PPARalpha and dyslipidemia.

Dyslipidemia is defined by abnormal levels of plasma lipoproteins. Several different types of dyslipidemia can be distinguished. An important group of drugs used in the treatment of dyslipidemia are the fibrates.

Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway.

Fifty years ago, Kornberg and Krebs established the glyoxylate cycle as the pathway for the synthesis of cell constituents from C2-units. However, since then, many bacteria have been described that do not contain isocitrate lyase, the key enzyme of this pathway. Here, a pathway termed the ethylmalonyl-CoA pathway operating in such organisms is described.

The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors.

Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum lipid levels.

Genome-wide analysis of PPARalpha activation in murine small intestine.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a fatty acid-activated transcription factor that governs a variety of biological processes. Little is known about the role of PPARalpha in the small intestine. Since this organ is frequently exposed to high levels of PPARalpha ligands via the diet, we set out to characterize the function of PPARalpha in small intestine using functional genomics experiments and bioinformatics tools.

Distal pancreatectomy: risk factors for surgical failure in 302 consecutive cases.

Objective: The objective of this study was to identify potential risk factors for mortality and morbidity after distal pancreatectomy, with special focus on the formation of pancreatic fistula.

Summary Background Data: Distal pancreatectomy can be performed with low mortality and acceptable morbidity rates. Pancreatic fistulas, occurring in 10% to 20% of cases, remain a problem that contributes significantly to morbidity, length of stay, and overall costs.

HitKeeper, a generic software package for hit list management.

Background: The automated annotation of biological sequences (protein, DNA) relies on the computation of hits (predicted features) on the sequences using various algorithms. Public databases of biological sequences provide a wealth of biological "knowledge", for example manually validated annotations (features) that are located on the sequences, but mining the sequence annotations and especially the predicted and curated features requires dedicated tools. Due to the heterogeneity and diversity of the biological information, it is difficult to handle redundancy, frequent updates, taxonomic information and "private" data together with computational algorithms in a common workflow.

PPARs, Obesity, and Inflammation.

The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion.

Strong mutagenic effects of diesel engine emissions using vegetable oil as fuel.

Diesel engine emissions (DEE) are classified as probably carcinogenic to humans. In recent years every effort was made to reduce DEE and their content of carcinogenic and mutagenic polycyclic aromatic compounds. Since 1995 we observed an appreciable reduction of mutagenicity of DEE driven by reformulated or newly designed fuels in several studies.

Increase in substance P precursor mRNA in noninflamed small-bowel sections in patients with Crohn's disease.

Background: Neuropeptides, such as substance P (SP), are mediators of neurogenic inflammation and play an important role in inflammatory disorders. To further investigate the role of the SP pathway in inflammatory bowel disease (IBD), we analyzed the following in normal intestinal tissue specimens and in tissue specimens from patients with Crohn's disease (CD) and ulcerative colitis (UC): neurokinin receptor-1 (NK-1R); its isoforms (NK-1R-L and NK-1R-S); its ligand SP, encoded by preprotachykinin-A (PPT-A); and the SP-degradation enzyme, neutral endopeptidase (NEP).

Methods: Real-time quantitative reverse transcription-polymerase chain reaction was used to simultaneously determine the expression of NK-1R-L, NK-1R-S, and PPT-A.

Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation.

Recently it has become evident that obesity is associated with low-grade chronic inflammation. The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) has been shown to have a strong antiinflammatory action in liver. However, the role of PPARalpha in obesity-induced inflammation is much less clear.

Design guidelines for the development of digital nutrigenomics learning material for heterogeneous target groups.

Nutritional genomics, or nutrigenomics, can be considered as the combination of molecular nutrition and genomics. Students who attend courses in nutrigenomics differ with respect to their prior knowledge. This study describes digital nutrigenomics learning material suitable for students from various backgrounds and provides design guidelines for the development of the learning material.

The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver.

Background/aims: The Peroxisome Proliferator-Activated Receptor (PPAR) alpha belongs to the superfamily of Nuclear Receptors and plays an important role in numerous cellular processes, including lipid metabolism. It is known that PPARalpha also has an anti-inflammatory effect, which is mainly achieved by down-regulating pro-inflammatory genes. The objective of this study was to further characterize the role of PPARalpha in inflammatory gene regulation in liver.

Regio- and stereoselective intermolecular oxidative phenol coupling in kotanin biosynthesis by Aspergillus niger.

The intermolecular, regio- and stereoselective phenol coupling for the biosynthesis of the bicoumarin kotanin in Aspergillus niger has been investigated. Feeding experiments with singly and doubly (13)C-labeled monomeric precursors clearly proved that it is not the coumarin siderin but its hydroxy derivative, demethylsiderin, that undergoes phenol coupling. However, siderin is demethylated regioselectively to demethylsiderin and it is the latter that is coupled to the corresponding dehydrodimer, orlandin.

Initial steps in the anoxic metabolism of cholesterol by the denitrifying Sterolibacterium denitrificans.

