Ligandability Assessment of IL-1ß by Integrated Hit Identification Approaches.

Human interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that plays a critical role in the regulation of the immune response and the development of various inflammatory diseases. In this publication, we disclose our efforts toward the discovery of IL-1ß binders that interfere with IL-1ß signaling. To this end, several technologies were used in parallel, including fragment-based screening (FBS), DNA-encoded library (DEL) technology, peptide discovery platform (PDP), and virtual screening. The utilization of distinct technologies resulted in the identification of new chemical entities exploiting three different sites on IL-1ß, all of them also inhibiting the interaction with the IL-1R1 receptor. Moreover, we identified lysine 103 of IL-1ß as a target residue suitable for the development of covalent, low-molecular-weight IL-1ß antagonists.

A Clinical Report Utilizing the VITOM 3D® Microvideoscope for Cleft Palate Repair.

Cleft palate surgery has traditionally presented numerous problems for cleft surgeons including ergonomics, limited visual fields restricting the opportunity for demonstration and teaching. Additionally, the move toward online teaching means the ability to record or livestream video is paramount. The following report of eight cleft palate repairs highlights the novel use of the Vitom 3D® microvideoscope as an innovative technique for cleft palate repair with our early experience demonstrating significant ergonomic and teaching benefits.

5,5- and 5,6-Membered Spirocyclic Indolinone Hit-Finding Libraries.

The production of two libraries based on spirocyclic indolinones is described. These libraries were selected from numerous spirocyclic indolinone scaffolds with a library evaluation procedure used routinely at Novartis, based on computed physicochemical properties and measured properties of prototype compounds. The library production yielded 176 and 428 compounds that could be isolated in sufficient amounts and purities based on two closely related scaffolds. The novelty and diversity analysis of these libraries shows their complementarity to the chemical space covered by the structures of the PubChem database.

Structure of lipoprotein lipase in complex with GPIHBP1.

Lipoprotein lipase (LPL) plays a central role in triglyceride (TG) metabolism. By catalyzing the hydrolysis of TGs present in TG-rich lipoproteins (TRLs), LPL facilitates TG utilization and regulates circulating TG and TRL concentrations. Until very recently, structural information for LPL was limited to homology models, presumably due to the propensity of LPL to unfold and aggregate. By coexpressing LPL with a soluble variant of its accessory protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and with its chaperone protein lipase maturation factor 1 (LMF1), we obtained a stable and homogenous LPL/GPIHBP1 complex that was suitable for structure determination. We report here X-ray crystal structures of human LPL in complex with human GPIHBP1 at 2.5-3.0 Å resolution, including a structure with a novel inhibitor bound to LPL. Binding of the inhibitor resulted in ordering of the LPL lid and lipid-binding regions and thus enabled determination of the first crystal structure of LPL that includes these important regions of the protein. It was assumed for many years that LPL was only active as a homodimer. The structures and additional biochemical data reported here are consistent with a new report that LPL, in complex with GPIHBP1, can be active as a monomeric 1:1 complex. The crystal structures illuminate the structural basis for LPL-mediated TRL lipolysis as well as LPL stabilization and transport by GPIHBP1.

Performance measures for endoscopic retrograde cholangiopancreatography and endoscopic ultrasound: A European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative.

The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology present a short list of key performance measures for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). We recommend that endoscopy services across Europe adopt the following seven key and one minor performance measures for EUS and ERCP, for measurement and evaluation in daily practice at centre and endoscopist level: 1 Adequate antibiotic prophylaxis before ERCP (key performance measure, at least 90%); 2 antibiotic prophylaxis before EUS-guided puncture of cystic lesions (key performance measure, at least 95%); 3 bile duct cannulation rate (key performance measure, at least 90%); 4 tissue sampling during EUS (key performance measure, at least 85%); 5 appropriate stent placement in patients with biliary obstruction below the hilum (key performance measure, at least 95%); 6 bile duct stone extraction (key performance measure, at least 90%); 7 post-ERCP pancreatitis (key performance measure, less than 10%); and 8 adequate documentation of EUS landmarks (minor performance measure, at least 90%). This present list of quality performance measures for ERCP and EUS recommended by the ESGE should not be considered to be exhaustive; it might be extended in future to address further clinical and scientific issues.

Performance measures for ERCP and endoscopic ultrasound: a European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative.

