Routine Endoscopy Prior to Surgical Ostomy Closure: An Obsolete Concept.

BACKGROUND: Closure of temporary diverting ostomies is commonly preceded by an endoscopic study of the colonic mucosa and anastomosis, despite lacking evidence of its relevance and impact on subsequent operative management. AIM: We sought to determine the incidence of pathological findings and therefore evaluate the clinical benefit of routine pre-operative endoscopy in asymptomatic patients, hypothesizing sole evaluation of the anastomotic integrity to be sufficient in these cases. METHODS: We retrospectively identified all adult patients with ostomy installations who were followed up for potential reversal surgery between 2002 and 2020 at the University Hospital of Zurich, Switzerland. Main outcome measures were the incidence of endoscopically identified pathological findings in the asymptomatic case cohort and their impact on the subsequent course of treatment. RESULTS: Pre-procedural endoscopic data of 187 cases evaluated for ostomy closure were evaluated. Relevant mucosal findings in the asymptomatic cohort were documented in 26.3% and findings at the anastomotic site detected in 8.7%. A change in subsequent surgical management was noted in 10 patients of the entire cohort (5.3%) and in 9 (5.1%) of all asymptomatic cases. Upon multivariate analyses, the age range of 51 to 60 years old was found to be significantly linked to the presence of endoscopic findings entailing a change in patient management. CONCLUSION: Our findings strongly suggest ostomy closure surgery without previous assessment of the bowel mucosa by means of endoscopy to be acceptable in asymptomatic patients. However, we found it to be indicated in all patients meeting the screening criteria for colorectal carcinoma.

Clarithromycin-based Helicobacter pylori eradication therapy is not associated with higher treatment failure compared with non-clarithromycin-based regimens in a tertiary referral hospital in Switzerland.

BACKGROUND AND AIMS: Due to increasing antibiotic resistance, various Helicobacter pylori eradication regimens other than clarithromycin-based therapies have been proposed. However, detailed data on which therapies were employed and their eradication success is lacking. The purpose of this study was to analyse the response rates of different eradication therapy schemes. METHODS: In this retrospective cohort study, we analysed data of 1721 patients and included 608 patients undergoing H. pylori eradication therapy at the Department of Gastroenterology at the University Hospital Zurich between 2004 and 2018. The primary endpoint was the success rates of clarithromycin- and non-clarithromycin-containing H. pylori eradication regimens. We furthermore analysed factors with potential impact on the outcome of H. pylori eradication therapies, such as demographics, and smoking and social status. RESULTS: The most common therapy scheme (71% of all cases) was proton pump inhibitor (PPI)-amoxicillin-metronidazole, followed by PPI-amoxicillin-clarithromycin (21%) and PPI-metronidazole-clarithromycin (6%). There was no difference between the H. pylori eradication success of clarithromycin vs non-clarithromycin-containing therapies (71% vs 71%, p = 0.764). CONCLUSION: Despite increasing clarithromycin resistance globally, there was no difference in the eradication success of clarithromycin- and non-clarithromycin-containing therapy regimens in Switzerland. As varying triple therapies do not increase eradication rates in real-world settings, other primary therapy options such as quadruple therapies should be explored.

Predisposing and precipitating risk factors for delirium in gastroenterology and hepatology: Subgroup analysis of 718 patients from a hospital-wide prospective cohort study.

Background and Aims: Delirium is the most common acute neuropsychiatric syndrome in hospitalized patients. Higher age and cognitive impairment are known predisposing risk factors in general hospital populations. However, the interrelation with precipitating gastrointestinal (GI) and hepato-pancreato-biliary (HPB) diseases remains to be determined. Patients and methods: Prospective 1-year hospital-wide cohort study in 29'278 adults, subgroup analysis in 718 patients hospitalized with GI/HPB disease. Delirium based on routine admission screening and a DSM-5 based construct. Regression analyses used to evaluate clinical characteristics of delirious patients. Results: Delirium was detected in 24.8% (178/718). Age in delirious patients (median 62 years [IQR 21]) was not different to non-delirious (median 60 years [IQR 22]), p = 0.45). Dementia was the strongest predisposing factor for delirium (OR 66.16 [6.31-693.83], p < 0.001). Functional impairment, and at most, immobility increased odds for delirium (OR 7.78 [3.84-15.77], p < 0.001). Patients with delirium had higher in-hospital mortality rates (18%; OR 39.23 [11.85-129.93], p < 0.001). From GI and HPB conditions, cirrhosis predisposed to delirium (OR 2.11 [1.11-4.03], p = 0.023), while acute renal failure (OR 4.45 [1.61-12.26], p = 0.004) and liver disease (OR 2.22 [1.12-4.42], p = 0.023) were precipitators. Total costs were higher in patients with delirium (USD 30003 vs. 10977; p < 0.001). Conclusion: Delirium in GI- and HPB-disease was not associated with higher age per se, but with cognitive and functional impairment. Delirium needs to be considered in younger adults with acute renal failure and/or liver disease. Clinicians should be aware about individual risk profiles, apply preventive and supportive strategies early, which may improve outcomes and lower costs.

