Frontiers of SLE: review of the 5th International Congress of Systemic Lupus Erythematosus, Cancun, Mexico, April 20-25, 1998.

Objective: To review the recent advances in clinical and experimental research in systemic lupus erythematosus (SLE). Methods: Review of the 5th International Congress of SLE that took place in Cancun, Mexico, on April 20-25, 1998. Results: The main topics presented at the conference are summarized. These include new findings about the genetics of SLE due to fine mapping of the patients' genes and lupus mouse models, the nucleosome as a major autoantigen in SLE, serving as an immunogen for pathogenic T helper and B cells and contributing to the development of lupus nephritis, abnormalities of apoptosis as a cause of SLE, and apoptotic mechanisms as a cause of autoimmunization. Other topics included the pathophysiologic role of anti-endothelial cell antibodies in lupus with central nervous system involvement, vasculitis, the thrombotic diathesis associated with the antiphospholipid syndrome, induction of endothelial cell apoptosis and its regulation by the idiotypic network, the penetration of antinuclear antibodies to the cytoplasm and nucleus and the subsequent interaction with cellular organelles, and new aspects in the antiphospholipid syndrome, including animal models of the disease and the importance of antibodies to beta-2-glycoprotein-I and prothrombin. Advances in the clinical aspects of SLE included clinical manifestations, diagnosis, pregnancy and neonatal SLE, infections, hormones, and treatment. Additionally, four "Lectures of A Lifetime," entitled (1) What causes lupus? (2) From natural autoimmunity to autoimmune disease; (3) The idiotypic network and SLE; and (4) Late-stage morbidity and mortality in SLE-the role of accelerated atherosclerosis were presented. Conclusions: Recent advances provide new insights into the pathogenesis of SLE, as well as hope for novel therapeutic modalities and diagnostic measures. These offer the possibility of improving life quality and decreasing mortality from the disease and its complications. Semin Arthritis Rheum 29:112-130. Copyright (C) 1999 by W.B. Saunders Company

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as “subtype-C-infected patients”) versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC(50)) change in susceptibility to nelfinavir only. Other mutations increased IC(50) correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ± 22% to 22% ± 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients

Features associated with epilepsy in the antiphospholipid syndrome

OBJECTIVE: To assess the frequency of epilepsy in primary and secondary antiphospholipid syndrome (APS); to analyze the clinical and laboratory features characterizing those with epilepsy in a cohort of 538 patients with APS; and to find associated features that would suggest risk factors for epilepsy in APS. METHODS: We analyzed the clinical features of patients with APS who had epilepsy and compared them to the clinical features of non-epileptic APS patients. RESULTS: Of 538 APS patients, 46 (8.6%) had epilepsy. Epilepsy was more prevalent among APS secondary to systemic lupus erythematosus (SLE) compared to primary APS (13.7% vs 6%; p < 0.05). The patients with epilepsy had a higher prevalence of central nervous system (CNS) manifestations including focal ischemic events (strokes or transient ischemic events, 54.3% vs 24.6%; p < 0.0001) and amaurosis fugax (15.2% vs 4.9%; p < 0.05). APS patients with epilepsy had a higher frequency of valvular pathology (30.4% vs 14.6%; p < 0.01), thrombocytopenia (43.5% vs 25%; p < 0.05), and livedo reticularis (26.1% vs 11.5%; p < 0.01). The multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio (OR) of 4.05 (95% confidence interval, CI: 2.05-8), followed by SLE (OR 1.4, 95% CI 1.2-4.7), and valvular vegetations (OR 2.87, 95% CI 1-8.27). CONCLUSION: Epilepsy is common in APS and most of the risk seems to be linked to vascular disease as manifested by extensive CNS involvement, valvulopathy, and livedo reticularis and to the presence of SLE. These factors, however, explain only part of the increased occurrence of epilepsy in APS and other causes such as direct immune interaction in the brain should be investigated

A Population-Structured HIV Epidemic in Israel: Roles of Risk and Ethnicity

<div><p>Background</p><p>HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning.</p><p>Methods</p><p>We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998–2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods.</p><p>Results</p><p>Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes.</p><p>Conclusions</p><p>Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.</p></div

BEAST of subtype A.

<p>Analysis of sequences from patients infected with subtype A (Including 61 reference sequences). Notations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135061#pone.0135061.g002" target="_blank">Fig 2</a>.</p

BEAST of subtype B.

<p>Analysis of sequences from patients infected with subtype B (Including 30 reference sequences). Notations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135061#pone.0135061.g002" target="_blank">Fig 2</a>.</p