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Previously disclosed TAFIa inhibitors having a urea zinc-binding motif were used as the starting point for the development of a novel class of highly potent inhibitors having a sulfamide zinc-binding motif. High-resolution X-ray cocrystal structures were used to optimize the structures and reveal a highly unusual sulfamide configuration. A selected sulfamide was profiled in vitro and in vivo and displayed a promising ADMET profile.

The design, synthesis, and structure-activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na + /H + exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with 13d as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of 13d then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally 13d, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas.

Background: In 2014, 15 500 persons in Germany were given the diagnosis of renal cell carcinoma. This disease is the third most common cancer of the urogenital system. The mean age at diagnosis is 68 years in men and 71 in men., Methods: Pertinent publications up to 2014 were retrieved by a systematic literature search and reviewed in a moderated, formalized consensus process. Key questions were generated and answered by the adaptation of existing international guidelines, on the basis of an independent literature review, and by expert consensus. Representatives of 30 medical specialty societies, patient self-help groups, and other organizations participated in the process., Results: The search for guidelines yielded 80 hits, 23 of which were judged by DELBI to be potentially relevant; 7 were chosen for adaptation. Smoking, obesity, and hypertension increase the risk of renal cell carcinoma. Its 5-year survival rate is 75% for men and 77% for women. Renal cell carcinoma accounts for 2.6% of all deaths from cancer in men and 2.1% in women. Nephrectomy and partial nephrectomy are the standard treatments. Locally confined tumors in clinical stage T1 should be treated with kidney-preserving surgery. Minimally invasive surgery is often possible as long as the surgeon has the requisite experience. For patients with metastases, overall and progression-free survival can be prolonged with VEGF and mTOR inhibitors. The resection or irradiation of metastases can be a useful palliative treatment for patients with brain metastases or osseous metastases that are painful or increase the risk of fracture., Conclusion: Minimally invasive surgery and new systemic drugs have expanded the therapeutic options for patients with renal cell carcinoma. The search for new predictive and prognostic markers is now in progress.

According to the German S3-guideline 'Palliative Medicine' which has been supported by the German Guideline Program in Oncology, constipation in palliative patients requires a consistent prophylaxis and therapy. Constipation is caused by immobilisation, poor health, exsiccosis, a low-fiber diet or a preexisting functional constipation. Further important causes are substances with constipating side effects, such as opioids or anticholinergic drugs. Pragmatically, constipation should be assessed by subjective parameters such as the feeling of incomplete evacuation, straining, or other complaints. Objective parameters are hard stool or reduced number of bowel movements. For the early detection of constipation the amount of the stool mass and the stool frequency are applicable. If constipation occurs, a standardized escalating protocol applying adequate fluid intake, a high fibre diet, and laxatives is recommended. New prokinetic agents, secretagogues, or opioid antagonists may be used as reserve drugs., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The Guidelines International Network (G-I-N) aims to promote high quality clinical guideline development and implementation. Guideline-based performance measures are a key implementation tool and are widely used internationally for quality improvement, quality assurance, and pay for performance in health care. There is, however, no international consensus on best methods for guideline-based performance measures. In order to address this issue, the G-I-N Performance Measures Working Group aimed to develop a set of consensus-based reporting standards for guideline-based performance measure development and re-evaluation., Methods: Methodology publications on guideline-based performance measures were identified from a systematic literature review and analyzed. Core criteria for the development and evaluation process of guideline-based performance measures were determined and refined into draft standards with an associated rationale and description of the evidence base. In a two-round Delphi-process, the group members appraised and approved the draft standards. After the first round, the group met to discuss comments and revised the drafts accordingly., Results: Twenty-one methodology publications were reviewed. The group reached strong consensus on nine reporting standards concerning: (1) selection of clinical guidelines, (2) extraction of clinical guideline recommendations, (3) description of the measure development process, (4) measure appraisal, (5) measure specification, (6) description of the intended use of the measure, (7) measure testing/validating, (8) measure review/re-evaluation, and (9) composition of the measure development panel., Conclusions: These proposed international reporting standards address core components of guideline-based performance measure development and re-evaluation. They are intended to contribute to international reporting harmonization and improvement of methods for performance measures. Further research is required regarding validity, acceptability, and practicality.