Diagnostic Delay in Patients With Eosinophilic Esophagitis Has Not Changed Since the First Description 30 Years Ago: Diagnostic Delay in Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic progressive disease. Diagnostic delay (DD) is associated with increased risk of esophageal strictures and food impactions. We aimed to assess the evolution of DD since the first description of EoE in 1993 until 2021. METHODS: We analyzed data from patients prospectively included in the Swiss EoE database. DD was calculated as the time interval between the first occurrence of EoE symptoms and the confirmed diagnosis. DD was analyzed annually over time (1989-2021) and according to milestone publications in the field (1993: first description; 2007: first consensus recommendations; and 2011: updated consensus recommendations). In addition, a Cox proportional hazards model has been used to describe the relation between DD and covariates. RESULTS: Complete data of 1,152 patients (857 male [74%]; median age at diagnosis: 38 years, interquartile range: 28-49, range: 1-86) were analyzed. Overall, median DD was 4 years (interquartile range: 1-11, range, 0-56), with DD ≥ 10 years in 32% of the population. Over time, DD did not significantly change, neither annually nor according to release dates of milestone publications with a persistently stable fraction of roughly one-third of all patients with a DD of ≥10 years. Both ages at diagnosis ( P < 0.001, with an increase in DD up to the age of 31-40 years) and at symptom onset (younger patients had a longer DD; P < 0.001) were significantly associated with DD. DISCUSSION: DD has not changed since the first description of EoE almost 30 years ago and remains substantial. Even today, one-third of patients have a persistently high DD of ≥10 years. Substantial efforts are warranted to increase awareness for EoE and its hallmark symptom, solid food dysphagia, as an age-independent red-flag symptom among healthcare professionals and presumably the general population alike to lower risk of long-term complications.

Prognostic factors for spinal chordomas and chondrosarcomas treated with postoperative pencil-beam scanning proton therapy: a large, single-institution experience.

OBJECTIVE: The aim of this paper was to evaluate the prognostic factors in surgical and adjuvant care for spinal chordomas and chondrosarcomas after surgery followed by high-dose pencil-beam scanning proton therapy (PBS-PT). METHODS: From 1997 to 2016, 155 patients (61 female patients; median age 55 years) with spinal (cervical, n = 61; thoracic, n = 29; lumbar, n = 13; sacral, n = 46; pelvic, n = 6) classic chordomas (n = 116) and chondrosarcomas (n = 39; most were low grade) were treated with maximal safe resection followed by PBS-PT (median dose prescribed: 74 Gy [relative biological effectiveness], range 48.6-77 Gy). The majority of patients (n = 153, 98.7%) had undergone at least 1 resection prior to PBS-PT (median 1, range 0-5; biopsy only, n = 2). Fewer than half (45.1%) of the surgeries were rated as gross-total resections (GTRs) prior to PBS-PT. Surgical stabilization (SS) was present in 39% of all patients (n = 60). Ninety-one patients (59%) presented with macroscopic tumor at the start of PBS-PT. The median follow-up duration was 64.7 months (range 12.2-204.8 months). RESULTS: The 5-year local tumor control, disease-free survival (DFS), and overall survival were 64.9% (95% CI 56.3%-73.5%), 59.4% (95% CI 50.6%-68.2%), and 77.9% (95% CI 70.6%-85.2%), respectively. In total, 63 patients (40.6%) experienced failure during the follow-up period: local only in 32 (20.6%), distal only in 7 (4.5%), local + distal in 19 (12.3%), surgical pathway failure (SPF) only in 2 (1.3%), local + SPF in 2 (1.3%), and distal + SPF in 1 (< 1%). Univariate analysis identified gross residual disease, the presence of SS, and treatment era prior to 2008 as highly significant for worse outcome, with all 3 remaining significant on multivariate analysis. The type of surgery (GTR or subtotal resection/biopsy) and whether GTR was achieved by en bloc or curettage did not show a significant prognostic effect. Surgical complications prior to PBS-PT were present in 42.5% of all surgically treated patients and were seen more commonly in patients with multiple surgical interventions (p = 0.005) and those operated on with the intent of en bloc resection (p = 0.006). CONCLUSIONS: The extent of resection and metallic stabilization substantially influenced clinical outcomes for patients with spinal chordoma or chondrosarcoma despite high-dose adjuvant PBS-PT. Optimal upfront surgical management of these tumors continues to include GTR, as possible, with prompt adjuvant proton therapy.

