic risks and pathogenesis of JDM.
The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR.
Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2×10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients.
Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.
In environmental epidemiology, measurements of exposure biomarkers often fall below the assay's limit of detection. Existing methods for handling this problem, including deletion, substitution, ...parametric regression, and multiple imputation, can perform poorly if the proportion of "nondetects" is high or parametric models are mis-specified. We propose an approach that treats the measured analyte as the modeled outcome, implying a role reversal when the analyte is a putative cause of a health outcome. Following a scale reversal as well, our approach uses Cox regression to model the analyte, with confounder adjustment. The method makes full use of quantifiable analyte measures, while appropriately treating nondetects as censored. Under the proportional hazards assumption, the hazard ratio for a binary health outcome is interpretable as an adjusted odds ratio: the odds for the outcome at any particular analyte concentration divided by the odds given a lower concentration. Our approach is broadly applicable to cohort studies, case-control studies (frequency matched or not), and cross-sectional studies conducted to identify determinants of exposure. We illustrate the method with cross-sectional survey data to assess sex as a determinant of 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and with prospective cohort data to assess the association between 2,4,4'-trichlorobiphenyl exposure and psychomotor development.
Multiple sclerosis (MS) affects over 2.5 million individuals worldwide, yet much of the disease course is unknown. Hemispheric vulnerability in MS may elucidate part of this process but has not yet ...been studied. The current study assessed neuropsychological functioning as it relates to hemispheric vulnerability in MS.
Verbal IQ, as measured by verbal comprehension index (VCI), nonverbal IQ, as measured by perceptual reasoning index (PRI) and memory acquisition were compared in right-handed (dextral) and non-right-handed (non-dextral) persons with MS (PwMS).
Linear mixed-effects modeling indicated a significant main effect of handedness, F(1, 195.35) = 3.95, p = .048, for a composite measure of VCI, PRI, and memory acquisition, with better performance for dextral PwMS. In examining differences for specific neuropsychological measures, the largest effect size between dextral and non-dextral participants was seen in PRI (d = 0.643), F(1,341) = 12.163, p = .001. No significant interaction effect between handedness and IQ was found, F(3, 525.60) = 0.75, p = .523.
Dextral PwMS perform better than non-dextral PwMS when assessing neuropsychological performance for memory and IQ combined. Results are suggestive of increased vulnerability in the left brain to the pathological process of MS.
Retraction: Dinse G.E. et al., Increasing Prevalence of Antinuclear Antibodies in the United States, Arthritis & Rheumatology 2020, 72(6), 1026–1035 (
...https://onlinelibrary.wiley.com/doi/10.1002/art.41214
). The above article, published online on April 7, 2020 in Wiley Online Library (
wileyonlinelibrary.com
), has been retracted by agreement among the authors, the journal Editor‐in‐Chief Daniel H. Solomon, MD, PhD, the American College of Rheumatology, and Wiley Periodicals LLC. The retraction was agreed upon due to the many corrections required because the Centers for Disease Control and Prevention removed some of the publicly released National Health and Nutrition Examination Survey (NHANES) data used in the original study and then released revised data; the retraction was not the result of any author wrongdoing or error. The corrections do not change the conclusions of the paper but are necessary for accuracy. The text, figure, and tables have been updated to reflect the currently available NHANES data and the paper republished here:
https://doi.org/10.1002/art.42330
.
•US national level Inflammatory Bowel Disease (IBD) Public Health surveillance is a priority but has not been implemented.•Overall US IBD prevalence is a key surveillance benchmark but currently not ...known with certainty.•NHANES survey data show that 1% of US adults, (two million persons) may have diagnosed IBD.•This study indicates that a national scale US IBD secondary prevention program may be feasible.•This is important as many in the US may not currently be not well-connected to IBD care.