Introduction: Specific recommendations form the centerpiece of medical guidelines. The intended strength of a recommendation is usually expressed by the use of different wordings. Recent investigations showed that guideline users (recipients) interpret the binding character of wordings in different ways. The perception of different wording and their binding character of the strength of guideline recommendations among guideline developers (sender) have so far not been investigated in the German-speaking area., Methods: German-speaking guideline developers were invited online and at specialist meetings to participate in a survey investigating 13 different terms used in guideline recommendations. The aim was to measure their perceived binding character on a visual analog scale (VAS: 0-100). Additional demographic and occupational data were collected. The results were compared with data from a previous survey among guideline users., Results: Overall, 136 guideline developers with an average of 4.2 (median 3) guideline (co-) authorships participated in the survey. While guideline developers interpreted the two imperative recommendations "must" and "must not" with a similarly high level of obligation, the level of obligation was not rated homogenously for strong and weak recommendations like "shall" or "should". Two out of five negative formulations were perceived as more binding than their corresponding positive formulations. In comparisons with the ratings of the guideline users the terms "darf nicht" (must not), (-5.8 VAS, p≤0.0001) and "muss" (must), (-2.9 VAS, p≤0.0006) were perceived as less binding by the guideline developers, as was "sollte nicht"(should not) (-6.6 VAS, p≤0.0001) and "kann nicht empfohlen werden" (cannot be recommended) (-9.4 VAS, p≤0.0001). Only "soll" (shall) was perceived as more binding (+8.7 VAS, p≤0.0001)., Discussion: The current survey demonstrates that guideline developers perceive the binding character of terms used in guideline recommendations in a similar way as it was found for guideline users in a previous survey. Negative recommendations are more often rated as more binding by guideline developers as the corresponding positive terms. The discordant ratings by the guideline developers can be explained by their methodological knowledge regarding formulations of recommendations. It would be desirable that efforts be made to identify wordings in guidelines which better discriminate the intended level of obligation of guideline recommendations with regard to these results., (Copyright © 2016. Published by Elsevier GmbH.)

Anabaenopeptins isolated from cyanobacteria were identified as inhibitors of carboxypeptidase TAFIa. Cocrystal structures of these macrocyclic natural product inhibitors in a modified porcine carboxypeptidase B revealed their binding mode and provided the basis for the rational design of small molecule inhibitors with a previously unknown central urea motif. Optimization based on these design concepts allowed for a rapid evaluation of the SAR and delivered potent small molecule inhibitors of TAFIa with a promising overall profile.

In 2008, the German Guidelines Program in Oncology (GGPO) was launched to promote the development and updating of evidence-based multidisciplinary practice guidelines. This paper describes the organizational structures and methods as well as the embeddedness of the program within a comprehensive strategy to enhance quality of cancer care. Using the example of the German Cancer Plan we argue that the GGPO guidelines are not only an instrument to transfer and exchange knowledge, but also provide an important basis for further initiatives in the field of quality improvement. It is illustrated what was achieved in the first seven years of the GGPO and which challenges will dominate the next years., (Copyright © 2015. Published by Elsevier GmbH.)

For several years patient versions of guidelines have become mandatory in the German Guidelines Program in Oncology (GGPO). Based on the methodology that has been developed for the German National Disease Management Guidelines Program, patient versions of guidelines translate the recommendations of clinical practice guideline into plain language and provide information about the harms and benefits of the interventions being addressed in the guideline. They are developed by a group of guideline authors (experts as well as patients), they are consensus-based and aim to create transparency in recommendations for physicians and their rationales. An automated analysis of readability shows that patient versions of guidelines are specific to the target group of educated lay people. Moreover, the responses to a reader feedback questionnaire indicate that comprehensibility, level of detail and depth of information are considered highly relevant and positive by users. Thus, patient versions of guidelines meet the needs of a specific target group. Nevertheless, the development of other formats for readers with low levels of health literacy or cognitive competencies is desirable. Currently it remains unclear if these simplified formats are able to reflect the complexity of high quality clinical practice guidelines., (Copyright © 2015. Published by Elsevier GmbH.)