Induced expression of a vestigial sexual signal.

Vestigial morphological traits are common and well known in a variety of taxa. Identification of vestigial genes has illustrated the potential for evolutionary reversals and the re-expression of atavistic traits. Here we induce expression of a behavioural sexual signal, male calling song, in a cricket species, Gryllus ovisopis, which lacks a functional calling song. We successfully used acetylcholine injections in the frontal space of the head of male crickets to activate cerebral command neurons for cricket calling, and we recorded calling songs with a temporal chirp pattern similar to that of G. ovisopis' close evolutionary relatives, G. firmus and G. pennsylvanicus, implying that the neural pattern generators that underlie cricket calling behaviour persist in a vestigial state in G. ovisopis To our knowledge, this is the first demonstration of the induced expression of a vestigial behaviour in any organism. The retention of latent neural capacity to express sexual behaviours could have important implications for rapid evolution, trait re-emergence and reproductive isolation.

Long-Term Outcomes and Prognostic Factors After Pencil-Beam Scanning Proton Radiation Therapy for Spinal Chordomas: A Large, Single-Institution Cohort.

PURPOSE: To evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas. METHODS AND MATERIALS: Between 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25-81 years) were treated with adjuvant PBS-PT at the Paul Scherrer Institute: cervical (n = 46), thoracic (n = 4), lumbar (n = 12), and sacral (n = 38). The majority (88%) received PBS-PT alone rather than combined photon-proton therapy. The median radiation therapy dose prescribed was 74 Gy (relative biological effectiveness [RBE]) (range, 59.4-77 Gy [RBE]). Thirty-nine patients (39%) had undergone surgical stabilization, primarily with titanium hardware, before radiation therapy. RESULTS: With a median follow-up of 65 months (range, 13-175 months), 5-year local control, disease control, and overall survival rates were 63% (95% confidence interval [CI] 57.7-68.7%; median, 103 months), 57% (95% CI 50.9-62.1%; median, 82 months), and 81% (95% CI 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of surgical stabilization was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (grade ≥3) toxicities were rare in both the acute (8%) and late (6%) settings. CONCLUSION: For spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiation therapy. The presence of metallic surgical stabilization prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of surgical stabilization on therapy for these challenging tumors.

Long-Term Clinical Outcomes of Pencil Beam Scanning Proton Therapy for Benign and Non-benign Intracranial Meningiomas.

PURPOSE: To assess and report long-term clinical outcomes regarding local control, overall survival, and toxicity-free survival after pencil beam scanning proton therapy for intracranial meningiomas at a single institution. PATIENTS AND METHODS: Ninety-six patients (male/female, 29/67; median age 52.8 years) with intracranial meningiomas (World Health Organization [WHO] grade 1, n=61 [63.5%]; WHO grade 2, n=33 [34.4%]; WHO grade 3, n=2 [2.1%]) were treated with pencil beam scanning proton therapy (n=53 [55.2%] at diagnosis, n=17 [17.7%] at recurrence, and n=26 [27.1%] for tumor progression). Median gross tumor volume before PBSPT was 21.4 cm3 (range, 0.0-546.5 cm3), with a median planning target volume of 123.4 cm3 (range, 4.6-1142.0 cm3). Median duration of follow-up was 56.9 months (range, 12.1-207.2 months). Late toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Thirteen failures (14%) (male/female, 6/7) were observed, of which the majority (n=9, 69%) were of non-benign histology. The 5-year actuarial local control and overall survival were 86.4% and 88.2%, respectively. Five-year grade ≥3 toxicity-free survival was 89.1%. On univariate analysis, local control was worse for patients with higher WHO grade (P≤.001), those treated after at least 1 recurrence (P=.006), those with non-skull base tumor location (P=.014), and males (P=.032). Significant prognosticators for 5-year overall survival were local control (P≤.001), age (P=.002), and timing of proton therapy (initial vs recurrence) (P=.002). CONCLUSIONS: Pencil beam scanning proton therapy is an effective and safe treatment for patients with intracranial meningiomas, resulting in high local control rates with limited toxicity. Up-front radiation likely results in improved outcomes and should be considered, especially for patients with non-benign tumors and/or for those with incomplete resections.

