From the Glovebox to the Benchtop: Air-Stable High Performance Molybdenum Alkylidyne Catalysts for Alkyne Metathesis.

Molybdenum alkylidynes endowed with tripodal silanolate ligands belong to the most active and selective catalysts for alkyne metathesis known to date. This paper describes a new generation that is distinguished by an unprecedented level of stability and practicality without sacrificing the chemical virtues of their predecessors. Specifically, pyridine adducts of type 16 are easy to make on gram scale, can be routinely weighed and handled in air, and stay intact for many months outside the glovebox. When dissolved in toluene, however, spontaneous dissociation of the stabilizing pyridine ligand releases an active species of excellent performance and functional group tolerance. Specifically, a host of polar and apolar groups, various protic sites, and numerous basic functionalities proved compatible. The catalysts are characterized by crystallographic and spectroscopic means, including 95Mo NMR; their activity and stability are benchmarked in detail, and the enabling properties are illustrated by advanced applications to natural product synthesis. For the favorable overall application profile and ease of handling, complexes of this new series are expected to replace earlier catalyst generations and help encourage a more regular use of alkyne metathesis in general.

Canopy Catalysts for Alkyne Metathesis: Investigations into a Bimolecular Decomposition Pathway and the Stability of the Podand Cap.

Molybdenum alkylidyne complexes with a trisilanolate podand ligand framework ("canopy catalysts") are the arguably most selective catalysts for alkyne metathesis known to date. Among them, complex 1 a endowed with a fence of lateral methyl substituents on the silicon linkers is the most reactive, although fairly high loadings are required in certain applications. It is now shown that this catalyst decomposes readily via a bimolecular pathway that engages the Mo≡CR entities in a stoichiometric triple-bond metathesis event to furnish RC≡CR and the corresponding dinuclear complex, 8, with a Mo≡Mo core. In addition to the regular analytical techniques, 95 Mo NMR was used to confirm this unusual outcome. This rapid degradation mechanism is largely avoided by increasing the size of the peripheral substituents on silicon, without unduly compromising the activity of the resulting complexes. When chemically challenged, however, canopy catalysts can open the apparently somewhat strained tripodal ligand cages; this reorganization leads to the formation of cyclo-tetrameric arrays composed of four metal alkylidyne units linked together via one silanol arm of the ligand backbone. The analogous tungsten alkylidyne complex 6, endowed with a tripodal tris-alkoxide (rather than siloxide) ligand framework, is even more susceptible to such a controlled and reversible cyclo-oligomerization. The structures of the resulting giant macrocyclic ensembles were established by single-crystal X-ray diffraction.

Acetylene as a Dicarbene Equivalent for Gold(I) Catalysis: Total Synthesis of Waitziacuminone in One Step.

The gold(I)-catalyzed reaction of acetylene gas with alkenes leads to (Z,Z)-1,4-disubstituted 1,3-butadienes and biscyclopropanes depending on the donor ligand on gold(I). Acetylene was generated in situ from calcium carbide and water in a user-friendly procedure. Reaction of acetylene with 1,5-dienes gives rise stereoselectively to tricyclo[5.1.0.02,4 ]octanes. This novel double cyclopropanation has been applied to the one step total synthesis of the natural product waitziacuminone from acetylene and geranyl acetone.

[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

[Gender specific differences in coping with colon cancer--empirical findings with special consideration of religious coping]. / Geschlechtsspezifische Unterschiede in der Bewältigung einer Darmkrebserkrankung--Empirische Befunde unter besonderer Berücksichtigung religiösen Copings.

The present study investigated whether women and men differ with regard to non-religious and religious coping with cancer, here: colon cancer--a question on which only little research has been done so far. 341 patients filled in a questionnaire during inpatient oncological rehabilitation. Statistical analyses showed that women reported higher mental strain than men. They used more bagatellization and wishful thinking, more depressive and less active problem-oriented coping strategies. A higher use of religious coping among women was to a high degree associated with their generally stronger religiosity. Correlations between coping strategies and measures of mental health indicated commonalities and differences. In particular, a positive correlation between active problem-oriented coping and mental health was found for men but not for women. In accordance with women's higher religiosity, the data indicate a stronger correlation between religious coping and adaptation among women than among men. The results suggest that gender differences and religiosity can be relevant in the context of treatment but that their significance must not be overinterpreted. In terms of patient orientation they speak for the necessity to individually assess the need for support, also with regard to the consideration of religiosity in the treatment process.

Religious commitment, religious coping and anxiety: a study in German patients with breast cancer.