The European Society of Gastrointestinal Endoscopy and United European Gastroenterology present a short list of key performance measures for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). We recommend that endoscopy services across Europe adopt the following seven key and one minor performance measures for EUS and ERCP, for measurement and evaluation in daily practice at center and endoscopist level: 1: Adequate antibiotic prophylaxis before ERCP (key performance measure, at least 90 %); 2: Antibiotic prophylaxis before EUS-guided puncture of cystic lesions (key performance measure, at least 95 %); 3: Bile duct cannulation rate (key performance measure, at least 90 %); 4: Tissue sampling during EUS (key performance measure, at least 85 %); 5: Appropriate stent placement in patients with biliary obstruction below the hilum (key performance measure, at least 95 %); 6: Bile duct stone extraction (key performance measure, at least 90 %); 7: Post-ERCP pancreatitis (key performance measure, less than 10 %). 8: Adequate documentation of EUS landmarks (minor performance measure, at least 90 %).This present list of quality performance measures for ERCP and EUS recommended by ESGE should not be considered to be exhaustive: it might be extended in future to address further clinical and scientific issues.

IgG4-related sclerosing cholangitis mimicking hilar cholangiocarcinoma (Klatskin tumor): a case report of a challenging disease and review of the literature.

BACKGROUND: Even though IgG4-related disease has gained increased attention worldwide, the diagnosis remains challenging. IgG4-related sclerosing cholangitis (IgG4-SC) is not well described in the western hemisphere and may mimic cholangiocarcinoma (CC), especially when occurring without other symptoms such as, e.g. concurrent pancreatitis or retroperitoneal fibrosis. We present a case to add further information to the diagnosis and treatment of this challenging disease. CASE REPORT: A 60-year-old male patient presented with painless jaundice. Prior medical history showed diabetes mellitus type I, high blood pressure, and deep vein thrombosis. Diagnostic investigations were strongly suspicious of a Klatskin tumor, although biopsies were inconclusive. The tumor marker Carbohydrate Antigen 19-9 (CA 19-9) was elevated. Prior to the recommended surgery, the patient had two second opinions in two different university hospitals, both arguing for surgery as well. The patient received hilar resection with right hemihepatectomy. During the postoperative course, some major complications occurred, i.e. recurrent pleural effusion, abscess in the liver resection area, sepsis, ileus, and restricted liver metabolism. Treatment with prednisolone did not show any improvement. Approximately 3 months after surgery, the patient died in consequence of acute respiratory failure. Histology showed no signs of CC, but IgG4-SC could be diagnosed. CONCLUSION: In the case of preoperative signs of CC, differential diagnosis of IgG4-SC needs to be considered, in particular, in cases with missing histologic proof of malignant disease.

The Effects of Twelve Weeks of Tai Chi Practice on Anxiety in Stressed But Healthy People Compared to Exercise and Wait-List Groups-A Randomized Controlled Trial.

OBJECTIVE: This randomized controlled trial was undertaken to determine whether 12 weeks of Tai Chi (TC) practice can reduce anxiety in healthy but stressed people. METHOD: Fifty participants were randomized into TC (n=17), exercise (n=17), and wait-list (WL) groups (n=16). Outcome measures used were State Trait Anxiety Inventory, Perceived Stress Scale 14 (PSS14), blood pressure and heart rate variability, visual analogue scale (VAS), and Short Form 36. RESULTS: Significant improvements were observed from baseline for both TC and exercise groups for both state (p <0.01) and trait (p <0.01) anxiety, PSS14 (p <0.01), VAS (p <0.01), mental health domain (p <0.01), and vitality domain (p <0.01). Superior outcomes were also observed for TC when compared with WL for state and trait anxiety (p <0.01) and mental health domain (p <0.05). CONCLUSION: TC reduces stress levels in healthy individuals and provides a safer, cost effective, and less physically vigorous alternative to exercise.

Development of a Novel Questionnaire for the Traditional Chinese Medicine Pattern Diagnosis of Stress.

Currently, there is no definitive diagnosis or list of signs and symptoms for "stress" in either modern biomedicine or Chinese medicine (CM). While modern theories on stress relate to the neurological interaction of a stressor or stimuli on the autonomic nervous system, it is generally regarded as subjective in nature and as such each individual will likely present varying somatic or cognitive signs and symptoms. A questionnaire was therefore developed, based on textual research, that incorporated both general as well as gender specific signs and symptom responses to determine the most common CM patterns associated with individuals who report as feeling stressed. For the 45 females who completed the questionnaire, the mean percentage of symptoms per CM pattern showed that the pattern with the highest average percentage was heart qi deficiency (61.88%) followed by liver blood deficiency (60.23%) and then heart blood deficiency (60.12%). For males (n = 16), heart qi deficiency was also the highest scoring CM pattern with a scoring percentage of 54.81%. In males, however, heart blood deficiency was second with 53.29% followed by liver blood deficiency with 51.10%. Of the general non gender-specific symptoms collected (n = 65 symptoms), the symptom most commonly reported by both men and women was "anxious or racing thoughts", followed by "constant worrying" and "inability to concentrate". The CM diagnostic pattern results may prove useful for clinicians as the change in diagnostic understanding will also modify the treatment principle and subsequent treatment with acupuncture or herbal medicine. Future CM research studies should consider including the questionnaire either as a diagnostic aid or as an outcome measure for acupuncture or herbal medicine studies related to stress.