Pencil beam scanned protons for the treatment of patients with Ewing sarcoma.

BACKGROUND: Few data exist regarding the clinical outcome of patients with Ewing sarcoma (EWS) treated with pencil beam scanning proton therapy (PT). We report the outcome of children, adolescents and young adults (AYA) treated with PT at the Paul Scherrer Institute. MATERIALS: Thirty-eight patients (median age, 9.9 years) received a median dose of 54.9 Gy(RBE) (where RBE is relative biologic effectiveness). Size of the tumor ranged from 1.7 to 24 cm. Most common primary site was axial/pelvic (n = 27; 71%). Four patients (11%) presented with metastases at diagnosis. Twenty (53%) patients had chemo-PT only. Median follow-up was 49.6 months (range, 9.2-131.7). RESULTS: The 5-year actuarial rate of local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were 81.5%, 76.4%, and 83.0%, respectively. All local recurrences occurred in field and in patients with nonextremity primaries. Six patients died, all of tumor progression. Age < 10 years was a favorable factor of borderline significance for LC (P = 0.05) and OS (P = 0.05), but was significant for DMFS (P = 0.003). Tumor volume <200 ml was a significant prognostic factors for DMFS (P = 0.03), but not for OS (P = 0.07). Metastasis at diagnosis was a strong predictor of local failure (P = 0.003). Only two grade 3 late toxicities were observed. The 5-year actuarial rate of grade 3 toxicity-free survival was 90.9%. CONCLUSIONS: These preliminary data suggest that the outcomes of children and AYA with EWS are good and PT was well tolerated with few late adverse events. The local and distant tumor control for older patients with large pre-PT tumor volumes remains problematic.

Use of a proactive duplex ultrasound protocol for hemodialysis access.

OBJECTIVE: Arteriovenous fistula (AVF) creation is the preferred approach for hemodialysis access; however, the maturation of AVFs is known to be poor. We established a proactive early duplex ultrasound (DUS) surveillance protocol for evaluating AVFs before attempted access. This study determined the effect of this protocol related to improving AVF maturation. METHODS: From 2008 to 2013, 153 patients received new upper extremity AVFs and an early DUS surveillance protocol at a single academic institution. The protocol involved an early DUS evaluation before hemodialysis cannulation of the AVF at 4 to 8 weeks after AVF creation. A positive DUS result was identified as a peak systolic velocity of >375 cm/s or a >50% stenosis on gray scale imaging, along with decreased velocity in the outflow vein. Patients with positive DUS findings underwent prophylactic endovascular or open intervention to assist with AVF maturation. Nature of secondary interventions, as well as AVF patency and maturation, were assessed. Overall clinical outcomes and fistula patency were investigated. RESULTS: During the study period, 183 upper extremity AVFs were created in 153 patients, including 82 radiocephalic, 63 brachiocephalic, and 38 brachiobasilic AVFs. A mortality rate of 43% (n = 66) was observed in a median follow-up period of 34.5 months (interquartile range, 19.6-46.9). A total of 164 early DUS were performed at a median of 6 weeks (interquartile range, 3.4-9.6 weeks) after the initial creation. Early DUS showed nine AVFs were occluded and were excluded from further analysis. Hemodynamically significant lesions were found in 62 AVFs (40%); however, only 17 (11%) were associated with an abnormal physical examination. Positive DUS finding prompted a secondary intervention in 81% of the patients. Among those with positive early DUS findings, AVF maturation was 70% in those undergoing a secondary intervention compared with 25% in those not undergoing a prophylactic intervention (P = .011). Primary-assisted patency for AVFs with early positive and negative DUS findings were 83% and 96% at 6 months, 64% and 89% at 1 year, and 52% and 82% at 2 years, respectively (P < .001). CONCLUSIONS: Early DUS surveillance of AVFs before initial access is reasonable to identify problematic AVFs that may not be reliably detected on clinical examination. Although DUS criteria for AVFs have yet to be universally accepted, proactive early postoperative DUS interrogation assists in the early detection of dysfunctional AVFs and improvement of fistula maturation. Despite improved patency in those with positive DUS findings who undergo prophylactic secondary intervention, overall patency remains inferior to those without an abnormality detected on early DUS imaging.

