Environmental influences on inflammatory bowel disease manifestations. Lessons from epidemiology

Environmental factors play an important role in the disease manifestation, course and prognosis of inflammatory bowel disease. Observations on temporal trends and geographical distribution point at risk factors associated with a Western lifestyle. A large number of studies have been performed on various factors such as diet, smoking, and several infectious agents. Childhood exposures modifying immune responses in later life form a particularly interesting field. However, so far, only smoking in Crohn's disease, and smoking cessation in ulcerative colitis can be considered established as risk factors for the manifestation of the disease. Smoking is also associated with a poor prognosis in Crohn's disease. A strong negative association of appendectomy with ulcerative colitis has been very consistent across many studies; however, the implications of this finding are still obscure.     

Role of prothrombin 19911 A>G polymorphism,blood group and male gender in patients with venous thromboembolism: Results of a German cohort study

Journal of Thrombosis and Thrombolysis - The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism...     

The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation

In this study, we have identified a unique combinatorial effect of the chemokines KC/MIP-2 and the cytokine granulocyte colony-stimulating factor (G-CSF) with respect to the rapid mobilization of neutrophils from the bone marrow in a model of acute peritonitis. At 2 hours following an intraperitoneal injection of thioglycollate, there was a 4.5-fold increase in blood neutrophil numbers, which was inhibited 84% and 72% by prior administration of blocking mAbs against either the chemokines KC/MIP-2 or G-CSF, respectively. An intraperitoneal injection of G-CSF acted remotely to stimulate neutrophil mobilization, but did not elicit recruitment into the peritoneum. Further, in vitro G-CSF was neither chemotactic nor chemokinetic for murine neutrophils, and had no priming effect on chemotaxis stimulated by chemokines. Here, we show that, in vitro and in vivo, G-CSF induces neutrophil mobilization by disrupting their SDF-1alpha-mediated retention in the bone marrow. Using an in situ perfusion system of the mouse femoral bone marrow to directly assess mobilization, KC and G-CSF mobilized 6.8 x 10(6) and 5.4 x 10(6) neutrophils, respectively, while the infusion of KC and G-CSF together mobilized 19.5 x 10(6) neutrophils, indicating that these factors act cooperatively with respect to neutrophil mobilization.     

Ten years' experience in aortic valve replacement with homografts in 389 cases

BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement using homografts is an accepted alternative to the use of other replacement devices, and has been established at the authors' institution for more than 10 years. METHODS: Since 1992, a total of 389 homografts was implanted, and 332 patients (mean age 54 years, 72% males) were followed up. The initial patients (n = 75) had subcoronary implantation, all subsequent patients had root replacement. Both aortic grafts (AG) and pulmonary grafts (PG) were used. Follow up was conducted with regard to the factors 'graft origin', 'implantation technique' and 'gender', and included clinical examination, ECG and transthoracic echocardiography on an annual basis. RESULTS: Overall 30-day mortality was 5.4% (AG patients 3.9%, PG patients 13.5%; p = 0.09). Among late deaths (n = 22), six were valve-related (all prosthetic infection). Four minor thrombembolic events were recorded due to amaurosis fugax and transient ischemic attacks (TIA). Freedom from reoperation was 86.5%. Indication for graft replacement was greater after subcoronary implantation than after root implantation (p = 0.04). Reoperation was necessary in 24 patients due to restenosis (n = 4), regurgitation grade >II (n = 5), paravalvular leak (n = 2) and prosthetic infection (n = 13). At the latest echocardiographic follow up, mean peak pressure gradient was 15.60 +/- 11.76 mmHg, homograft regurgitation grade was 0.82 +/- 0.66, left ventricular end-diastolic diameter (EDD) was 49.1 +/- 7.54 mm, and mean aortic root diameter was 30.54 +/- 5.48 mm. When comparing parameters at a mean of five years postoperatively, the pressure gradient increased from 10.26 to 15.02 mmHg, regurgitation grade increased from 0.53 to 0.81, and EDD decreased from 52.3 to 50.4 mm. Other variables showed no significant differences. CONCLUSION: The present results confirmed good midterm-results for aortic valve replacement with homografts. These prostheses are vulnerable to infection, and root replacement was superior to the subcoronary implantation technique.     

Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.     

Evaluation of Cobas TaqMan MTB for Direct Detection of the Mycobacterium tuberculosis Complex in Comparison with Cobas Amplicor MTB

The Roche Cobas Amplicor MTB assay, recently replaced by the Roche Cobas TaqMan MTB assay, was one of the first commercially available assays for detection of the Mycobacterium tuberculosis complex based on nucleic acid amplification. We reported previously on the limited specificity of the Cobas Amplicor MTB assay, in particular for positive samples with an optical density at 660 nm (OD₆₆₀) of <2.0. Using a selected set of respiratory samples, which were scored as false positive by the Cobas Amplicor test, we demonstrate here that the specificity of the Cobas TaqMan assay is significantly improved. In addition, our study of a set of 133 clinical samples revealed that the Cobas TaqMan MTB assay showed significantly less PCR inhibition than the Cobas Amplicor test. An overall concordance of 98.2% was observed between the two assays. In a subsequent prospective study, we evaluated the performance of the Roche Cobas TaqMan MTB assay on 1,143 clinical specimens, including respiratory (n = 838) and nonrespiratory (n = 305) specimens. Using culture as the gold standard, we found a sensitivity of 88.4% and a specificity of 98.8% for the 838 respiratory specimens, compared to a sensitivity of 63.6% and a specificity of 94.6% for the 305 nonrespiratory specimens. We conclude that the Cobas TaqMan MTB assay is a significantly improved tool for the direct detection of M. tuberculosis DNA in clinical specimens.