Histopathologische Diagnostik und Differenzialdiagnostik serratierter Polypen im Kolorektum

Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas - because of their cytological atypia - were recognized as precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression, mainly because hyperplastic polyps lack cytological atypia. Meanwhile, it is evident that the lesions formerly classified as hyperplastic represent a heterogeneous group of polyps, some of which exhibit a significant risk of neoplastic progression. These lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CIMP pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas (SSA), traditional serrated adenomas (TSA) and mixed polyps, showing serrated and "classical" adenomatous features. In a consensus conference of the working group of gastroenterological pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein.     

Probing Secondary Glutaminyl Cyclase (QC) Inhibitor Interactions Applying an in silico‐Modeling/Site‐Directed Mutagenesis Approach: Implications for Drug Development

Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate‐modified amyloid peptides deposited in neurodegenerative disorders such as Alzheimer’s disease. Inhibitors of QC are currently in development as potential therapeutics. The crystal structures of the potent inhibitor PBD150 bound to human and murine QC (hQC, mQC) have been described recently. The binding modes of a dimethoxyphenyl moiety of the inhibitor are significantly different between the structures, which contrasts with a similar K_i value. We show the conformation of PBD150 prone to disturbance by protein–protein interactions within the crystals. Semi‐empirical calculations of the enzyme–inhibitor interaction within the crystal suggest significant differences in the dissociation constants between the binding modes. To probe for interactions in solution, a site‐directed mutagenesis on hQC was performed. The replacement of F325 and I303 by alanine or asparagine resulted in a 800‐fold lower activity of the inhibitor, whereas the exchange of S323 by alanine or valine led to a 20‐fold higher activity of PBD150. The results provide an example of deciphering the interaction mode between a target enzyme and lead substance in solution, if co‐crystallization does not mirror such interactions properly. Thus, the study might provide implications for rapid screening of binding modes also for other drug targets.     

Sleep and cognition at baseline and the effects of REM sleep diminution after 1 week of antidepressive treatment in patients with depression

It has been hypothesized that non-rapid eye movement (NREM) sleep facilitates declarative memory consolidation, and rapid eye movement (REM) sleep is particularly important in promoting procedural learning. The aim of this study was to examine the effects of pharmacological REM sleep suppression on performance in different neuropsychological tasks. For our baseline, we chose 41 moderately depressed patients (age range 19-44 years), who were not taking antidepressants. In the morning after polysomnography, we tested memory recall and cognitive flexibility by assessment of verbal and figural fluency, a shift of attention task and the Trail Making Test B. After recording baseline values, patients were assigned randomly to one of three treatment groups: medication with citalopram; medication with reboxetine; or exclusive treatment with psychotherapy. Retesting took place 1 week after onset of treatment. The main results were: (1) an association of slow-wave sleep with verbal memory performance at baseline; (2) a suppression of REM sleep in patients taking citalopram and reboxetine; (3) no differences regarding neuropsychological performance within the treatment groups; and (4) no association of REM sleep diminution with decreases in memory performance or cognitive flexibility in patients treated with citalopram or reboxetine. In line with other studies, our results suggest that there are no negative effects of a decrease in REM sleep on memory performance in patients taking antidepressants.     

Up-regulation of the chemokine CCL18 by macrophages is a potential immunomodulatory pathway in cutaneous T-cell lymphoma

Mycosis fungoides (MF) is the most frequent form of cutaneous T-cell lymphoma (CTCL), which can deteriorate from patch stage to dermal-based tumors and systemic involvement in years. The interaction of chemokines in the skin with CTCL cells might have implications for the pathogenesis of the disease. In this study, we show by PCR analysis and immunofluorescence staining that the chemokine CCL18 is present in skin biopsy specimens of patients with MF and its precursor form parapsoriasis en plaque but not in healthy tissue. In addition, the serum levels of CCL18 were increased threefold in MF patients compared with those in healthy controls. In skin, CCL18 was specifically expressed by CD163(+) CD209(+) macrophages at the invasive margin of the tumor and not expressed by mature CD208(+) dendritic cells in the center of the tumor. The chemokine CCL17 was, by contrast, ubiquitously expressed. Furthermore, CCL18 promoted the chemotaxis but not the proliferation of CTCL cells. CCL18 inhibited proliferation of tumor cells and abolished the CXCL12-induced growth of a CTCL cell line. These data link the increased expression of CCL18 with CTCL and suggest an immunomodulatory effect of the chemokine in the pathogenesis of CTCL.     

Meta‐analysis of standard,restrictive and supplemental fluid administration in colorectal surgery

Background:

Optimal fluid therapy for colorectal surgery remains uncertain.

Methods:

A simple model was applied to define standard, restrictive and supplemental fluid administration. These definitions enabled pooling of data from different trials. Randomized controlled trials on fluid amount (standard versus restrictive or supplemental amount) and on guidance for fluid administration (goal‐directed fluid therapy by oesophageal Doppler‐derived variables versus conventional haemodynamic variables) in patients with colorectal resection were eligible for inclusion. The primary outcome measure was postoperative morbidity. Secondary endpoints were mortality, cardiopulmonary morbidity, wound infection, anastomotic failure, recovery of bowel function and hospital stay. A random‐effects model was applied.

Results:

Nine randomized controlled trials were included. Restrictive fluid amount (odds ratio (OR) 0·41 (95 per cent confidence interval (c.i.) 0·22 to 0·77); P = 0·005) and goal‐directed fluid therapy by means of oesophageal Doppler‐derived variables (OR 0·43 (95 per cent c.i. 0·26 to 0·71); P = 0·001) significantly reduced overall morbidity. There were no significant differences in the secondary endpoints analysed.

Conclusion:

Using standardized definitions, this meta‐analysis suggests that restrictive rather than standard fluid amount according to current textbook opinion, and goal‐directed fluid therapy rather than fluid therapy guided by conventional haemodynamic variables, reduce morbidity after colorectal resection. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.     

Pathomechanismen des Organversagens

Proinflammatory mediators as well as increased formation of reactive oxygen and nitrogen species impair cellular respiration during sepsis. In particular, the highly reactive peroxynitrite irreversibly damages lipids, proteins and nucleic acids and also inhibits enzyme complexes of the respiratory chain. In this way cellular metabolic functions and subsequently organ functions are also impaired. Repair of DNA by poly(ADP-ribose)polymerase consumes large amounts of nicotinamide adenine dinucleotide (NAD⁺) which leads to cellular NAD⁺ depletion further promoting inflammation. This article summarizes central aspects of the pathophysiology of mitochondrial dysfunction during sepsis and gives an overview about newly developed strategies which proved effective in experimental studies and may have a potential clinical application in the future.