Reduced expression of the epidermal growth factor signaling system in preeclampsia.

INTRODUCTION: The epidermal growth factor (EGF) signaling system regulates trophoblast differentiation, and its disruption could contribute to perinatal disease. We hypothesized that this pathway is altered in preeclampsia, a disorder associated with trophoblast apoptosis and failure to invade and remodel the uterine spiral arteries. METHODS: Six EGF family peptides and a truncated EGF receptor splice variant (p110/EGFR) were examined using immunohistochemistry in the trophoblast of placentas (N = 76) from women with preeclampsia, and compared to placentas from women of similar gestational age (GA) with preterm labor (PTL) or small for gestational age (SGA) fetuses, as well as normal term placentas. EGF, transforming growth factor-α (TGFA), and heparin-binding EGF-like growth factor (HBEGF) were evaluated using ELISA in maternal plasma from another 20 pregnancies with or without preeclampsia. Cell death was evaluated in the HTR-8/SVneo human cytotrophoblast cell line using TUNEL to evaluate the protective effects of EGF peptides. RESULTS: Trophoblast HBEGF, TGFA, and EGF were significantly reduced in preeclampsia compared to PTL and SGA, while p110/EGFR accumulated significantly on the surface of the chorionic villi (p < 0.05). Plasma EGF levels were significantly decreased in preeclamptic patients, compared to non-preeclamptic patients (p < 0.05). HBEGF, EGF, TGFA, epiregulin, and betacellulin each blocked cytotrophoblast cell death in vitro (p < 0.05). DISCUSSION: Three members of the EGF family are dysregulated in placentas with preeclampsia, whereas p110/EGFR, a potential EGF receptor antagonist, is overexpressed. These findings are consistent with the concept that disruption of the EGF signaling system contributes to aberrant trophoblast development associated with preeclampsia.

Factors associated with recurrence of varicose veins after thermal ablation: results of the recurrent veins after thermal ablation study.

BACKGROUND: The goal of this retrospective cohort study (REVATA) was to determine the site, source, and contributory factors of varicose vein recurrence after radiofrequency (RF) and laser ablation. METHODS: Seven centers enrolled patients into the study over a 1-year period. All patients underwent previous thermal ablation of the great saphenous vein (GSV), small saphenous vein (SSV), or anterior accessory great saphenous vein (AAGSV). From a specific designed study tool, the etiology of recurrence was identified. RESULTS: 2,380 patients were evaluated during this time frame. A total of 164 patients had varicose vein recurrence at a median of 3 years. GSV ablation was the initial treatment in 159 patients (RF: 33, laser: 126, 52 of these patients had either SSV or AAGSV ablation concurrently). Total or partial GSV recanalization occurred in 47 patients. New AAGSV reflux occurred in 40 patients, and new SSV reflux occurred in 24 patients. Perforator pathology was present in 64% of patients. CONCLUSION: Recurrence of varicose veins occurred at a median of 3 years after procedure. The four most important factors associated with recurrent veins included perforating veins, recanalized GSV, new AAGSV reflux, and new SSV reflux in decreasing frequency. Patients who underwent RF treatment had a statistically higher rate of recanalization than those treated with laser.