Within the last few years the relationship between religiousness and psychosocial adjustment has become a subject of increasing interest. However, previous research did not explicitly differentiate between dispositional religious commitment and situation-specific religious coping. The current cross-sectional study investigated the relative power of religious commitment, positive and negative religious coping, and religious commitment x religious coping interactions in the prediction of anxiety. The sample consisted of 167 German breast cancer patients who were assessed during an inpatient rehabilitation programme. Results indicated that positive and negative religious coping were more strongly related to anxiety than dispositional religious commitment. Furthermore, hierarchical regression analysis revealed a religious commitment x negative religious coping interaction. According to this interaction, there seems to be some synergistic effect of high levels of religious commitment and high levels of negative religious coping. In contrast, positive religious coping did not function as a moderator and appeared to be closely related to religious commitment. This may be due to the specific religious-cultural background in Germany.

[CT-free image guided acetabulum navigation in clinical routine]. / Die CT-freie bildgesteuerte Pfannennavigation in der klinischen Routine.

After experimental and preclinical evaluation (HAP Paul Award 2001) of the CT-free image-guided surgical navigation system for acetabular cup placement (SurgiGATE C-arm cup" by Medivision, Switzerland), the system was introduced into clinical routine. The computation of the angular orientation of the cup is based on reference coordinates from the anterior pelvic plane concept. A hybrid strategy for pelvic landmark acquisition has been introduced involving percutaneous pointer-based digitization with the noninvasive biplanar landmark reconstruction using multiple registered fluoroscopy images. From January 2001 to December 2002, a total of 256 consecutive patients with primary osteoarthrosis (mean age 69 years, 161 male, 95 female, 132 left, and 124 right hip joints) were operated on with the hybrid CT-free navigation system. During each operation the angular orientation of the inserted implant was recorded. To determine the placement accuracy of the acetabular components, 50 consecutive patients underwent a CT scan 7-10 days postoperatively to analyze the cup position related to the anterior pelvic plane. This was all done blinded by the same investigator with the planning software of the CT-based navigation system of Medivision. There was no significant learning curve observed for the use of the system. The mean value for postoperative inclination was 43 degrees (SD 3.0, range: 37 degrees -49 degrees ) and for anteversion 19 degrees (SD 3.9, range: 10 degrees -28 degrees ). The resulting system accuracy, i.e., the difference between intraoperatively calculated cup orientation and postoperatively measured implant position showed a mean error of 1.5 degrees for the inclination (maximum 5 degrees, SD 1.1) and 2.4 degrees for the anteversion (maximum 6 degrees, SD 1.3). An accuracy of better than 5 degrees inclination and 6 degrees anteversion was achieved under clinical conditions, which implies that there is no significant difference in performance from the established CT-based navigation methods. Image-guided CT-free cup navigation provides a reliable solution for future THA.

[Muir-Torre syndrome]. / Muir-Torre-Syndrom.

The Muir-Torre syndrome (MTS) is a rare, autosomal-dominant inherited disease characterized by sebaceous gland tumors and at least one internal malignancy. In many cases a genetic defect known as microsatellite instability can be identified. Similar pathogenetic mechanisms are found in patients with the hereditary non-polyposis colon cancer syndrome, so that at least some patients with MTS are considered as having a phenotypic variant of that syndrome. A 66-year-old woman with MTS, developed multiple malignant cutaneous and visceral tumors over 32 years; in addition, she had multiple sebaceous gland adenomas. Microsatellite instability could be proved with 2 out of 5 studied markers. The family history was positive as numerous relatives of the patient's mother were reported to have developed internal malignancies.

[Validation of the new German translation version of the "Short Inflammatory Bowel Disease Questionnaire" (SIBDQ)]. / Validierung der deutschsprachigen Version des "Short Inflammatory Bowel Disease Questionnaire" (SIBDQ).

