Thrombopoietin production in wild-type and interleukin-6 knockout mice with acute inflammation.

Clinical and laboratory studies indicate that thrombopoietin (TPO) gene expression increases during inflammation. To clarify the role of interleukin 6 (IL-6) in this process, blood cell counts, plasma TPO concentrations, and hepatic and renal TPO mRNA levels were investigated in wild-type and IL-6 knockout mice, with sterile abscesses produced by subcutaneous injection of turpentine oil. Treatment did not cause a change in blood cell counts during the 72 h period of observation. The numbers of thrombocytes and erythrocytes were slightly lower in the IL-6 knockout mice than in the wild-type littermates under all conditions. Plasma IL-6 and TPO concentrations increased on turpentine injection only in the wild-type mice. In addition, turpentine treatment of these caused an increase in hepatic TPO mRNA levels as assessed by competitive polymerase chain reaction (RT-PCR) and real-time PCR, whereas renal TPO mRNA levels were unaltered. TPO mRNA levels did not increase in the livers of IL-6 knockout mice on turpentine treatment. These results support the concept that TPO behaves like an acute-phase protein in that its synthesis is induced by IL-6 in the liver.     

A novel perfusion system for the endothelialisation of PTFE grafts under defined flow.

OBJECTIVES: to develop a perfusion system for culturing human endothelial cells on small-diameter PTFE grafts under defined pulsatile shear stress. METHODS: to benefit from a stronger adhesion of endothelial cells to the substrate, we developed a perfusion system which enables culture of endothelial cells on PTFE grafts to confluence under a wide range of shear stress. We also developed an in situ staining method for the determination of the endothelialisation stage by upper light microscopy. RESULTS: the application of pulsatile flow with high shear stress (6.6 dyn/cm2, 5 min) to a graft endothelialised under perfusion did not lead to a disruption of the confluent cell layer. In contrast, a shear stress of 3 dyn/cm2 applied for 5 min was sufficient to wash more than 50% of endothelial cells off the PTFE graft when cultured to confluence under static conditions. CONCLUSIONS: this technique induces a stronger cell adherence of endothelial cells to a PTFE graft in comparison with grafts endothelialised under static conditions. Endothelialised vascular grafts can be pre-conditioned to defined shear stress values.     

Beware of the heart: the multiple picture of cardiac involvement in myositis.

A 42-yr-old woman with dermatomyositis had two myocardial infarctions, episodes of acute chest pain and an acute lung oedema. These events were initially misinterpreted as atherosclerotic ischaemic heart disease accompanying the autoimmune disease. The lack of improvement of cardiac symptoms with anti-ischaemic and immunosuppressive drugs indicated other mechanisms. Intracoronary drug provocation as well as myocardial biopsy revealed a coincidence of small-vessel disease and vasospastic angina as a cause for the severe cardiac symptoms. After initiating therapy with high doses of calcium channel blockers, marked improvement of cardiac symptoms occurred. In the pathogenesis of cardiac involvement in dermatomyositis, two different mechanisms should be considered: inflammatory processes due to dermatomyositis and vasoconstriction caused by an impaired regulation of vascular tone, such as abnormal vessel reactivity or disturbed neuropeptide release. Signs of this generalized vasopathy are Raynaud's phenomenon, Prinzmetal's angina and small-vessel disease, which can coincide. In patients with severe cardiac symptoms and autoimmune diseases, Prinzmetal's angina should be excluded by intracoronary drug provocation using acetylcholine.     

Long‐term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: An open,observational, extension study of a three‐month,randomized, placebo‐controlled trial

Objective

Treatment of ankylosing spondylitis (AS) with infliximab, an anti–tumor necrosis factor α monoclonal antibody, was shown to be efficacious in patients with active disease during a 3‐month treatment period. The purpose of this study was to evaluate the efficacy and safety of infliximab treatment of AS for a 1‐year period.