Update in Natural Orifice Translumenal Endoscopic Surgery (NOTES).

PURPOSE OF REVIEW: The recent developments and clinical applications of natural orifice translumenal endoscopic surgery (NOTES)-procedures and technologies are going to be presented. RECENT FINDINGS: In experimental as well as clinical settings, NOTES-procedures are predominantly performed in hybrid technique. Current experimental studies focus on the implementation of new surgical approaches as well as on the training of procedures. One emphasis in the clinical application is transrectal and transanal interventions. Transanal total mesorectal excision is equivalent to laparoscopic procedures but with the benefit of an even less invasive access. Transvaginal cholecystectomy can achieve results that are comparable to surgeries that are performed with laparoscopic techniques alone. An analysis of the German NOTES-Register concerning appendectomies as well as the national performance of NOTES-interventions in Switzerland is presented. Apart from intraabdominal approaches, several centers proclaim transoral thyroidectomies and transoral mediastinoscopies. SUMMARY: NOTES-procedures are performed in animal experiments as well as in clinical setting although with less frequency. At this time, hybrid techniques using rigid instruments are mainly applied.

Reliability of the NICMAN Scale: An Instrument to Assess the Quality of Acupuncture Administered in Clinical Trials.

BACKGROUND: The aim of this study was to examine the reliability of a scale to assess the methodological quality of acupuncture administered in clinical research. METHODS: We invited 36 acupuncture researchers and postgraduate students to participate in the study. Firstly, participants rated two articles using the scale. Following this initial stage, modifications were made to scale items and the exercise was repeated. Interrater reliability was assessed for individual items using the Fleiss kappa statistic, whilst the overall scale used the intraclass correlation coefficient statistic. A threshold agreement of ≥0.61 was acceptable. RESULTS: We received 26 responses and a 72% response rate. The first phase of testing found moderate reliability with intraclass correlation coefficients of 0.46 and 0.55 for the articles. The interrater reliability of the scales varied between and within the researchers (0.35, 0.60) and was more consistent with the postgraduate students (0.54, 0.54). Five items on the scale scored below the threshold and were revised for further testing. In this phase the intraclass correlation coefficient demonstrated variability between articles but improved to achieve reliability above the agreed threshold. CONCLUSION: This study provides evidence of the reliability of the NICMAN scale although improvements to a small number of items remain.

Protocol: Testing the Relevance of Acupuncture Theory in the Treatment of Myofascial Pain in the Upper Trapezius Muscle.

A protocol for a prospective single-blind parallel four-arm randomized placebo-controlled trial with repeated measures was designed to test the effects of various acupuncture methods compared with sham. Eighty self-selected participants with myofascial pain in the upper trapezius muscle were randomized into four groups. Group 1 received acupuncture to a myofascial trigger point (MTrP) in the upper trapezius. Group 2 received acupuncture to the MTrP in addition to relevant distal points. Group 3 received acupuncture to the relevant distal points only. Group 4 received a sham treatment to both the MTrP and distal points using a deactivated acupuncture laser device. Treatment was applied four times within 2 weeks with outcomes measured throughout the trial and at 2 weeks and 4 weeks posttreatment. Outcome measurements were a 100-mm visual analog pain scale, SF-36, pressure pain threshold, Neck Disability Index, the Upper Extremity Functional Index, lateral flexion in the neck, McGill Pain Questionnaire, Massachusetts General Hospital Acupuncture Sensation Scale, Working Alliance Inventory (short form), and the Credibility Expectance Questionnaire. Two-way analysis of variance (ANOVA) with repeated measures were used to assess the differences between groups.

[Update in pediatric endoscopy]. / Pädiatrische Endoskopie ­ ein Update.

Pediatric endoscopy is a good example of a multidiscipliniary approach. In many, but not all hospitals, endoscopy in pediatric patients is performed by conventional gastroenterologists and only in some centers by pediatric gastroenterologists. This is due to the fact that not as many pediatric gastroenterologists are available. Some of the centers are very experienced. There is only limited literature on pediatric endoscopy available. Therefore, an update may be relevant for both the adult and pediatric gastroenterologists. Here we describe current knowledge on endoscopic procedures in pediatric patients.

The EndoRotor(®): endoscopic mucosal resection system for non-thermal and rapid removal of esophageal, gastric, and colonic lesions: initial experience in live animals.