Background and Objectives: In 2013 the first German S-3 guidelines on the diagnosis, treatment, and follow-up of melanoma were published in the framework of the German Guideline Program on Oncology. Quality indicators were developed at the same time as the guideline development process in order to implement the guideline recommendations., Patients and Methods: A multidisciplinary, interprofessional working group developed quality indicators following a standardized process., Results: Twelve quality indicators directly linked to guideline recommendations were generated and agreed on by consensus. They were integrated into the catalogue of requirements for dermato-oncological centers certified by the German Cancer Society., Conclusions: The close cooperation between the guideline group and commission for certification allowed the guideline contents to be implemented in the form of quality indicators in everyday clinical practice. Adherence to the guidelines is required and continuously evaluated as part of certification., (© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

The American Board of Internal Medicine (ABIM) Foundation launched the Choosing Wisely campaign in 2012 and until today convinced more than 50 US specialist societies to develop lists of interventions that may not improve people's health but are potentially harmful. We suggest combining these new efforts with the already existing efforts in clinical practice guideline development. Existing clinical practice guidelines facilitate a more participatory and evidence-based approach to the development of top 5 lists. In return, adding top 5 lists (for overuse and underuse) to existing clinical practice guidelines nicely addresses a neglected dimension to clinical practice guideline development, namely explicit information on which Do or Don't do recommendations are frequently disregarded in practice., (Copyright © 2014. Published by Elsevier GmbH.)

Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor resulted from a rational optimization process. Starting from compound 14, with low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 μM, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene P1 fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs factor Xa and thrombin (with Ki's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 μM) in the thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.

The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130 years. Still today, NO-donor drugs are important in the management of cardiovascular diseases. However, inhaled NO or drugs releasing NO and organic nitrates are associated with noteworthy therapeutic shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and nonspecific effects, such as post-translational modification of proteins. The beneficial actions of NO are mediated by stimulation of soluble guanylate cyclase (sGC), a heme-containing enzyme which produces the intracellular signaling molecule cyclic guanosine monophosphate (cGMP). Recently, two classes of compounds have been discovered that amplify the function of sGC in a NO-independent manner, the so-called sGC stimulators and sGC activators. The most advanced drug, the sGC stimulator riociguat, has successfully undergone Phase III clinical trials for different forms of pulmonary hypertension., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

Importance: During guideline development, it is essential to systematically review existing guidelines that may be suitable for adaptation; however, such review is laborious and may not always uncover useful guidelines., Objective: To identify existing clinical practice guidelines and assess their methodologic quality and suitability for adaptation in the German evidence-based guideline "Prevention of Skin Cancer.", Evidence Acquisition: A systematic literature search was performed across a range of databases and homepages of guideline development institutions. The AGREE Instrument (Appraisal of Guidelines Research and Evaluation) was used to assess the methodologic quality of selected guidelines., Results: A total of 480 citations were identified and screened. Of these, 12 guidelines were deemed suitable for potential adaptation. After comprehensive quality assessment, only 2 melanoma guidelines, one from Australia/New Zealand and the other from Scotland, were identified as being of high methodologic quality according to predefined selection criteria. Subsequent synopsis, however, revealed that neither of these guidelines was sufficiently comprehensive for full adaptation., Conclusions and Relevance: It is surprising that most existing skin cancer guidelines that contain aspects on prevention are not appropriate for adaptation, with most lacking methodologic quality, particularly rigor applied during the development process. Of the 2 guidelines that met the predefined quality criteria, only a few aspects--limited to malignant melanoma--were adaptable. We conclude that, despite the labor-intensive search for existing guidelines, a de novo development, including systematic literature review, is indispensible for the development of the German evidence-based guideline Prevention of Skin Cancer.

Novel guanylate cyclase stimulators are disclosed. Design, synthesis, SAR, and pharmacological profile of the compounds are discussed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: About 10,000 persons are diagnosed as having carcinoma of the oral cavity or the throat in Germany every year. Squamous-cell carcinoma accounts for 95% of cases., Methods: We systematically reviewed the pertinent literature on predefined key questions about these tumors (which were agreed upon by a consensus of the investigators), concerning imaging, the removal of cervical lymph nodes, and resection of the primary tumor., Results: 246 clinical trials were selected for review on the basis of 3014 abstracts. There was only one randomized, controlled trial (evidence level 1-); the remaining trials reached evidence levels 2++ to 3. Patients with mucosal changes of an unclear nature persisting for more than two weeks should be examined by a specialist without delay. The diagnosis is made by computed tomography or magnetic resonance imaging along with biopsy and a standardized histopathological examination. Occult metastases are present in 20% to 40% of cases. Advanced disease (stages T3 and T4) should be treated by surgery followed by radiotherapy, with or without chemotherapy. 20% of the patients overall go on to have a recurrence, usually within 2 to 3 years of the initial treatment. The 5-year survival rate is somewhat above 50%. Depending on the radicality of surgery and radiotherapy, there may be functional deficits, osteoradionecrosis, and xerostomia. The rate of loss of implants in irradiated bone is about 10% in 3 years., Conclusion: The interdisciplinary planning and implementation of treatment, based on the patient's individual constellation of findings and personal wishes, are prerequisites for therapeutic success. Reconstructive measures, particularly microsurgical ones, have proven their usefulness and are an established component of surgical treatment.