Determining the overall US prevalence of Inflammatory Bowel Disease (IBD) is essential to national level prevention programs and population risk assessment; however currently US IBD prevalence remains uncertain. We used US National Health and Nutrition Examination Survey (NHANES) data to estimate the population-based prevalence of a self-reported history of medically diagnosed IBD, comparing to prior reports. Lifetime IBD prevalence for adults aged 20 + years was estimated in the independently conducted NHANES II (1976–80) and NHANES 2009–10 surveys. Participants were considered to have IBD if they reported being told by a physician they had Crohn’s Disease (CD) or ulcerative colitis (UC). Clinically relevant NHANES data were analyzed to assess the self-reports. Survey design variables and sample weights were used to account for the complex survey design. The NHANES 2009–10 US IBD diagnosed prevalence was 1.2% (95% CI 0.8,1.6%), or an estimated 2.3 million persons. UC prevalence was 1.0% (95% CI 0.5,1.4%; 1.9 million persons) and CD prevalence was 0.3% (95% CI 0.1,0.4%; 578,000 persons). NHANES II UC prevalence was 1.0 (95% CI 0.8,1.2%), similar to 2009–10. UC prevalence was higher for ages ≥ 50 years in both surveys. NHANES 2009–10 data showed no UC sex differences, but women had higher UC prevalence in NHANES II. Remarkably, UC prevalence was similar between the two NHANES surveys fielded 30 years apart. The NHANES data are consistent with IBD prevalences reported in previous US nationally representative surveys, indicating that diagnosed IBD may affect approximately 1% of the US adult population.
The aim was to assess environmental factors associated with disease flare in juvenile and adult dermatomyositis (DM).
An online survey of DM patients from the USA and Canada examined smoking, sun ...exposure, infections, medications, vaccines, stressful life events and physical activity during the 6 months before flares, or in the past 6 months in patients without flares. Differences were evaluated by χ 2 and Fisher's exact tests, and significant univariable results were examined in multivariable logistic regression. Residential locations before flare were correlated with the National Weather Service UV index.
Of 210 participants (164 juvenile and 46 adult DM), 134 (63.8%) experienced a disease flare within 2 years of the survey. Subjects more often reported disease flare after sun exposure odds ratio (OR) = 2.0, P = 0.03, although use of photoprotective measures did not differ between those with and without flare. Urinary tract infections (OR = 16.4, P = 0.005) and gastroenteritis (OR = 3.2, P = 0.04) were more frequent in the preceding 6 months in those who flared. Subjects who flared recently used NSAIDS (OR = 3.0, P = 0.0003), blood pressure medicines (OR = 3.5, P = 0.049) or medication for depression or mood changes (OR = 12.9, P = 0.015). Moving to a new house (OR = 10.3, P = 0.053) was more common in those who flared. Only sun exposure (OR = 2.2) and NSAIDs (OR = 1.9) were significant factors in multivariable analysis.
Certain classes of environmental agents that have been associated with the initiation of DM, including sun exposure and medications, may also play a role in disease flares.
IgG isotypes can differentially bind to Fcγ receptors and complement, making the selection of which isotype to pursue for development of a particular therapeutic antibody important in determining the ...safety and efficacy of the drug. IgG2 and IgG4 isotypes have significantly lower binding affinity to Fcγ receptors. Recent evidence suggests that the IgG2 isotype is not completely devoid of effector function, whereas the IgG4 isotype can undergo in vivo Fab arm exchange leading to bispecific antibody and off-target effects. Here an attempt was made to engineer an IgG1-based scaffold lacking effector function but with stability equivalent to that of the parent IgG1. Care was taken to ensure that both stability and lack of effector function was achieved with a minimum number of mutations. Among the Asn297 mutants that result in lack of glycosylation and thus loss of effector function, we demonstrate that the N297G variant has better stability and developability compared with the N297Q or N297A variants. To further improve the stability of N297G, we introduced a novel engineered disulfide bond at a solvent inaccessible location in the CH2 domain. The resulting scaffold has stability greater than or equivalent to that of the parental IgG1 scaffold. Extensive biophysical analyses and pharmacokinetic (PK) studies in mouse, rat, and monkey further confirmed the developability of this unique scaffold, and suggest that it could be used for all Fc containing therapeutics (e.g. antibodies, bispecific antibodies, and Fc fusions) requiring lack of effector function or elimination of binding to Fcγ receptors.
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