Cell surface proteolysis is essential for communication between cells and results in the shedding of membraneprotein ectodomains. However, physiological substrates of the contributing proteases are largely unknown. We developed the secretome protein enrichment with click sugars (SPECS) method, which allows proteome-wide identification of shedding substrates and secreted proteins from primary cells, even in the presence of serum proteins. SPECS combines metabolic glycan labelling and click chemistry-mediated biotinylation and distinguishes between cellular and serum proteins. SPECS identified 34, mostly novel substrates of the Alzheimer protease BACE1 in primary neurons, making BACE1 a major sheddase in the nervous system. Selected BACE1 substrates-seizureprotein 6, L1, CHL1 and contactin-2-were validated in brains of BACE1 inhibitor-treated and BACE1 knock-out mice. For some substrates, BACE1 was the major sheddase, whereas for other substrates additional proteases contributed to total substrate shedding. The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. SPECS is also suitable for quantitative secretome analyses of primary cells and may be used for the discovery of biomarkers secreted from tumour or stem cells.

!Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganisation of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Zusammenfassung

Data from this large representative population show strong associations between smoking and various markers of systemic inflammation in men. They also show that cessation of smoking is associated with a decreased inflammatory response, which may represent one mechanism responsible for the reduced cardiovascular risk in these subjects.

Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

No abstract

p8 is a stress-induced DNA-binding protein, biochemically related to the architectural chromatin binding HMG protein family and whose function is presently unknown. We obtained ®broblast from mice lacking p8 and found that p8 is involved in cell growth regulation and in apoptosis. p8 7/7 mouse embryonic ®broblasts (MEFs) grow more rapidly than p8 +/+ MEFs. This might be explained by the higher intracellular level and activity of the Cdk2 and Cdk4 observed in p8 7/7 MEFs, which in turn may result, at least in part, from the concomitant decrease observed in the amount of cyclindependent kinase inhibitor p27. We also report that p8 mRNA expression is strongly activated in ®broblasts after cell growth arrest induced by serum deprivation or con¯uence. As expected, MEFs expressing p8 arrest their growth more rapidly after serum deprivation than MEFs lacking p8, which strongly suggests that p8 overexpression is implicated in cell growth arrest. On the other hand, p8 +/+ MEFs are more sensitive than p8MEFs to the apoptosis induced by adriamycin treatment. p53 might be involved, as p8 expression increases its intracellular amount and trans-activation capacity. Finally, demonstration that p53 is a negative transactivator of p8 suggests the presence of a complex autoregulatory loop. In conclusion, p8 is a cell growth inhibitor that facilitates apoptosis induced in ®broblasts by DNA damage.

Abstract-Infectious agents may be involved in atherothrombogenesis. The potential pathogenic pathway, however, remains unclear. We investigated the association between various infectious agents and lipoproteins known to have an atherogenic effect. We recruited 470 healthy blood donors and 238 patients with angiographically proven coronary heart disease (CHD), aged 40 to 68 years. Seropositivity to Chlamydia pneumoniae (CP), chlamydial lipopolysaccharide, and cytomegalovirus (CMV) was determined; infection with Helicobacter pylori (HP) was assessed by using the [ 13 C]urea breath test. In all subjects, total cholesterol, high density lipoprotein (HDL) cholesterol, lipoprotein(a), and various apolipoproteins (apos) were determined. In unadjusted analysis, mean HDL cholesterol concentration was significantly decreased in HP-positive healthy subjects (1.36 vs 1.44 mmol/L, Pϭ0.006) compared with HP-negative subjects. The HDL cholesterol to total cholesterol ratio was significantly decreased in HP-positive (0.259 vs 0.276, Pϭ0.01) and CP-seropositive (0.266 vs 0.280, Pϭ0.04) healthy subjects compared with (sero)negatives. Mean apoAI levels were significantly lower in HP-positive healthy subjects (1.46 vs 1.51 g/L, Pϭ0.03) and in CMV-positive healthy subjects (1.47 vs 1.52 g/L, Pϭ0.01) compared with (sero)negative subjects. After multivariable adjustment by means of linear regression analysis, only the association between HP infection and decreased HDL cholesterol (Pϭ0.002), decreased HDL cholesterol to total cholesterol ratio (Pϭ0.005), decreased apoAI (Pϭ0.02), and increased apoB (Pϭ0.02) persisted and remained significant. There was no independent association between other lipoproteins and serological markers of CP or CMV infection. Current infection with HP, but not seropositivity to CP or CMV, was associated with an atherogenic, modified lipid profile. These lipid alterations could explain, at least in part, the reported weak association between chronic HP infection and atherosclerotic diseases.

The p8 protein is involved in the cellular stress response of many tissues. Because p8 is overexpressed in many cancers, we investigated whether its expression was required for tumour development. Mouse embryo fibroblasts (MEFs) from p8 +/+ and p8 -/-animals were transformed with the pBaberas V12 /E1A retroviral vector, which expresses both the ras V12 mutated protein and the E1A oncogene. As expected, transformed p8 +/+ MEFs could form colonies in soft agar. However, transformed p8 -/-MEFs could not. In addition, subcutaneous or intraperitoneal injections of transformed p8 +/+ MEFs always led to tumour formation in nude mice, but, again, no tumour was observed with transformed p8 -/-MEFs. However, restoring p8 expression in transformed p8 -/-MEFs before injection led to tumour formation. In the tumours, p8 expression was induced during tumour development. It was concluded that p8 expression in transformed MEFs is necessary for tumour formation, suggesting that the stress-response mechanisms governed by p8 are required for tumour establishment.