The anoxic metabolism of the ubiquitous triterpene cholesterol is challenging because of its complex chemical structure, low solubility in water, low number of active functional groups, and the presence of four alicyclic rings and two quaternary carbon atoms. Consequently, the aerobic metabolism depends on oxygenase catalyzed reactions requiring molecular oxygen as co-substrate. Sterolibacterium denitrificans is shown to metabolize cholesterol anoxically via the oxidation of ring A, followed by an oxygen-independent hydroxylation of the terminal C-25 of the side chain.

Six steps from head to hand: a simulator based transfer oriented psychological training to improve patient safety.

Unlabelled: The incidence of human errors in the field of medicine is high. Two strategies to increase patient safety are simulator training and crew resource management (CRM) seminars, psychological courses on human performance and error management.

Aim: To establish a CRM course combining psychological training on human error with simulator training.

Pancreaticojejunostomy versus pancreaticogastrostomy: systematic review and meta-analysis.

Objective: Pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreaticoduodenectomy (PD). The ideal choice of anastomosis remains a matter of debate.

Data Sources: Articles published until end of March 2006 comparing PJ and PG after PD were searched.

A pilot study testing whether concentrations of levofloxacin in interstitial space fluid of soft tissues may serve as a surrogate for predicting its pharmacokinetics in lung.

Recent observations indicate that pharmacokinetics of beta-lactam antibiotics in the lung can be predicted by the use of concentration versus time profiles in peripheral soft tissues. If this observation is transferred to other classes of antimicrobials, measurement of antimicrobial concentrations in peripheral tissues would enable prediction of the pharmacokinetics of antimicrobials at the site of the respiratory tract infection. We set out to test the hypothesis that concentrations of the fluoroquinolone levofloxacin in the respiratory tract can be predicted on the basis of knowledge of its pharmacokinetics in peripheral soft tissues.

Premature cellular senescence induced by pyocyanin, a redox-active Pseudomonas aeruginosa toxin.

Pseudomonas aeruginosa is an important nosocomial pathogen that can cause acute and chronic infection, particularly of the respiratory system. Pyocyanin is a major P. aeruginosa virulence factor that displays redox activity and induces oxidative stress in cellular systems.

Middle segmental pancreatic resection: An option to treat benign pancreatic body lesions.

Objective: To clarify whether middle segmental pancreatic resection can be performed with comparable morbidity and mortality to classic pancreatic resections for lesions in the mid-portion of the pancreas.

Summary Background Data: Pancreaticoduodenectomies or distal pancreatectomy, traditionally used to treat lesions of the pancreatic body, sacrifice a significant amount of normal pancreatic tissue. Middle segmental pancreatic resection has therefore been introduced to minimize loss of functioning pancreatic tissue.

Surgical palliation in patients with pancreatic cancer.

Background: The aim of palliative strategies in patients with pancreatic cancer is the relief of tumor-associated symptoms such as biliary and duodenal obstruction and tumor growth. Due to high mortality and morbidity rates of surgery, treatment of patients with advanced pancreatic cancer is mainly in the hand of gastroenterologists.

Rationale: In recent years, surgery of pancreatic cancer in specialized centres developed strongly, which makes it a viable option even in the treatment of advanced disease.

Characterization of benzaldehyde lyase from Pseudomonas fluorescens: A versatile enzyme for asymmetric C-C bond formation.

The thiamin-diphosphate-dependent enzyme benzaldehyde lyase is a very import catalyst for chemoenzymatic synthesis catalyzing the formation and cleavage of (R)-hydroxy ketones. We have studied the stability of the recombinant enzyme and some enzyme variants with respect to pH, temperature, buffer salt, cofactors and organic cosolvents. Stability of BAL in chemoenzymatic synthesis requires the addition of cofactors to the buffer.

Diminished expression of multidrug resistance-associated protein 1 (MRP1) in bronchial epithelium of COPD patients.

Cigarette smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD). Multidrug resistance proteins, such as multidrug resistance-associated protein-1 (MRP1), P-glycoprotein (P-gp), and lung resistance-related protein (LRP), may protect against oxidative stress and toxic compounds generated by cigarette smoking. Expression of MRP1, P-gp, and LRP was evaluated in bronchial epithelium of two study groups of COPD patients and their controls and was associated with disease status and smoking history.

Role of lymphotoxins in the development of Peyer's patches and mesenteric lymph nodes: relevance to intestinal inflammation and treatment.

Hallmarks of the adaptive immune system are antigen-specific cellular and humoral immune responses. Secondary lymphoid organs serve as sites of contact between antigen-presenting cells (APCs) and immune effector T and B lymphocytes. The gut-associated lymphatic system (GALT) as the intestinal branch of the immune system provides different mechanisms to protect organisms against pathogens.

Factors mediating activity, selectivity, and substrate specificity for the thiamin diphosphate-dependent enzymes benzaldehyde lyase and benzoylformate decarboxylase.

Benzaldehyde lyase from Pseudomonas fluorescens and benzoylformate decarboxylase from Pseudomonas putida are homologous thiamin diphosphate-dependent enzymes that catalyze carboligase and carbolyase reactions. Both enzymes catalyze the formation of chiral 2-hydroxy ketones from aldehydes. However, the reverse reaction has only been observed with benzaldehyde lyase.