Expression and functional coupling of liver ß2 - adrenoceptors in the human hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. There are now multiple lines of evidence demonstrating that the ß-adrenoceptor ( ß-AR) signaling plays an important role in the progression and metastasis of cancer and may become a novel target for cancer therapy. Little information exists regarding the status of ß-ARs and their postreceptor intracellular signaling cascade in the development of human HCC. This study was conducted to detect the expression signal transduction of the ß-ARs in liver membranes obtained from patients with HCC and elucidate their possible implication on HCC development. METHODS: The ß-AR density and subtype distribution were determined by receptor binding studies. Protein levels of the ß(2)-AR and G(s)(α) protein were determined by Western blot analysis. The receptor coupling efficiency and biochemical activities of the adenylate cyclase(AC) was also determined. RESULTS: In HCC liver membranes, the ß(2)-AR density was higher than the density in the nonadjacent nontumor liver membranes. The ß(2)-AR protein expression was 1.5-fold increased as compared with nonmalignant controls, and positively correlated with the receptor density. The G s protein expression as well as the receptor, AC and G protein-stimulated activation of the cAMP formation was reduced in HCC. CONCLUSION: The ß(2)-AR was upregulated in human HCC. Despite this upregulation of the receptor,there was an altered postreceptor signal transduction in HCC liver. The mechanisms responsible for this change in the growth of HCC and the nature of this alteration remain unclear.

Determinants of adverse events in vascular surgery.

BACKGROUND: Patient safety is a national priority. Patient Safety Indicators (PSIs) monitor potential adverse events during hospital stays. Surgical specialty PSI benchmarks do not exist, and are needed to account for differences in the range of procedures performed, reasons for the procedure, and differences in patient characteristics. A comprehensive profile of adverse events in vascular surgery was created. STUDY DESIGN: The Nationwide Inpatient Sample was queried for 8 vascular procedures using ICD-9-CM codes from 2005 to 2009. Factors associated with PSI development were evaluated in univariate and multivariate analyses. RESULTS: A total of 1,412,703 patients underwent a vascular procedure and a PSI developed in 5.2%. PSIs were more frequent in female, nonwhite patients with public payers (p < 0.01). Patients at mid and low-volume hospitals had greater odds of developing a PSI (odds ratio [OR] = 1.17; 95% CI, 1.10-1.23 and OR = 1.69; 95% CI, 1.53-1.87). Amputations had highest PSI risk-adjusted rate and carotid endarterectomy and endovascular abdominal aortic aneurysm repair had lower risk-adjusted rate (p < 0.0001). PSI risk-adjusted rate increased linearly by severity of patient indication: claudicants (OR = 0.40; 95% CI, 0.35-0.46), rest pain patients (OR = 0.78; 95% CI, 0.69-0.90), ulcer (OR = 1.20; 95% CI, 1.07-1.34), and gangrene patients (OR = 1.85; 95% CI, 1.66-2.06). CONCLUSIONS: Patient safety events in vascular surgery were high and varied by procedure, with amputations and open abdominal aortic aneurysm repair having considerably more potential adverse events. PSIs were associated with black race, public payer, and procedure indication. It is important to note the overall higher rates of PSIs occurring in vascular patients and to adjust benchmarks for this surgical specialty appropriately.

European initiative towards quality standards in education and training for discovery, development and use of medicines.

This position paper recommends a set of standards for quality assessment of continuing professional development (CPD) for medicines research and development (R&D). We have developed these standards to help us achieve the education and training goals of the Innovative Medicines Initiative (IMI; www.imi.europa.eu/), which is developing courses to address the skills gaps in European medicines R&D. The IMI shared standard for course quality will enable professionals in medicines R&D to create a personalized portfolio of education and training that best suits their needs. Individuals already working in the pharmaceutical industry will be able to select modules for study on an as-needs basis, which may be combined to gain a qualification that is recognized throughout Europe. By seeking input from the medicines R&D community, especially professional bodies involved in the career development of biomedical scientists, we hope to initiate the creation of a mutually recognized framework for lifelong learning in medicines R&D. The shared standards call for defined and transparent admission criteria, a predefined set of teaching objectives leading to defined learning outcomes, assessment of the students' achievement, a system for collecting, assessing and addressing feedback, and provision of appropriate and updated reference material. This framework will make it easier for professionals to develop the skills required by industry, and easier for employers to recognize professionals with appropriate skills. It will obviate some of the need for retraining personnel who have already developed appropriate skills in a different setting, thereby saving the industry additional effort. Fulfilment of quality standards by course providers will be made transparent within the IMI's catalogue of courses, on-course (www.on-course.eu), which will be made publicly available during 2012.

Monitoring of antibiotic consumption in livestock: a German feasibility study.