In the face of a hardly predictable course of illness--potentially effecting a severe diminution of daily activities--the quality of life (QOL) represents a chief outcome measure in the treatment of inflammatory bowel diseases (IBD). For the German-speaking area an economical disease-specific instrument measuring QOL has been missing, so far. Therefore, we translated and adapted the recently validated "Short Inflammatory Bowel Disease Questionnaire" SIBDQ (11). Bowel symptoms, systemic symptoms, moods, and social activities are represented by a total of 10 items. Along with this questionnaire 7 accepted instruments assessing QOL-components were administered to 125 outpatients (54 ulcerative colitis, 71 Crohn's disease) and 51 healthy controls. The psychometric properties are good. Consistency is alpha = .84, thereby slightly surpassing the Anglo-American SIBDQ (alpha = .78). Retest-reliability after 26 weeks is r = .60. Systematic covariations with accepted QOL-instruments give evidence for its convergent and discriminatory validity. Differences between groups (high vs. low inflammatory activity vs. healthy controls) substantiate its sensitivity. Thus, the German adaptation of the accepted SIBDQ supplies an economic, reliable, and valid instrument that proved able to assess clinically relevant differences in QOL in patients with IBD. We suggest that it should be used by its overall score rather than its subscales. The instrument is appropriate to be used in therapy outcome and evaluation studies. It allows international comparison.

Genetic variability determinants of Helicobacter pylori: influence of clinical background and geographic origin of isolates.

Helicobacter pylori has an unusual pattern of genetic variation, which complicates research on this organism. To gain a better understanding of the forces behind this phenomenon, the extent to which recombination and single point mutations affect genetic variability in H. pylori was quantified and the influence of both geographical distance and clinical background were assessed. Site-directed restriction-endonuclease digestion of 2 gene fragments was performed on 168 isolates from Montreal and Berlin. Allelic diversity was found to be much higher for H. pylori than for other bacterial species. This finding is consistent with those of previous studies on H. pylori that were conducted using other techniques. However, nucleotide diversity was within the range reported for other bacterial species. Phylogenetic analysis found no grouping of strains with clinical background or geographical origin. Recombination at a rate that resulted in linkage equilibrium within genes can explain these observations.

Deficiency of epithelial basement membrane laminin in ulcerative colitis affected human colonic mucosa.

Imbalances in epithelium-matrix interactions have been discussed as a pathomechanism in ulcerative colitis, causing a colonic mucosal barrier dysfunction. Laminin, the major noncollagenous component of the basement membrane, plays a role in epithelial basal lamina formation and promotes differentiation of human enterocytes. We therefore investigated the distribution of laminin in ulcerative colitis affected colonic tissues. Tissue specimens from both affected and nonaffected colonic regions were obtained from ten patients with ulcerative colitis during colonoscopies or operations. Healthy tissue from five patients with colorectal cancer was used as control. After histological classification, the localization and distribution of the basement membrane associated extracellular matrix proteins were determined by immunohistochemistry. Paraffin-embedded sections were incubated with antibodies against laminin and type IV and V collagen. No positive immunoreactivity against laminin was found in most of the epithelial basement membranes surrounding the crypts in affected colonic tissues, without involvement of the subendothelial structures. In contrast, a type IV and V collagen accumulation occurred in all these tissue samples. The lack of laminin in combination with an overexpression of type IV and V collagen, as reported for the first time in this paper, leads to changes in basement membrane structure. These findings indicate that the three-dimensional network of the colonic epithelial basement membrane and its function are seriously disturbed in exacerbating ulcerative colitis. This provides new insights into the importance of cell-matrix interactions for physiological and pathological mechanisms in the etiology of ulcerative colitis.

Increased lipid utilization in weight losing and weight stable cancer patients with normal body weight.

OBJECTIVE: Cachexia and weight loss are frequently seen in cancer patients. We investigated lipid metabolism to elucidate a metabolic basis for adequate nutrition of cancer patients. DESIGN: Lipid metabolism was assessed by indirect calorimetry and triglyceride clearance rates after randomised injection of a lipid bolus (long-chain triglycerides (LCT) or medium-chain triglycerides (MCT) during an euglycemic clamp protocol in cancer patients. SETTING: Rudolf-Virchow Krankenhaus, Berlin, Germany. SUBJECTS: Eighteen patients were included. Twelve patients had upper gastrointestinal cancer: a weight stable cancer group (Caws, n = 6) with a body mass index (BMI) of 22.9 +/- 1.7 kg/m2 and a weight losing cancer group (Cawl, n = 6) with a mean weight loss of 7.4 +/- 3.1 kg or 11% of the initial body weight during the previous three months (present BMI 21.8 +/- 0.8 kg/m2). The data were compared with six control patients with benign gastrointestinal diseases (BMI = 25.0 +/- 0.8 kg/m2). MAIN OUTCOME: Cancer patients had an increased basal lipid oxidation rate that was more pronounced in Cawl (+92% vs +42% in Caws; P < 0.01 and 0.05 vs controls, respectively). Utilisation of LCT was increased in cancer patients, this was most pronounced in Cawl (+150 vs +65% in Caws; P < 0.01 and 0.05, respectively). Metabolically, there were no differences in the utilisation of LCT and MCT/LCT containing lipid emulsions. CONCLUSIONS: Cancer patients have an increased lipid oxidation and an enhanced utilisation of exogeneous lipids. This is most pronounced in Cawl. To prevent further weight loss or to increase body weight, they should increase their fat intake. In contrast, fat-reduced or prudent diets seem to be inadequate for the nutrition of cancer patients.

