Premature atherosclerosis is associated with hypovitaminosis d and angiotensin-converting enzyme inhibitor non-use in lupus patients

The ultimate goal is to identify and target modifiable risk factors that will reduce major cardiovascular events in African American lupus patients. As a first step toward achieving this goal, this study was designed to explore risk factor models of preclinical atherosclerosis in a predominantly African American group of patients with systemic lupus erythematosus (SLE) using variables historically associated with endothelial function in nonlupus populations. Fifty-one subjects with SLE but without a history of clinical cardiovascular events were enrolled. At entry, a Framingham risk factor history and medication list were recorded. Sera and plasma samples were analyzed for lipids, lupus activity markers and total 25-hydroxyvitamin D (25 OH)D) levels. Carotid ultrasound measurements were performed to determine total plaque area (TPA) in both carotids. Cases had TPA values above age-matched controls from a vascular prevention clinic population. Logistic regression and machine learning analyses were performed to create predictive models. 25(OH)D levels were significantly lower, and SLE disease duration was significantly higher in cases. 25(OH)D levels inversely correlated with age-adjusted TPA. Angiotensin-converting enzyme (ACE) inhibitor nonuse associated with case status. Logistic regression models containing ACE inhibitor use, 25(OH)D levels and low-density lipoprotein levels had a diagnostic accuracy of 84% for predicting accelerated atherosclerosis. Similar results were obtained with machine learning models, but hydroxychlo-roquine use associated with controls in these models. This is the first study to demonstrate an association between atherosclerotic burden and 25(OH)D insufficiency or ACE inhibitor nonuse in lupus patients. These findings provide strong rationale for the study of ACE inhibitors and vitamin D replenishment as preventive therapies in this high-risk population. © Copyright 2012 Southern Society for Clinical Investigation

The Effect of Travel Burden on Depression and Anxiety in African American Women Living with Systemic Lupus

The United States has a deficit of rheumatology specialists. This leads to an increased burden in accessing care for patients requiring specialized care. Given that most rheumatologists are located in urban centers at large hospitals, many lupus patients must travel long distances for routine appointments. The present work aims to determine whether travel burden is associated with increased levels of depression and anxiety among these patients. Data for this study were collected from baseline visits of patients participating in a lupus study at MUSC. A travel/economic burden survey was assessed as well as the 8-item Patient Health Questionnaire (PHQ-8) and the 7-item Generalized Anxiety Disorder (GAD-7) survey as measures of depression and anxiety, respectively. Linear regression models were used to assess the relationship between travel burden and depression and anxiety. Frequency of healthcare visits was significantly associated with increased depression (β = 1.3, p = 0.02). Significant relationships were identified between anxiety and requiring time off from work for healthcare appointments (β = 4, p = 0.02), and anxiety and perceived difficulty in traveling to primary care providers (β = 3.1, p = 0.04). Results from this study provide evidence that travel burden can have an effect on lupus patients’ anxiety and depression levels

The status of the world's land and marine mammals: diversity, threat, and knowledge

Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action

Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom's 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia

Inhibition of sphingosine kinase-2 in a murine model of lupus nephritis.

Sphingosine-1-phosphate (S1P), a potent bioactive lipid, is emerging as a central mediator in inflammation and immune responses. We have previously implicated S1P and its synthetic enzyme sphingosine kinase (SK) in inflammatory and autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis. Generation of S1P requires phosphorylation of sphingosine by SK, of which there are two isoforms. Numerous studies have implicated SK1 in immune cell trafficking, inflammation and autoimmune disorders. In this study, we set out to determine the role of SK and S1P in lupus nephritis (LN). To this end, we examined S1P and dihydro-S1P (dh-S1P) levels in serum and kidney tissues from a mouse model of LN. Interestingly dh-S1P was significantly elevated in serum and kidney tissue from LN mice, which is more readily phosphorylated by SK2. Therefore, we employed the use of the specific SK2 inhibitor, ABC294640 in our murine model of LN. Treatment with ABC294640 did not improve vascular or interstitial pathology associated with LN. However, mice treated with the SK2 inhibitor did demonstrate decreases in glomerular pathology and accumulation of B and T cells in the spleen these were not statistically different from lpr mice treated with vehicle. LN mice treated with ABC294640 did not have improved urine thromboxane levels or urine proteinuria measurements. Both S1P and dh-S1P levels in circulation were significantly reduced with ABC294640 treatment; however, dh-S1P was actually elevated in kidneys from LN mice treated with ABC294640. Together these data demonstrate a role for SKs in LN; however, they suggest that inhibition of SK1 or perhaps both SK isoforms would better prevent elevations in S1P and dh-S1P and potentially better protect against LN

Inducible nitric oxide synthase inhibitors reduce urinary markers of systemic oxidant stress in murine proliferative lupus nephritis

Proliferative lupus nephritis (PLN) is characterized by increased expression of inducible nitric oxide (NO) synthase (iNOS). Inhibition of iNOS with NG-monomethyl L-arginine (L-NMMA) abrogates renal disease in two models of murine PLN, but the mechanism of this effect is unknown. Reactive oxygen species have both direct and indirect pathogenic effects in inflammatory lesions and are therefore potentially an important therapeutic target in PLN. We hypothesized that inhibition of iNOS activity would reduce ROS production in murine PLN. A dose escalation of L-NMMA (0, 20, 100, and 500 mg/kg/day) was performed in New Zealand Black x New Zealand White F1 (NZB/W) mice with active renal disease. Twenty-four-hour urine nitrate + nitrite (NOX) was measured with a chemiluminescence NO analyzer. Twenty-four-hour urine 8-isoprostane F2alpha (8-iso-PGF2alpha) was measured by gas chromatography-negative ion chemical ionization mass spectrometry. MRL-MpJFASlpr (MRL/lpr) and NZB/W mice were divided into three groups and given either L-NMMA, L-N6-iminoethyl-lysine (L-NIL), or distilled water for 2 weeks. Urine NOX and 8-iso-PGF2alpha were determined after 2 weeks. L-NMMA reduced both urine NOX and 8-iso-PGF2alpha levels in a dose-dependent fashion in NZB/W and MRL/lpr mice. Urine NOX and 8-iso-PGF2alpha levels were highly correlated. Both specific (L-NIL) and nonspecific (L-NMMA) iNOS inhibition reduced urine NOX and 8-iso-PGF2alpha levels in both models of murine PLN. These findings suggest that iNOS activity is a major source of reactive oxidant stress in these models of murine PLN. Future studies will address the pathogenic role of reactive oxygen stress in PLN