Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis

Summary Interleukin-6 (IL-6) was detected at low levels in plasma [0.014±0.006 ng/ml (mean ± SEM] and in high amounts in synovial fluid [SF; 2.6±2.2 ng/ml (mean ± SEM)] of patients with rheumatoid arthritis. No correlation of IL-6 levels in plasma or SF with the ESR (n=15) or with histological parameters of acute local synovitis (n=10) was observed. In contrast, SF IL-6 was positively correlated with histological characteristics of chronic synovitis (n=10; P0.01) and elevated plasma IgG concentrations (n=15; P0.05). In vitro concentrations of IL-6 comparable to those detected in SF increased the production of both IgG and IgM by synovial membrane mononuclear cells. The present results contribute to the view that high local IL-6 concentrations in SF promote chronic synovitis in RA.     

Immunogenicity of attenuated vesicular stomatitis virus vectors expressing HIV type 1 Env and SIV Gag proteins: comparison of intranasal and intramuscular vaccination routes

An experimental AIDS vaccine based on attenuated, recombinant vesicular stomatitis virus (rVSV), when administered by a combination of parenteral and mucosal routes, has proven effective at preventing AIDS in a rhesus macaque model (Rose NF, et al.: Cell 2001;106:539-549). In an effort to determine the optimal route of vaccine administration we evaluated the ability of rVSV-based vaccine vectors expressing HIV-1 Env and SIV Gag proteins, when given either intramuscularly (i.m.) or intranasally (i.n.), to elicit antigen-specific cellular and humoral immune responses, and to protect from a subsequent vaginal challenge with simian-human immunodeficiency virus (SHIV89.6P). Our results demonstrate that macaques vaccinated by the i.n. route developed significantly higher antigen-specific cellular immune responses as determined by MHC class I tetramer staining, IFN-gamma ELISPOT, and cytotoxic T cell assays. However, systemic and mucosal humoral immune responses did not vary significantly with the route of vaccine administration. Given the importance of cell-mediated immune responses in slowing AIDS progression, intranasal delivery of a VSV-based AIDS vaccine may be an optimal as well as practical route for vaccination and should be considered in design of clinical trials.     

Renal receptors for calcitonin: coordinate occurrence with calcitonin-activated adenylate cyclase.

High affinity binding of 125I-labeled salmon calcitonin ([125I]SCT) and calcitonin-activated adenylate cyclase were detectable in renal plasma membranes from the rat. Addition of 5'-guanylyl-imidodiphosphate lowered the threshold for enzyme activation by peptide hormones. Renal plasma membranes from man, dog and cow contained little or no calcitonin-sensitive adenylate cyclase and showed no high affinity binding of [125I]SCT. High affinity binding sites were distributed during membrane fractionation in fractions where the specific activity of hormone-sensitive adenylate cyclase was greatest. Calcitonin binding and activation of the adenylate cyclase enzyme occurred at similar hormone concentrations. The relative potencies of calcitonin analogues were similar whether measured by competition for high affinity binding sites or by effect on adenylate cyclase. Low concentrations of Lubrol-PX, a nonionic detergent, did not affect catalytic function of the enzyme determined in the presence of sodium fluoride but caused parallel loss of high affinity [125I]SCT binding and hormonal sensitivity of the enzyme. This observation provided further evidence that interaction of calcitonin with specific receptors (identified with [125I]SCT binding) is essential for calcitonin activation of adenylate cyclase, but showed that catalytic activity of enzyme does not require functioning hormone receptors.     

Three-dimensional echocardiographic analysis of valve anatomy as a determinant of mitral regurgitation after surgery for atrioventricular septal defects

Mitral regurgitation (MR) is a significant complication after atrioventricular septal defect (AVSD) surgery. The relation of the valve leaflet morphology and the MR mechanism remains a conundrum. Two-dimensional echocardiography depicts leaflet edges, whereas volume-rendered 3-dimensional echocardiography provides direct visualization of the surface areas of the mitral valve leaflets. This study examines the relation of mitral valve anatomy as determined by 3-dimensional echocardiography with MR origins in patients after AVSD repair. Twenty-seven patients with AVSD surgery and Doppler color MR were prospectively enrolled (median age was 5 years and 16 patients had Down syndrome). Doppler color flow imaging of the MR jet and 3-dimensional echocardiography of the mitral valve were performed with a probe in the transthoracic or transesophageal position. Enface 3-dimensional views of the mitral valve from the left atrium were reconstructed. Analysis of the 3-dimensional data was possible in 21 of the 27 patients. Mean area ratios of the 3 mitral leaflets were calculated (superior 40 +/- 7%, inferior 35 +/- 5%, mural 25 +/- 6%). Both intra and interobserver variability on the area measurements were <5%. In 12 patients (group 1) the jet appeared to emanate medially from the region of coaptation of the superior and inferior components of the anterior leaflet. In 9 patients (group 2) the jet emanated more laterally from the region toward the mural leaflet. The area ratios of the inferior leaflet were 32 +/- 4% in group 1 and 38 +/- 6% in group 2 (p = 0.02). The area ratios of the mural leaflet were 28 +/- 5% in group 1 and 21 +/- 5% in group 2 (p = 0.007). The superior leaflet area ratio was not different in groups 1 and 2, 40 +/- 9% and 41 +/- 6%, respectively. Three-dimensional echocardiography provides new insight into the anatomic determinants of MR following AVSD surgery.     

Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study.

OBJECTIVES: The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels. BACKGROUND: Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)-gamma agonists lower inflammatory markers and reduce CVD in type 2 diabetes. METHODS: In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman's rank test. RESULTS: At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 +/- 2.42 mg/l to 2.48 +/- 1.77 mg/l and 3.26 +/- 2.02 mg/l to 2.81 +/- 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 +/- 1.97 mg/l to 2.06 +/- 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group. CONCLUSIONS: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.     

Long term survival in primary pulmonary hypertension

The mean survival of patients with severe primary pulmonary hypertension (PPH) is < 3 years without appropriate treatment. There are no long term reports on the spontaneous course of mild PPH over a longer period. Stable long term follow up is described of a 39 year old patient with PPH without treatment over a 30 year period. PPH had been diagnosed 30 years previously after right heart catheterisation (mean pulmonary artery pressure 35 mm Hg) and 30 years later, repeated measurements showed nearly unchanged haemodynamic parameters. Further examinations confirmed the diagnosis of PPH. It is suggested that PPH with modestly limited physical activity (New York Heart Association functional class II) does not always seem to coincide with progression of the disease and, therefore, it may be feasible to withhold treatment while closely monitoring these patients.     

The Impact of Intensive Outreach on HIV Prevention Activities of Homeless, Runaway, and Street Youth in San Francisco: The AIDS Evaluation of Street Outreach Project (AESOP)

We evaluated the impact of an HIV prevention intervention combining street outreach, storefront prevention services, and subculture-specific activities for homeless, runaway, and street youth. Using systematic, street-based sampling techniques, we conducted 1,146 interviews in cross-sectional surveys at intervention and comparison sites prior to and during intervention implementation. Youth in both sites reported high rates of risky sexual and injection drug use behaviors. In logistic regression the intervention did not impact HIV risk behaviors, but was independently associated with increased outreach worker (OW) contact and referrals for services. Higher levels of OW contact were associated with following through with HIV-related referrals and using new syringes. Youth-oriented needle exchange increased use of new syringes. While our study did not demonstrate an intervention effect on HIV risk behaviors, intensive, subculture-specific outreach, including needle exchange, may improve the lives of street youth.     

Bedside filtration of blood products in the prevention of HLA alloimmunization--a prospective randomized study. Alloimmunisation Study Group

To test the efficacy of poststorage bedside leucodepletion of blood products in the prevention of primary HLA alloimmunization and its clinical sequelae, 172 patients with hematologic malignancy requiring intensive red blood cell and platelet support were randomized to receive either standard or filtered red blood cells and platelets. Quality control of bedside filtration was explored by sequential sampling downstream of the filter, but this did not predict the total number of leucocytes transfused. After exclusions, 123 evaluable patients were assessed every two weeks until the end of therapy. HLA antibodies developed in 21 of 56 (37.5%) nonfilter (NF) and 15 of 67 (22%) filter (F) patients (risk ratio estimate, 0.60 [95% confidence interval, 0.34 to 1.05]; P = .07). Patients with acute myeloid leukemia (AML; n = 53) had higher alloimmunization rates in both arms of the study, with a greater effect of filtration (62.5% NF and 31.0% F; P = .025). Bedside filtration did not affect the overall incidence of febrile transfusion reactions (FTRs; 37% NF and 34% F; P = .71) or of platelet refractoriness assessed in 50 patients (30% NF and 26% F), despite an association between broad HLA reactivity and both FTRs and refractoriness. However, FTRs were also seen in 28 patients without HLA antibodies. Five alloimmunized refractory patients (2 F and 3 NF) required HLA-selected platelets. This report, the first prospective study of bedside filtration, has failed to show clear clinical benefit. Methodological limitations may account in part for this failure, notably the difficulties in accurately assessing the number of leucocytes transfused.