Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized, two-center placebo-controlled study.

INTRODUCTION: We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA). METHODS: A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15 mg or 7.5 mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP). RESULTS: All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures. CONCLUSIONS: Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00746512.

Differential effects of advanced glycation end-products on renal tubular cell inflammation.

AIM: The authors recently showed that advanced glycation end-products (AGE) in the form of glycated albumin (GA) upregulated renal tubular expression of interleukin (IL)-8 and soluble intercellular adhesion molecule-1 (sICAM-1), but not other important cytokines known to mediate diabetic nephropathy. This implies that other molecules such as the carbonyl intermediates of AGE or other modified protein lysine-albumin may participate in diabetic tubular injury. METHODS: Human proximal tubular epithelial cells (PTEC) were growth-arrested and exposed to methylglyoxal (MG), MG-bovine serum albumin (BSA)-AGE, carboxymethyllysine (CML)-BSA, AGE-BSA or BSA with or without prior addition of rosiglitazone that was previously shown to attenuate the pro-inflammatory effect of GA alone. RESULTS: MG-BSA-AGE and AGE-BSA upregulated tubular expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)-ß, and vascular endothelial growth factor (VEGF), whereas CML-BSA stimulated expression of IL-6, CCL-2, CTGF, TGF-ß and VEGF. These AGE compounds also activated nuclear factor (NF)-κB and their effects were attenuated by pre-incubation with anti-RAGE antibody. MG and BSA did not affect the expression of any of these molecules. Rosiglitazone did not affect the in vitro biological effects of MG, MG-BSA-AGE, AGE-BSA or CML-BSA on PTEC. CONCLUSION: AGE exhibit differential inflammatory and fibrotic effects on PTEC via RAGE activation and NF-κB signal transduction. Rosiglitazone had no effect on these responses. Further investigations on compounds that nullify the downstream effects of these AGE are warranted.

Regulation of CCN2/CTGF and related cytokines in cultured peritoneal cells under conditions simulating peritoneal dialysis.

BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) is a major treatment modality for end-stage renal failure. The peritoneal membrane exhibits pathological changes that correlate with the duration of dialysis. These changes are due to the exposure of the peritoneum to non-physiologic peritoneal dialysis solution (PDS) with a high glucose content, and containing potentially toxic substances including glucose degradation products (GDP) and advanced glycation end products (AGE). Connective tissue growth factor (CTGF/CCN2) is one of the determinants of progressive fibrosis and peritoneal membrane dysfunction in CAPD. In this study, we examined the CCN2 expression and its regulation in peritoneal resident cells using a cell culture model. METHODS: The expression of transforming growth factor-beta (TGF-beta), CCN2 and vascular endothelial growth factor (VEGF) in human peritoneal mesothelial cells (HPMC), human peritoneal fibroblasts (HPF) or endothelial cell line EA.hy926 (EC) cultured with various PDS and their components was examined by quantitative PCR (qPCR). The modulation of CCN2 synthesis under the crosstalk between HPMC and HPF or EC was examined using a conditioned medium transfer system in which HPMC was exposed to conditioned media obtained from HPF or EC incubated with PDS and their components. The differential effects of TGF-beta, CCN2 and VEGF in inducing the expression of transcriptional factors as well as interleukin-6 (IL-6), matrix metallopeptidase 9 (MMP-9) and collagen I were examined by electrophoretic mobility-shift assay (EMSA) and qPCR. RESULTS: PDS and their components differentially modulated the expression of TGF-beta, CCN2 and VEGF in HPMC, HPF and EC. The expression of CCN2 by HPMC was significantly increased after cultured with a HPF-conditioned medium and an EC-conditioned medium. Neutralizing anti-TGF-beta antibodies reduced but not completely abolished the CCN2 synthesis in HPMC cultured with the HPF- or EC-conditioned medium. CCN2, TGF-beta and VEGF activated distinct transcriptional factors in HPMC, which resulted in divergent biological responses in terms of IL-6, MMP-9 and collagen I mRNA expression. CONCLUSION: AGE and GDPs in PDS differentially regulate the synthesis of CCN2 by peritoneal resident cells. The CCN2 synthesis by HPMC can be further amplified by TGF-beta released from HPF or EC. The differential activation of different transcriptional factors and diverse response of HPMC towards CCN2, TGF-beta and VEGF suggest that these cytokines/growth factors have an overlapping and distinct role on HPMC.

The genetics of hair shaft disorders.

Many of the genes causing hair shaft defects have recently been elucidated. This continuing medical education article discusses the major types of hair shaft defects and associated syndromes and includes a review of histologic features, diagnostic modalities, and findings in the field of genetics, biochemistry, and molecular biology. Although genetic hair shaft abnormalities are uncommon in general dermatology practice, new information about genetic causes has allowed for a better understanding of the underlying pathophysiologies.

Hot tub folliculitis or hot hand-foot syndrome caused by Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a ubiquitous gram-negative rod that can cause a well-recognized, acquired skin infection from bacterial colonization of contaminated water called "hot tub folliculitis." We report an outbreak of pseudomonas skin infection associated with the use of a hot tub at a pool party in 33 children. In particular, 2 of the children were admitted to our hospital; both presented with high leukocyte counts, intermittent low grade fevers, and painful, erythematous nodules and papules on their palms and soles. One of the 2 children also presented with small erythematous pustular lesions on the face and trunk, which led to the diagnosis. Cultures from these pustules grew P aeruginosa. Thirty two other children at this pool/hot tub party developed similar lesions of varying severity 6 to 48 hours after the party. These findings were most consistent with the diagnosis of pseudomonas folliculitis/hot hand.