Lymphoma risk in systemic lupus: effects of disease activity versus treatment.

OBJECTIVE: To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE). METHODS: We performed case-cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren's syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses. RESULTS: We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls. CONCLUSIONS: In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.

Cancer risk in systemic lupus: an updated international multi-centre cohort study.

OBJECTIVE: To update estimates of cancer risk in SLE relative to the general population. METHODS: A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS: Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin's lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION: These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.

Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions.

OBJECTIVE: Vitamin D may promote cardiovascular health in general population and in chronic kidney disease (CKD) through inhibition of the renin-angiotensin system and anti-inflammatory effects. Although proteinuria is a marker of kidney and cardiovascular disease, few studies have examined vitamin D levels, inflammation, and proteinuria simultaneously in CKD. We evaluated the relationship between calcidiol (25D), calcitriol (1,25D), inflammation, and albuminuria in Study of Early Evaluation of Kidney Disease, a multicenter CKD cohort. DESIGN: A cross-sectional study was carried out. PARTICIPANTS: A total of 1,847 participants were studied, of which 387 were randomly selected for inflammatory biomarker assessment. PREDICTORS AND OUTCOMES: The primary predictors were 25D and 1,25D. The outcome was albuminuria (urine albumin to creatinine ratio [UACR]: >30 mg/g). RESULTS: Albuminuric patients were more likely to have decreased 25D and 1,25D levels and higher interleukin-6 (IL-6) levels compared with normoalbuminuric patients. The lowest tertiles of 25D and 1,25D were associated with 2 to 3 times increased odds of albuminuria compared with the highest tertiles when adjusted for age, gender, race, systolic blood pressure, and diabetes (OR for 25D: 3.0; 95% CI: 1.3 to 7.0; OR for 1,25D: 2.6; 95% CI: 1.7 to 3.9). In analogous linear regression models, 25D and 1,25D were significantly associated with log UACR (P < .0001, for both). In participants for whom inflammatory markers were measured, demographics-adjusted linear regression models that included IL-6 described attenuation of the relationship between 25D, 1,25D, and UACR. CONCLUSIONS: Low 25D and 1,25D levels are independently associated with albuminuria. IL-6 may be an important intermediary between vitamin D deficiency and albuminuria, or vitamin D deficiency may contribute to inflammation and subsequent albuminuria.

Vitamin D deficiency and anemia in early chronic kidney disease.

Vitamin D has a number of pleiotropic effects in a variety of tissues, in addition to its well-known effects on mineral metabolism. To determine whether it has an effect on erythropoiesis, we studied the association of the components of the vitamin D axis with the prevalence and severity of anemia in chronic kidney disease. We measured the concentrations of 25-hydroxyvitamin D (25D), 1,25-dihydroxyvitamin D (1,25D), and hemoglobin in a cross-sectional study of 1661 subjects in SEEK, a multi-center cohort study of chronic kidney disease patients in the United States, of whom 41% met the criteria for anemia. The mean hemoglobin concentrations significantly decreased with decreasing tertiles of 25D and 1,25D. These linear trends remained significant after adjustment for age, gender, ethnicity, eGFR, diabetes, and parathyroid hormone. In similarly adjusted models, the lowest tertiles of 25D and 1,25D were independently associated with 2.8- and 2.0-fold increased prevalence of anemia compared with their respective highest tertiles. Patients with severe dual deficiency of 25D and 1,25D had a 5.4-fold prevalence of anemia compared with those replete in both. Our study shows that 25D and 1,25D deficiency are independently associated with decreased hemoglobin levels and anemia in chronic kidney disease. Whether this association is causal requires further study.

Depression Is Associated with Readmission for Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