Methods

This study was an open, observational, extension study of a 3‐month, randomized, placebo‐controlled trial. All patients who had tolerated infliximab (infliximab/infliximab group) or placebo (placebo/infliximab 12‐week crossover group) therapy for 3 months entered the open extension trial (n = 65). Infliximab was administered at a dosage of 5 mg/kg every 6 weeks after the induction phase (weeks 0, 2, and 6). The primary end point was a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

Results

At week 54, a total of 54 of the 69 patients (78%) continued to take infliximab. The intent‐to‐treat primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% confidence interval 31–63) and 51% of the patients in the placebo/infliximab group (95% confidence interval 36–67) achieved 50% improvement in BASDAI scores. In the analysis of those who completed the study, the mean BASDAI scores improved between weeks 0 and 54 in both treatment groups: from 6.6 to 2.4 in the infliximab/infliximab group and from 6.3 to 2.6 in the placebo/infliximab group. The dosage of nonsteroidal antiinflammatory drugs was reduced in ∼70% of the patients. There were significant improvements in measures of functioning, metrologic parameters, and quality of life. Between weeks 12 and 54, a total of 4 patients had serious adverse events that were possibly related to infliximab and resulted in their discontinuing the study.

Conclusion

Infliximab therapy in AS patients resulted in a rapid and significant improvement in BASDAI scores (>50% improvement) and a durable response for 1 year. The safety profile of infliximab in AS was comparable to that observed in the postmarketing experience for the approved indications.

     

Positiver Rheumafaktor oder positive ANA als Zufallsbefund

Rheumatoid factor and antinuclear antibodies are detectable in many different conditions and are ordered by various specialities. The interpretation of results, however, is quite complex. The objective of this article is to help apply these tests correctly and enable an accurate interpretation of the test results. Furthermore, we describe the steps in the differential diagnostics for selecting those patients who need to be referred to a rheumatologist.     

Human anti-mouse antibody response induced by anti-CD4 monoclonal antibody therapy in patients with rheumatoid arthritis

The development of human anti-mouse monoclonal antibodies (HAMAs) was investigated in 10 patients with rheumatoid arthritis (RA) who had undergone an experimental therapeutic trial with an anti-CD4 monoclonal antibody. In this patient group, the antibody 16H5 of the IgG1 isotype had been administered in a median total dosage of 140 mg per treatment cycle. Four patients took part in a second treatment regimen 6-8 weeks later. After the first treatment cycle, detectable HAMAs developed in 5 out of 10 patients. In 4 individuals undergoing a second course of therapy, increases of HAMAs were evident only in the 3 patients with previous HAMA responses. HAMAs were primarily of the IgG isotype, while the presence of rheumatoid factors usually interfered with the detectability of IgM HAMAs. However, using isolated F(ab)2 fragments of the monoclonal reagent used for therapy, HAMAs of the IgM isotype were also detectable. HAMAs of the IgG isotype did not exceed levels of 2.0 mg/liter after a single treatment cycle and 2.2 mg/liter after a repeated cycle. No IgE responses were detectable. Absorption experiments indicated that approximately 25% of the HAMA activity was directed against specific determinants of the 16H5 monoclonal antibody, presumably including anti-idiotypic reactivities. These data demonstrate that HAMAs developed only in a proportion of RA patients treated with the anti-CD4 monoclonal antibody 16H5. However, the amounts were rather low compared to other monoclonal reagents used in cancer patients and were therefore allowed for repeated applications without an apparent loss of efficacy.     

The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes—A molecular study

The disease burden of chronic‐relapsing and therapy‐refractory superficial dermatophytosis dramatically increased in India within the past 5‐6 years. In order to evaluate the prevalence of this trend, 201 skin scrapings were collected from patients from all parts of India and were tested for dermatophytes using both fungal culture and a PCR‐ELISA directly performed with native skin scrapings. Fungal culture material was identified by genomic Sanger sequencing of the internal transcribed spacer (ITS) region and the translation elongation factor (TEF)‐1α gene. In total, 149 (74.13%) out of the 201 samples showed a dermatophyte‐positive culture result. Out of this, 138 (92.62%) samples were identified as Trichophyton (T.) mentagrophytes and 11 (7.38%) as Trichophyton rubrum. The PCR‐ELISA revealed similar results: 162 out of 201 (80.56%) samples were dermatophyte‐positive showing 151 (93.21%) T mentagrophytes‐ and 11 (6.79%) T rubrum‐positive samples. In this study, we show for the first time a dramatic Indian‐wide switch from T rubrum to T mentagrophytes. Additionally, sequencing revealed a solely occurring T mentagrophytes “Indian ITS genotype” that might be disseminated Indian‐wide due to the widespread abuse of topical clobetasol and other steroid molecules mixed with antifungal and antibacterial agents.