BACKGROUND AND STUDY AIMS: The EndoRotor(®) is a novel, non-thermal, automated mechanical endoscopic resection system designed to remove benign mucosal neoplastic tissue throughout the gastrointestinal tract. It uses suction pressure to pull in mucosa and rapidly and precisely cut it while automatically transporting the samples to a collection trap for later histologic evaluation. PATIENTS AND METHODS: To study the technical properties and therapeutic potential of this new tool, we performed multiple upper and lower gastrointestinal endoscopic mucosal resections in three healthy live pigs. Animals were anesthetized and kept artificially ventilated while two physicians performed multiple qualitative mucosal resections on various sites of the pigs' esophagus, stomach, duodenum, and colon. RESULTS: Rapid resection of flat and slightly elevated mucosa up to several centimeters in size/diameter was performed. No major bleeding occurred during and after resections. When used properly, no gastrointestinal wall perforations occurred during superficial resections. Perforations in the colon were only observed when the device was deliberately pushed against deeper sub-mucosal layers or when exceptional force was applied to penetrate the gastrointestinal wall. Histologic specimens showed complete mucosal removal at resection sites. The flexible catheter could be moved and directed towards most of the areas of interest in the gastrointestinal tract. CONCLUSION: The EndoRotor rapidly and easily resects flat and slightly elevated gastrointestinal mucosa with a short learning curve. Future studies in humans should be performed to prove its ability for large-area mucosal resections in benign conditions such as laterally spreading adenomas in the colon, or Barrett's mucosa in the distal esophagus.

Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS.

Organic anion transporting polypeptides (OATPs) are polyspecific organic anion transporters, which are expressed in the blood-brain barrier, the choroid plexus, and other organs. The physiologic function of OATPs in extrahepatic tissues remains ambiguous. In rat retina, members of the OATP family are expressed. We therefore investigated the human retina for the expression of OATP1A2 and OATP2B1 and extended the study to human brain. Furthermore, we searched for peptide neurotransmitters as novel OATP substrates. OATP1A2 displayed a broad expression pattern in human retina as assessed by immunofluorescence localization. It is expressed in photoreceptor bodies and somas of amacrine cells. OATP1B2 expression is restricted to the inner nuclear layer and to the inner plexiform layer. Using paraffin sections from human cortex, cerebellum, and hippocampus, OATP1A2 was localized to neurons and neuronal processes, while OATP2B1 is expressed in endothelial cells of brain capillaries. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 and OATP2B1. Double-labeling immunofluorescence of human retina demonstrated the presence of substance P and of vasoactive intestinal peptides in neurons expressing OATP1A2 and OATP2B1, respectively. The expression of OATP1A2 and OATP2B1 in retinal neurons implies a role of these transporters in the reuptake of peptide neurotransmitters released from retinal neurons. The abundant expression of OATP1A2 in brain neurons points to the possibility that OATP1A2 could be involved in the homeostasis of neurosteroids. The high expression of OATP2B1 in brain capillaries supports an important function of OATPs in substance penetration across the blood-brain barrier.

Protocol: the effect of 12 weeks of Tai Chi practice on anxiety in healthy but stressed people compared to exercise and wait-list comparison groups: a randomized controlled trial.

Stress is a major problem in today's fast-paced society and can lead to serious psychosomatic complications. The ancient Chinese mind-body exercise of Tai Chi may provide an alternative and self-sustaining option to pharmaceutical medication for stressed individuals to improve their coping mechanisms. The protocol of this study is designed to evaluate whether Tai Chi practice is equivalent to standard exercise and whether the Tai Chi group is superior to a wait-list control group in improving stress coping levels. This study is a 6-week, three-arm, parallel, randomized, clinical trial designed to evaluate Tai Chi practice against standard exercise and a Tai Chi group against a nonactive control group over a period of 6 weeks with a 6-week follow-up. A total of 72 healthy adult participants (aged 18-60 years) who are either Tai Chi naïve or have not practiced Tai Chi in the past 12 months will be randomized into a Tai Chi group (n = 24), an exercise group (n = 24) or a wait-list group (n = 24). The primary outcome measure will be the State Trait Anxiety Inventory with secondary outcome measures being the Perceived Stress Scale 14, heart rate variability, blood pressure, Short Form 36 and a visual analog scale. The protocol is reported using the appropriate Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) items.

Cyclic carbo-isosteric depsipeptides and peptides as a novel class of peptidomimetics.

A novel and highly efficient cyclization method has been developed to access a new class of cyclic carbo-isosteric depsipeptides and carbo-isosteric peptides. Our strategy requires easily accessible C-terminal methyl ketone ester or amide functionalized linear precursors as starting materials. The well-known reductive amination has then been used to afford cyclic tetra- to octa-pseudopeptides via a selective intramolecular formation of a glycine peptidomimetic unit under moderate dilution.