RATIONALE: Hospitalization for acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and health care costs, and hospitals in the United States are now penalized by the Centers for Medicare and Medicaid Services for excessive readmissions. Identifying patients at risk of readmission is important, but modifiable risk factors have not been clearly established, and the potential contributing role of psychological disease has not been examined adequately. We hypothesized that depression and anxiety would increase the risk of both short- and long-term readmissions for acute exacerbation of COPD. OBJECTIVES: To characterize the associations between depression and anxiety and COPD readmission risk. METHODS: We examined the medical records for all patients with a primary diagnosis of acute exacerbation of COPD by International Classification of Diseases, Ninth Revision codes admitted to the University of Alabama at Birmingham Hospital between November 2010 and October 2012. Those who did not meet the standardized study criteria for acute exacerbation of COPD and those with other respiratory illnesses as the primary diagnosis were excluded. Comorbidities were recorded on the basis of physician documentation of the diagnosis and/or the use of medications in the electronic medical record. Multivariable regression analyses identified factors associated with readmission for acute exacerbation of COPD at 1 year and within 30 and 90 days. MEASUREMENTS AND MAIN RESULTS: Four hundred twenty-two patients were included, with 132 readmitted in 1 year. Mean age was 64.8 ± 11.7 years, and mean percent predicted FEV1 was 48.1 ± 18.7%. On univariate analysis, readmitted patients had lower percent predicted FEV1 (44.9 ± 17.3% vs. 50.2 ± 19.4%; P = 0.05) and a higher frequency of depression (47.7% vs. 23.4%; P < 0.001). On multivariable analysis, 1-year readmission was independently associated with depression (adjusted odds ratio [OR], 2.67; 95% confidence interval [CI], 1.59-4.47) and in-hospital tobacco cessation counseling (adjusted OR, 0.34; 95% CI, 0.18-0.66). Depression also predicted readmission at 30 days (adjusted OR, 3.83; 95% CI, 1.84-7.96) and 90 days (adjusted OR, 2.47; 95% CI, 1.34-4.55). CONCLUSIONS: Depression is an independent risk factor for both short- and long-term readmissions for acute exacerbation of COPD and may represent a modifiable risk factor. In-hospital tobacco cessation counseling was also associated with reduced 1-year readmission.

Reentrant synclinic phase in an electric-field-temperature-phase diagram for enantiomeric mixtures of an antiferroelectric liquid crystal.

The threshold electric field E(th) for a transition from the anticlinic to the synclinic phase of enantiomeric mixtures of the liquid crystal TFMHPOBC was measured as a function of temperature T and enantiomeric excess X. For small X the phase boundary curve on a temperature-electric-field phase diagram exhibits the phase sequence synclinic-anticlinic-reentrant synclinic on decreasing the temperature. At one point along the curve the quantity dT/dE--> infinity. For large values of enantiomeric excess a reentrant phase is not observed. The results are discussed using a simple phenomenological theory that accounts for layer-layer interactions, such that the electric-field-induced transition to the synclinic phase, although completed by solitary-wave propagation, is facilitated by a percolation mechanism.

Stability of connected cylindrical liquid bridges.

Two cylindrical liquid bridges, with a conduit to facilitate flow of liquid from one bridge to the other, were levitated against gravity in a magnetic field gradient. The stability limit of the bridges subjected to near zero total body force was measured as a function of their slenderness ratios, and found to be in good agreement with theoretical predictions.

End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.

OBJECTIVE: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. METHODS: APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. RESULTS: Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10(-9)), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10(-6)). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes (P = 0.01). CONCLUSION: APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.

(1-34) Parathyroid hormone infusion acutely lowers fibroblast growth factor 23 concentrations in adult volunteers.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Parathyroid hormone (PTH) infusion for 24 hours stimulated FGF23 secretion in healthy volunteers. The extent to which this was due to a direct stimulatory effect of PTH versus an indirect effect of increasing 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels was unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Changes in FGF23 in 26 adults undergoing 6-hour (1-34) PTH infusion were examined, focusing particularly on the effects of PTH on FGF23 in the early period of infusion before sustained increases in 1,25(OH)(2)D. RESULTS: FGF23 levels declined in parallel with serum phosphate during infusion (P<0.05 for both), with both analytes decreasing within the first hour and reaching their respective nadirs at 6 hours. These changes were observed despite no change in 1,25(OH)(2)D levels during the first hour and a significant increase in 1,25(OH)(2)D from baseline after 6 hours (P<0.001). There were no differences in these responses by race. However, modest racial differences in the phosphaturic response to (1-34) PTH were observed (P=0.04 for interaction), with a higher rate of increase in fractional phosphate excretion in blacks than in whites. CONCLUSIONS: During short-term (1-34) PTH infusion, FGF23 levels decreased in parallel with serum phosphate levels and despite significant increases in 1,25(OH)(2)D. When coupled with the results of prior longer-term infusion studies, these findings suggest that acute increases in PTH initially act to suppress FGF23 secretion, perhaps to mitigate urinary phosphate losses, before the stimulatory effect of 1,25(OH)(2)D on FGF23 eventually begins to predominate.

Twist elasticity and anchoring in a lamellar nematic phase.

Electro-optic measurements were performed on a lamellar nematic phase in which the mesogenic moieties lie in lamellae that are separated by partially perfluorinated side groups. The twist elastic constant K22, viscosity gamma(1), and the quadratic and quartic anchoring strength coefficients are reported. K22 and gamma(1) are found to be considerably smaller than that of typical three-dimensional nematics. The small K22 is due to the greatly weakened interactions between the spatially separated lamellae.