Use of precision cut human liver slices for studying the metabolism and genotoxic potential of xenobiotics by means of the (32)P-postlabelling technique: steps towards method validation using testosterone and 2-aminofluorene.

In the present study, a new in vitro model combining the short-term incubation of precision-cut human liver slices with DNA-adduct analysis by the (32)P-postlabelling technique is proposed for investigation of the genotoxic potential of xenobiotics. For method validation, the metabolic turnover of testosterone (TES) and the DNA-adduct inducing potential of 2-aminofluorene (2-AF) were used. Precision-cut human liver slices were prepared from a total of 12 human liver samples which were freshly obtained as parts of resectates from liver surgery. The slices were incubated as submersion cultures with TES and 2-AF for up to 6 h in 12-well tissue culture plates at concentrations of 10-50 and 0.06-28 µM, respectively. Slices recovered from the slicing procedure in the 4 °C cold Krebs-Henseleit buffer as indicated by intracellular potassium concentrations which increased for 2 h and then remained stable until the end of the incubation. TES was extensively metabolized by human liver slices with a similar metabolite pattern as observed in vivo. Almost 90% of the metabolites were conjugates. Major phase-I metabolites were androstendione, 6ß-OH-androstendione, 6ß-OH-TES, and 15ß-OHTES. After incubation with 2-AF, substance related DNA-adducts were detected which increased dose-dependently from 12 to 1146 adducts per 10(9) nucleotides. The adduct pattern consisted of one major adduct spot, A, representing 80-90% of the total adduct level and up to four minor adduct spots, B-E. In summary, the present data demonstrate that precision-cut liver slices are a valuable alternative in vitro system for DNA-adduct determination to screen chemicals for potential genotoxicity in humans.

A case of Crohn's disease with increased CD8 T-cell activation and remission during therapy with intravenous immunoglobulins.

BACKGROUND: Crohn's disease (CD) represents a chronic inflammatory bowel disease with abnormal CD8 T-cell function in a subgroup of patients. METHODS: A 55-year-old woman presented with CD on the basis of clinical, endoscopic, radiologic, histologic, and sonographic examination. Since the disease could not be controlled with conventional anti-inflammatory therapy, a detailed analysis of cellular and humoral immune functions was performed and showed a dysbalanced T-cell activation pattern with an inverse CD4/CD8 ratio due to an increased number of CD8 T cells. Additionally, high IgM and low IgG2 antibody levels were detected. Treatment with intravenous immunoglobulin (IVIG) was started as immunomodulatory therapy. During this therapy the condition improved markedly. CD8 T-cell levels returned to normal, and IgM decreased as well. CONCLUSION: This case shows that selected cases of CD may be associated with abnormal functions and that such patients may benefit from IVIG treatment.

DNA adduct formation of selected sex steroids in human liver slices in vitro.

We report investigations into the potential of the steroid hormones chlormadinone acetate (CMA), cyproterone acetate (CPA), dexamethasone (DEX), estradiol (E(2)), ethinylestradiol (EE(2)), gestodene (GEST), levonorgestrel (LNG), megestrol acetate (MGA), medroxy progesterone acetate (MPA), mifepristone (MIFE), norethisterone (NET), prednisolone (PRED), progesterone (P) and testosterone (T) to form DNA adducts in precision-cut human liver slices in vitro from 14 male and female donors using the (32)P-postlabelling technique. The synthetic steroid hormones CPA, CMA and MGA generated DNA adducts in human liver slices obtained from all donors. MPA-related adduct spots were only observed in some of the livers tested. No DNA adduct formation was detectable with DEX, EE(2), E(2), GEST, LNG, MIFE, NET, PRED, P and T. The total DNA adduct levels and adduct patterns were different for each compound. On average, total DNA adduct levels decreased in the following order: CPA>MGA>CMAMPA. The DNA adduct levels varied inter-individually. At a treatment concentration of 1mug/ml, the coefficient of variation of the total adduct levels ranged from 38% to 101%. A sex-specific distribution of the DNA adduct formation was only detected after incubation with MPA. MPA-related adduct spots were observed predominantly in the livers of female donors.