Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases.

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

Background Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth. Methods This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts. Results Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively. Conclusion Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

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PURPOSE The purpose of this study was to evaluate sensitivity, specificity, and positive and negative likelihood ratios of laryngeal height, lung function, and diagnostic questionnaires for screening and diagnosis of chronic obstructive pulmonary disease (COPD). METHODSWe undertook a cross-sectional study of 233 people aged between 40 and 75 years. Measured variables were age, sex, weight, height, body mass index, tobacco use, maximum laryngeal height, and spirometry, and we administered a COPD questionnaire and the Lung Function Questionnaire.RESULTS For laryngeal height, we found a positive likelihood ratio of 5.21, and for the Lung Function Questionnaire, we found a negative likelihood ratio of 0.10. Combining a maximum laryngeal height of ≤4 cm with Lung Function Questionnaire findings of ≤18 yielded a positive likelihood ratio of 29.06, and a negative likelihood ratio of 0.26. CONCLUSIONSThe intrinsic validity of the lung function questionnaire makes it useful for screening. Combining Lung Function Questionnaire results and laryngeal height can help confirm or dismiss COPD. INTRODUCTIONI n addition to having a major socioeconomic impact, 1 chronic obstructive pulmonary disease (COPD) is associated with high morbidity and high mortality. Various symptoms and exploratory signs of COPD have been studied, 2,3 but findings from a physical examination are rarely diagnostic. 4 Questionnaires, such as a COPD diagnostic questionnaire 5,6 (which addresses allergies and lower respiratory track symptoms, as well as cough, age, smoking pack-year, body mass index) and the Lung Function Questionnaire 7 (which addresses age, smoking history, frequency of productive cough, chest sounds, and breathing difficulty during physical activity), have been proposed to select individuals for spirometry because of their validity and simple application in family medicine practice. In 2000 laryngeal height began to be evaluated as a diagnostic sign 8 without much continuity. 9 Because sternal elevation produced by the thoracic hyperinsufflation found in this disease is thought to decrease laryngeal and tracheal heights, laryngeal height, tracheal height, and laryngeal descent are also thought to be diagnostic signs of COPD.Although the validity of examinations that facilitate screening and diagnosis has demonstrated their usefulness, research on exploratory tests is scarce. Our objective was to evaluate the sensitivity, specificity, and positive and negative likelihood ratios of maximum laryngeal height, the Lung Function Questionnaire, and the COPD diagnostic questionnaire for screening and diagnosis in a primary health care population. For this study, we used the maximum laryngeal height, measured from the suprasternal notch to the top of thyroid cartilage at the end of an expiration, as proposed by Strauss and colleagues. 8,9 Verónica Casado, MD METHODSA cross-sectional investigational study was conducted using a random sampling of a general population aged between 40 to 75 years in a basic health area of 26,108 inhabitant...

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.