Every application of antibacterial drugs in veterinary medicine may encourage selection for resistant bacteria. In Germany no valid data are available which would be suitable for a species specific estimation of drug consumption especially regarding food producing animals. Therefore, a representative monitoring of consumption of antibacterial drugs in food producing animals should be implemented. As a first step, a feasibility project was conducted to identify the technical preconditions and develop a concept for a regular monitoring system within Germany as a country with a non-central federal state system. The data were collected via the forms obligatory by German law concerning the treatment of animals and the delivery of animal drugs to the animal owners by the veterinarian. 24 veterinary practices and 65 farmers were visited, and all applications of antibiotics to farm animals during the course of one year (September 1, 2006 to August 31, 2007) were entered into a central database. A total of 95,584 records were collected and analysed statistically. Consumption of antibiotics was calculated in kg, but also the number of applications was analysed. The consumption of tetracyclines in kg reached 54.3% of all antimicrobial substances applied to pigs, but only 25.7% of all doses applied to pigs were tetracyclines. For the farms' data, the number of daily doses per animal year (DD(ay)) was estimated based on the number of daily doses recorded and on the number of animals kept in the farm. Correct and detailed data regarding the structures of the farms as well as of veterinary practices are necessary to estimate the consumption of antibiotics reliably. The proposed system is able to function as a monitoring system for antibiotic use in Germany, when the monitoring data are linked to the agricultural data (farm sizes) accounting for differences between German regional agricultural and animal husbandry structures. Furthermore, the results of the antibiotic use analyses may serve as basis to assess the results of the sales data of the pharmaceutical industry. Results are comparable to the outcome of respective systems in other European countries, e.g. the Netherlands and Denmark, and therefore it will contribute to a better understanding and development of strategies for the control of antimicrobial resistances on the European level.

Altered liver α1-adrenoceptor density and phospholipase C activity in the human hepatocellular carcinoma.

The human hepatocellular carcinoma (HCC) is a common cancer with high mortality rate. We examined the density and coupling to phospholipase C (PLC) of the α(1)-adrenoceptors. In HCC liver, the α(1)-adrenoceptor density - as assessed by [³H]-Prazosin binding - was significantly reduced to about 75% when compared to non-adjacent non-tumorous liver (NA-NL) (P=0.0002). The decrease in maximal α(1)-adrenoceptor concentration (B(max)) was accompanied by a significant reduction in noradrenaline-stimulated PLC activity (P<0.032 versus NA-NL) (assessed by [³H]-PIP(2) hydrolysis). GTPγS-stimulated PLC activity in HCC livers did not statistically differ from NA-NL livers. NaF, which activates all G-proteins, stimulated PLC in both HCC and NA-NL livers to a similar extent. The altered noradrenaline-induced functional responsiveness of HCC livers was not reflected by changes in the binding affinity of [³H]-Prazosin for α(1)-adrenoceptors (NA-NL: 0.066 ± 0.010 pmol/l; tumour: 0.067 ± 0.020 pmol/l). These results demonstrate that human HCC causes profound alteration of the hepatic α(1)-adrenoceptor signal transduction pathway and may account for a negative cancer related metabolism of carbohydrates and wasting syndrome in tumour patients.

Growth and differentiation of primary and passaged equine bronchial epithelial cells under conventional and air-liquid-interface culture conditions.

BACKGROUND: Horses develop recurrent airway obstruction (RAO) that resembles human bronchial asthma. Differentiated primary equine bronchial epithelial cells (EBEC) in culture that closely mimic the airway cells in vivo would be useful to investigate the contribution of bronchial epithelium in inflammation of airway diseases. However, because isolation and characterization of EBEC cultures has been limited, we modified and optimized techniques of generating and culturing EBECs from healthy horses to mimic in vivo conditions. RESULTS: Large numbers of EBEC were obtained by trypsin digestion and successfully grown for up to 2 passages with or without serum. However, serum or ultroser G proved to be essential for EBEC differentiation on membrane inserts at ALI. A pseudo-stratified muco-ciliary epithelium with basal cells was observed at differentiation. Further, transepithelial resistance (TEER) was more consistent and higher in P1 cultures compared to P0 cultures while ciliation was delayed in P1 cultures. CONCLUSIONS: This study provides an efficient method for obtaining a high-yield of EBECs and for generating highly differentiated cultures. These EBEC cultures can be used to study the formation of tight junction or to identify epithelial-derived inflammatory factors that contribute to lung diseases such as asthma.