Background and Aim: Hepatocellular carcinoma (HCC) is the third most common reason for cancer-related death worldwide. Many countries either lack appropriate clinical practice guidelines for the diagnosis and treatment of HCC or the quality of their guidelines has never been evaluated. The main objective of our work was to identify published HCC guidelines and assess their quality with the Appraisal of Guidelines for Research and Evaluation instrument (AGREE) and their suitability regarding adaptation for future guidelines., Methods: We performed a systematic literature search on HCC clinical practice guidelines of MEDLINE, National Guidelines Clearinghouse and the Guidelines International Network. Methodological quality of selected guidelines was assessed by the AGREE instrument, Version 2001., Results: A total of 286 citations were screened and 32 relevant guidelines were identified. Overall, the guidelines performed well in the clarity and presentation domain with a mean score of 67%, followed by scope and purpose (55%) and rigor of development (50%). In contrast, poor scores were given for the remaining domains: stakeholder involvement (23%), applicability (28%) and editorial independence (31%). According to the AGREE instrument, four guidelines can be strongly recommended, 18 with provisos and alterations while the remaining cannot be recommended for adaptation due to poor methodological quality., Conclusion: Although existing HCC guidelines may accurately reflect agreed clinical practice, many guidelines lack proper methodological quality. Future guidelines should place more emphasis on these methodological shortcomings., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Aims: Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects., Methods: We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics., Results: We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost-effective., Conclusions: Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Ulcers as a result of diabetes mellitus are a serious problem with an enormous impact on the overall global disease burden due to the increasing prevalence of diabetes. Because of long hospital stays, rehabilitation, often required home care and the use of social services diabetic foot complications are costly. Therapy with growth factors could be an effective and innovative add-on to standard wound care., Research Questions: What is the benefit of therapies with growth factors alone or in combination with other technologies in the treatment of diabetic foot ulcer assessed regarding medical, economical, social, ethical and juridical aspects?, Methods: We systematically searched relevant databases limited to English and German language and publications since 1990. Cost values were adjusted to the price level of 2008 and converted into Euro. A review and an assessment of the quality of publications were conducted following approved methodical standards conforming to evidence-based medicine and health economics., Results: We identified 25 studies (14 randomized controlled trials (RCT), nine cost-effectiveness analyses, two meta-analyses). The RCT compared an add-on therapy to standard wound care with standard wound care/placebo alone or extracellular wound matrix: in six studies becaplermin, in two rhEGF, in one bFGF, and in five studies the metabolically active skin grafts Dermagraft and Apligraf. The study duration ranged from twelve to 20 weeks and the study population included between 17 to 382 patients, average 130 patients. The treatment with becaplermin, rhEGF and skin implants Dermagraft and Apligraf showed in eight out of 13 studies an advantage concerning complete wound closure and the time to complete wound healing. Evidence for a benefit of treatment with bFGF could not be found. In four out of 14 studies the proportion of adverse events was 30% per study group with no difference between the treatment groups. The methodological quality of the studies was affected by significant deficiencies. The results showed becaplermin being cost-effective whereas no obvious statement can be made regarding Dermagraft and Apligraf because of diverging cost bases and incremental cost-effectiveness ratios., Discussion: Differences in standard wound care are complicating the comparison of study results. Taking into consideration the small to very small sample sizes and other methodological flaws with high potential of bias, the validity of the results with regard to effectiveness and cost-effectiveness has to be considered limited. The duration of treatment and follow-up examinations is not long enough to assess the sustainability of the intervention and the surveillance of ulcer recurrences or treatment related adverse events like the development of malignancy., Conclusions: There are indications of an advantage for the add-on therapy with growth factors in diabetic foot ulcers concerning complete wound closure and the time to complete wound healing. Further more studies of high methodological quality with adequate sample sizes and sufficient follow-up periods are necessary also investigating patient-relevant parameters like the health-related quality of life, the acceptance and tolerance of the intervention in addition to clinical outcomes.

