Secretion,blood levels and cutaneous expression of TL1A in psoriasis patients

TL1A is a TNF‐like cytokine which has been shown to co‐stimulate TH1 and TH17 responses during chronic inflammation. The expression of this novel cytokine has been investigated in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, but little is known about expression and induction in psoriasis. Indeed, the pathogenesis in psoriasis is still not fully understood and it is speculated that cytokines other than TNF‐α are important in subsets of patients. Also, for patients with severe disease that are treated with systemic anti‐TNF‐α blockade, novel candidates to be used as disease and response biomarkers are of high interest. Here, we demonstrate TL1A expression in biopsies from psoriatic lesions. Also, we investigated spontaneous and induced TL1A secretion from PBMCs and blood levels from a cohort of psoriasis patients. Here, increased spontaneous secretion from PBMCs was observed as compared to healthy controls and a small subset of patients had highly elevated TL1A in the blood. Interestingly, activation of PBMCs with various cytokines showed a decreased sensitivity for TL1A activation in psoriasis patients compared to healthy controls.TL1A levels in blood and biopsies could not be correlated with disease activity with this patient cohort. Thus, additional large‐scale studies are warranted to investigate TL1A as a biomarker.     

The demise of the randomised controlled trial: bibliometric study of the German-language health care literature, 1948 to 2004

Background  

In order to reduce systematic errors (such as language bias) and increase the precision of the summary treatment effect estimate, a comprehensive identification of randomised controlled trials (RCT), irrespective of publication language, is crucial in systematic reviews and meta-analyses. We identified trials in the German general health care literature.     

Involvement of ADAM10 in axonal outgrowth and myelination of the peripheral nerve

The disintegrin and metalloproteinase 10 (ADAM10) is a membrane‐anchored metalloproteinase with both proteolytic and disintegrin characteristics. Here, we investigate the expression, regulation, and functional role of ADAM10 in axonal outgrowth and myelination of the peripheral nerve. Expression pattern analysis of 11 ADAM family members in co‐cultures of rat dorsal root ganglia (DRG) neurons and Schwann cells (SCs) demonstrated the most pronounced mRNA expression for ADAM10. In further studies, ADAM10 was found to be consistently upregulated in DRG‐SC co‐cultures before the induction of myelination. Neurons as well as SCs widely expressed ADAM10 at the protein level. In neurons, the expression of ADAM10 was exclusively limited to the axons before the induction of myelination. Inhibition of ADAM10 activity by the hydroxamate‐based inhibitors GI254023X and GW280264X resulted in a significant decrease in the mean axonal length. These data suggest that ADAM10 represents a prerequisite for myelination, although its activity is not required during the process of myelination itself as demonstrated by expression analysis of myelin protein zero (P0) and Sudan black staining. Hence, during the process of myelin formation, ADAM10 is highly upregulated and appears to be critically involved in axonal outgrowth that is a requirement for myelination in the peripheral nerve. © 2009 Wiley‐Liss, Inc.     

Early Intestinal Changes Following Abdominal Radiotherapy

PURPOSE: To compare tests for intestinal function with clinical scores after abdominal irradiation. PATIENTS AND METHODS: At the Department of Radiotherapy, Erfurt, Germany, intestinal changes were studied in 91 patients receiving abdominal radiotherapy between 1992 and 1996. Conventional fractionation (1.8-2 Gy per fraction, total doses 30.6-62.5 Gy) was applied. Before and at weekly intervals during radiotherapy, the clinical response was scored according to RTOG/EORTC for the upper and lower gastrointestinal (GI) tract. Resorption tests for vitamin B(12) and D-xylose were performed before the onset and immediately after treatment. RESULTS: The clinical response displayed a well-defined dose-effect relationship with grade 1 effects in 5% and 50% of the patients at about 10 Gy and 50 Gy, respectively. For grade 2 reactions, 5%- and 50%-effective doses were 20-30 Gy and 60-80 Gy. Effects in the upper and lower GI tract were highly correlated. Changes in body weight did not show a correlation with other clinical symptoms. Changes in resorption also displayed a significant dose effect. However, no correlation was found with the clinical symptoms in the individual patient. CONCLUSION: In the present study, the clinical manifestation of intestinal side effects according to RTOG/EORTC criteria was reflected by neither the vitamin B(12) nor by the D-xylose resorption test. Hence, these tests cannot be regarded as useful for objective quantitation of intestinal radiation injury.     

Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg

To cover intermediate sensitive Candida glabrata in ICU patients,fluconazole plasma peak levels at least in the range of 16–32µg/ml appear necessary for treatment. Previous studiesdid not reach these fluconazole levels under continuous veno-venoushaemofiltration (CVVHF) with dosages of 200–600 mg fluconzoledaily. In the present study, nine patients simultaneously requiringCVVHF for treatment of acute oligoanuric renal failure and antimycotictherapy of Candida septicemia received fluconazole 800 mg/day.Fluconazole plasma levels were determined to evaluate whetherthis dosage is adequate to reach the advised fluconazole levels.Patients were dialysed on two consecutive days with an ultrafiltrationrate (UF) of 1000 ml/h or 2000 ml/h, respectively, in a randomizedorder. The predilution was 800 ml/h and 1800 ml/h, respectively.The treatment was tolerated without adverse effects. All patientsreached plasma fluconazole concentrations between 16 and 32µg/ml, remaining in this range for a minimum of 1 up to24 h with a mean of 9.6 h and a UF rate of 2000 ml/h, and 15.7h with a UF rate of 1000 ml/h. So far, there are no in vivodata on the fluconazole plasma concentrations required for effectivetreatment. However, our data demonstrate, that at least thefluconazole concentrations desirable on the basis of in vitrosusceptibility testing can be reached in critically ill patientson CVVHF in an ICU setting. However, in these patients, 800mg fluconazole/day are necessary to achieve fungicidal drugconcentrations.     

The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats.

The goal of the present study was to test the impact of administration time of the angiotensin II type 1-receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 +/- 8), infarct size in candesartan-treated groups was smaller (59 +/- 5, 68 +/- 10, 28 +/- 3, and 15 +/- 3, respectively; P<0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 +/- 0.18, 1.80 +/- 0.13), other treatment regimens resulted in improved neuroscores (1.33 +/- 0.16, 1.11 +/- 0.11, 0.73 +/- 0.15; P<0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 +/- 0.09 mL x g(-1) x min(-1) and 44% +/- 7% of baseline compared with 0.49 +/- 0.06 mL x g(-1) x min(-1) and 37% +/- 6%, microspheres and laser-Doppler flowmetry; P<0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.     

Detection of the Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms of the NOD2/CARD15 gene by real-time PCR with melting curve analysis.

Crohn's disease is a complex disorder, with multiple genetic traits. A frameshift mutation (Leu1007fsinsC) and two missense mutations (Gly908Arg and Arg702Trp) in the NOD2/CARD15 gene are strongly associated with susceptibility to Crohn's disease. The presence of one of these risk alleles confers a 2- to 4-fold increase in the risk of developing Crohn's disease, and the presence of two mutant alleles increases the risk over 20-fold. To facilitate the analysis of these polymorphisms, we developed three LightCycler assays to detect the missense mutations Arg702Trp and Gly908Arg and the frameshift mutation Leu100fsinsC in the NOD2/ CARD15 gene. All three assays can be run simultaneously on one LightCycler using identical cycling parameters. Analysis of 53 DNAs from Crohn's patients helped to identify carriers at allele frequencies similar to other Caucasian populations. The sequencing of such DNAs confirmed the accuracy of the assays. In conclusion, we present three rapid and robust assays to detect the Arg702Trp, the Gly908Arg and the Leu1007fsinsC ins mutations in the NOD2/CARD15 gene [corrected]