Many phenolic compounds show high boiling points, low molecular weights, moderate polarities or high toxicities. Therefore, conventional wastewater treatment is limited or expensive. Recycling of the separated compounds is often not possible. But, if liquid-liquid reactive extraction is linked to a non-porous membrane, some or all of the above mentioned limitations may be overcome. The key element is a composite membrane with a dense, hydrophobic top layer which avoids the mixing of the two aqueous fluid streams. The dilute phenol stream is one of them, the other is caustic soda as stripping solvent. Since the basics of this technology have been discussed before, the scope of this study is to facilitate process implementation and integration. To this end, a life cycle assessment framework is used to identify the optimal equipment size for the treatment of wastewater that may, for example, originate from the production of polycarbonate. Limiting for this application is not the environmental performance though, but most likely process economics.

Background: The maintenance of internal pH in bacterial cells is challenged by natural stress conditions, during host infection or in biotechnological production processes. Comprehensive transcriptomic and proteomic analyses has been conducted in several bacterial model systems, yet questions remain as to the mechanisms of pH homeostasis., Results: Here we present the comprehensive analysis of pH homeostasis in C. glutamicum, a bacterium of industrial importance. At pH values between 6 and 9 effective maintenance of the internal pH at 7.5 +/- 0.5 pH units was found. By DNA microarray analyses differential mRNA patterns were identified. The expression profiles were validated and extended by 1D-LC-ESI-MS/MS based quantification of soluble and membrane proteins. Regulators involved were identified and thereby participation of numerous signaling modules in pH response was found. The functional analysis revealed for the first time the occurrence of oxidative stress in C. glutamicum cells at neutral and low pH conditions accompanied by activation of the iron starvation response. Intracellular metabolite pool analysis unraveled inhibition of the TCA and other pathways at low pH. Methionine and cysteine synthesis were found to be activated via the McbR regulator, cysteine accumulation was observed and addition of cysteine was shown to be toxic under acidic conditions., Conclusions: Novel limitations for C. glutamicum at non-optimal pH values were identified by a comprehensive analysis on the level of the transcriptome, proteome, and metabolome indicating a functional link between pH acclimatization, oxidative stress, iron homeostasis, and metabolic alterations. The results offer new insights into bacterial stress physiology and new starting points for bacterial strain design or pathogen defense.

We studied the requirement for potassium and for potassium transport activity for the biotechnologically important bacterium Corynebacterium glutamicum, which is used for large-scale production of amino acids. Different from many other bacteria, at alkaline or neutral pH, C. glutamicum is able to grow without the addition of potassium, resulting in very low cytoplasmic potassium concentrations. In contrast, at acidic pH, the ability for growth was found to depend on the presence of K+. For the first time, we provide experimental evidence that a potential potassium channel (CglK) acts as the major potassium uptake system in a bacterium and proved CglK's function directly in its natural membrane environment. A full-length CglK protein and a separate soluble protein harboring the RCK domain can be translated from the cglK gene, and both are essential for full CglK functionality. As a reason for potassium-dependent growth limitation at acidic pH, we identified the impaired capacity for internal pH homeostasis, which depends on the availability and internal accumulation of potassium. Potassium uptake via CglK was found to be relevant for major physiological processes, like the activity of the respiratory chain, and to be crucial for maintenance of the internal pH, as well as for the adjustment of the membrane potential in C. glutamicum.

The soil bacterium Corynebacterium glutamicum is a model organism in amino acid biotechnology. Here we present the identification of two different L-methionine uptake systems including the first characterization of a bacterial secondary methionine carrier. The primary carrier MetQNI is a high affinity ABC-type transporter specific for l-methionine. Its expression is under the control of the transcription factor McbR, the global regulator of sulfur metabolism in C. glutamicum. Besides MetQNI, a novel secondary methionine uptake system of the NSS (neurotransmitter:sodium symporter) family was identified and named MetP. The MetP system is characterized by a lower affinity for methionine and uses Na(+) ions for energetic coupling. It is also the main alanine transporter in C. glutamicum and is expressed constitutively. These observations are consistent with models of methionine, alanine, and leucine bound to MetP, derived from the X-ray crystal structure of the LeuT transporter from Aquifex aeolicus. Complementation studies show that MetP consists of two components, a large subunit with 12 predicted transmembrane segments and, surprisingly, an additional subunit with one predicted transmembrane segment only. Thus, this new member of the NSS transporter family adds a novel feature to this class of carriers, namely, the functional dependence on an additional small subunit.

An in vivo system was developed for the biotransformation of D-fructose into D-mannitol by the expression of the gene mdh encoding mannitol dehydrogenase (MDH) from Leuconostoc pseudomesenteroides ATCC12291 in Bacillus megaterium. The NADH reduction equivalents necessary for MDH activity were regenerated via the oxidation of formate to carbon dioxide by coexpression of the gene fdh encoding Mycobacterium vaccae N10 formate dehydrogenase (FDH). High-level protein production of MDH in B. megaterium required the adaptation of the corresponding ribosome binding site. The fdh gene was adapted to B. megaterium codon usage via complete chemical gene synthesis. Recombinant B. megaterium produced up to 10.60 g/L D-mannitol at the shaking flask scale. Whole cell biotransformation in a fed-batch bioreactor increased D-mannitol concentration to 22.00 g/L at a specific productivity of 0.32 g D-mannitol (gram cell dry weight)(-1) h(-1) and a D-mannitol yield of 0.91 mol/mol. The nicotinamide adenine dinucleotide (NAD(H)) pool of the B. megaterium producing D-mannitol remained stable during biotransformation. Intra- and extracellular pH adjusted itself to a value of 6.5 and remained constant during the process. Data integration revealed that substrate uptake was the limiting factor of the overall biotransformation. The information obtained identified B. megaterium as a useful production host for D-mannitol using a resting cell biotransformation approach.

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1 to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, patient surveys have revealed lack of satisfaction with the efficacy of available treatments and a high rate of non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) initiated a project to develop evidence-based guidelines for the management of psoriasis. These resulting Guidelines focus on induction therapy in cases of mild, moderate, and severe plaquetype psoriasis in adults. The Guidelines include evidence-based evaluation of the efficacy of all currently available therapeutic options in Germany. In addition, they offer detailed information on how best to administer the various treatments and give information on contraindications, adverse drug reactions, and drug interactions as well as estimates of practicability and cost. The Guidelines were developed following the recommendations of the Arbeitsgemeinschaft wissenschaftlicher medizinischer Fachgesellschaften (AWMF). The therapeutic recommendations were developed by an expert group and finalized during interdisciplinary consensus conferences.

Background: Information overload, increasing time constraints, and inappropriate search strategies complicate the detection of clinical practice guidelines (CPGs). The aim of this study was to provide clinicians with recommendations for search strategies to efficiently identify relevant CPGs in SUMSearch and Google Scholar., Methods: We compared the retrieval efficiency (retrieval performance) of search strategies to identify CPGs in SUMSearch and Google Scholar. For this purpose, a two-term GLAD (GuideLine And Disease) strategy was developed, combining a defined CPG term with a specific disease term (MeSH term). We used three different CPG terms and nine MeSH terms for nine selected diseases to identify the most efficient GLAD strategy for each search engine. The retrievals for the nine diseases were pooled. To compare GLAD strategies, we used a manual review of all retrievals as a reference standard. The CPGs detected had to fulfil predefined criteria, e.g., the inclusion of therapeutic recommendations. Retrieval performance was evaluated by calculating so-called diagnostic parameters (sensitivity, specificity, and "Number Needed to Read" [NNR]) for search strategies., Results: The search yielded a total of 2830 retrievals; 987 (34.9%) in Google Scholar and 1843 (65.1%) in SUMSearch. Altogether, we found 119 unique and relevant guidelines for nine diseases (reference standard). Overall, the GLAD strategies showed a better retrieval performance in SUMSearch than in Google Scholar. The performance pattern between search engines was similar: search strategies including the term "guideline" yielded the highest sensitivity (SUMSearch: 81.5%; Google Scholar: 31.9%), and search strategies including the term "practice guideline" yielded the highest specificity (SUMSearch: 89.5%; Google Scholar: 95.7%), and the lowest NNR (SUMSearch: 7.0; Google Scholar: 9.3)., Conclusion: SUMSearch is a useful tool to swiftly gain an overview of available CPGs. Its retrieval performance is superior to that of Google Scholar, where a search is more time consuming, as substantially more retrievals have to be reviewed to detect one relevant CPG. In both search engines, the CPG term "guideline" should be used to obtain a comprehensive overview of CPGs, and the term "practice guideline" should be used if a less time consuming approach for the detection of CPGs is desired.

Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1-S126, 2006; or http://www.psoriasis-leitlinie.de ).

Clinical guidelines have been defined as "systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances". They are designed to evaluate and implement the ever-increasing amount of evidence and opinion on best current practice. They can assist doctors and other health care professionals in making decisions about appropriate and effective care for their patients. Depending on the level of evidence, expert knowledge based and evidence-based guidelines can be distinguished. This article reviews the methods of guideline development, the state of international guidelines in dermatology and the state of the recent German psoriasis-guideline-project.

Some toxicological data and case reports have suggested that patients taking potentially hepatotoxic drugs may have an increased risk of benign and malignant liver tumours. Pharmacoepidemiological studies on this issue are sparse, most of them focusing on the association between hepatocellular carcinoma (HCC) and the use of oral contraceptives (OC). The objectives of our study were to examine the risk of HCC in patients taking the drugs mentioned in these case reports and toxicological studies. We used data from an international case - control study which had investigated the risk of HCC in women taking OC including 317 cases of HCC and 1060 frequency age-matched hospital controls. We investigated the risk for oral antidiabetic and immunosuppressive drugs, methyldopa, nitrofurantoin and clofibrate using unconditional logistic regression analysis. The analysis was adjusted for age, hepatitis B, hepatitis C, alcohol abuse and other risk factors of HCC. The adjusted odds ratios for ever-use of the investigated drugs varied between 0.67 and 1.64, none of them being statistically significant. There was equally no significantly increased risk for long-term use of these drugs. Altogether there is no evidence for an increased risk of HCC in patients taking the drugs investigated, however, the relatively small statistical power for certain drugs with a low exposure prevalence has to be taken into account. Copyright (c) 2000 John Wiley & Sons, Ltd.

Thermography in rheumatology is most often used in a static manner: after having fulfilled the conditions of standardized preparation of the patient in a cold examination room one or more thermograms are taken in standard positions for the respective joints. In our hospital the thermograms are more or less supplementary. The main examination result is a rewarming curve of the skin over the knee joints. The rewarming is provoked by dry cooling of the skin for one minute. Calculation of the slope of the rewarming curve and plotting the slope on a logarithmic scale shows two different rewarming processes in the skin overlying inflamed joints. The faster one is the rewarming by the arterial blood flow in the skin and the slower one is an additional rewarming by a pathological venous skin blood flow originating from deeper tissues under the skin. One has to suppose that the occurrence of excessive nitric oxide production in inflamed tissues is responsible for this pathological venous skin blood flow. Until now only nine patients receiving for the first time methylprednisolone could be included in a therapy study. Therefore only slight indications can be seen in the results. Whereas the erythrocyte sedimentation rate (ESR [mm/h] becomes more homogeneous (lower confidence interval CI 95) over the course of the treatment with decreasing drug dose, the thermal signs of inflammatory activity as measured by dynamic thermography have greater CI 95 values at the end than at the beginning of the treatment under study. This indicates that not all patients had sufficient antiinflammatory medication with the final 6 mg/d of methylprednisolone as measured by dynamic thermography but not by ESR or CRP.

We describe a 73-year-old forest owner with widespread erythema, myalgia, and proximal muscle weakness. The clinical signs and the results of electromyography, magnetic resonance imaging, and a muscle biopsy were consistent with dermatomyositis. However, serology was positive for Borrelia burgdorferi. More importantly, B burgdorferi DNA was detected in skin by polymerase chain reaction techniques, and spirochete-like organisms were detected in the muscle by silver staining. Lyme disease with muscle involvement can mimic or trigger dermatomyositis and should be considered in the differential diagnosis of dermatomyositis.