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Celiac disease (CD) is a known risk factor for osteoporosis and fractures. The prevalence of CD in patients with a recent fracture is unknown. We therefore systematically screened patients at a fracture liaison service (FLS) to study the prevalence of CD. Patients with a recent fracture aged ≥ 50 years were invited to VieCuri Medical Center's FLS. In FLS attendees, bone mineral density (BMD) and laboratory evaluation for metabolic bone disorders and serological screening for CD was systematically evaluated. If serologic testing for CD was positive, duodenal biopsies were performed to confirm the diagnosis CD. Data were collected in 1042 consecutive FLS attendees. Median age was 66 years (Interquartile range (IQR) 15), 27.6% had a major and 6.9% a hip fracture, 26.4% had osteoporosis and 50.8% osteopenia. Prevalent vertebral fractures were found in 29.1%. CD was already diagnosed in two patients (0.19%), one still had a positive serology. Three other patients (0.29%) had a positive serology for CD (one with gastro-intestinal complaints). In two of them, CD was confirmed by duodenal histology (0.19%) and one refused further evaluation. The prevalence of biopsy-proven CD was therefore 0.38% (4/1042) of which 0.19% (2/1042) was newly diagnosed. The prevalence of CD in patients with a recent fracture at the FLS was 0.38% and within the range of reported prevalences in the Western-European population (0.33-1.5%). Newly diagnosed CD was only found in 0.19%. Therefore, standard screening for CD in FLS patients is not recommended.

Objective: For palliation of extrahepatic bile duct obstruction, self-expandable metal stents (SEMS) are superior to plastic stents in terms of stent patency and occurrence of stent dysfunction. We assessed health-related quality of life (HRQoL) after stent placement to investigate whether this also results in a difference in HRQoL between patients treated with a plastic stent or SEMS., Patients and Methods: This randomized multicenter trial included 219 patients who were randomized to receive plastic stent (n=73) or SEMS [uncovered (n=75) and covered (n=71); n=146] placement. HRQoL was assessed with two general questionnaires (EQ-5D-3L and QLQ-C30) and one disease-specific questionnaire (PAN-26). Scores were analyzed using linear mixed model regression and included all patients with baseline and at least one follow-up measurement., Results: HRQoL data were available in 140 of 219 patients (64%); 71 patients (32%) declined participation and in eight patients (4%) only baseline questionnaires were available. On the QLQ-C30, the interaction between follow-up time and type of stent was significantly different on two of five functional scales [physical functioning (P=0.004) and emotional functioning (P=0.01)] in favor of patients with a SEMS. In addition, patients with SEMS reported significantly less frequent symptoms of fatigue (P=0.01), loss of appetite (P=0.02), and nausea and vomiting (0.04) over time. The EQ-VAS score decreased with time in both treatment groups, indicating a statistically significant decrease in HRQoL over time., Conclusion: In patients with inoperable malignant extrahepatic bile duct obstruction, SEMS placement results in better scores for general and disease-specific HRQoL over time compared with plastic stent placement.

Background & Aims: Endoscopic stents are placed for palliation of extrahepatic bile duct obstruction. Although self-expandable metal stents (SEMS) remain patent longer than plastic stents, they are more expensive. We aimed to evaluate which type of stent (plastic, uncovered SEMS [uSEMS], or partially covered SEMS [pcSEMS]) is the most effective and we assessed costs., Methods: We performed a multicenter randomized trial in 219 patients at 18 hospitals in The Netherlands from February 2008 through February 2013. Patients were assigned randomly for placement of a plastic stent (n = 73), uSEMS (n = 75), or pcSEMS (n = 71) during endoscopic retrograde cholangiopancreatography. Patients were followed up for up to 1 year. Researchers were not blinded to groups. The main study end points included functional stent time and costs., Results: The mean functional stent times were 172 days for plastic stents, 288 days for uSEMS, and 299 days for pcSEMS (P < .005 for uSEMS and pcSEMS vs plastic). The initial placement of plastic stents (€1042 or $1106) cost significantly less than placement of SEMS (€1973 or $2094) (P = .001). However, the total cost per patient at the end of the follow-up period did not differ significantly between plastic stents (€7320 or $7770) and SEMS (€6932 or $7356) (P = .61). Furthermore, in patients with short survival times (≤3 mo) or metastatic disease, the total cost per patient did not differ between plastic stents and SEMS. No differences in costs were found between pcSEMS and uSEMS., Conclusions: Although placement of SEMS (uncovered or partially covered) for palliation of extrahepatic bile duct obstruction initially is more expensive than placement of plastic stents, SEMS have longer functional time. The total costs after 1 year do not differ significantly with stent type. Dutch Clinical Trial Registration no: NTR1361., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

What Is Already Known About This Subject: The efficacy-tolerability profile of tamsulosin in patients with benign prostatic hyperplasia (BPH) is assumed to be associated both with the α1-adrenoceptor selectivity profile of the drug and a small peak : trough ratio in the plasma pharmacokinetic (PK) profile. Tamsulosin is highly bound to plasma proteins, notably α1-acid glycoprotein (AGP). This protein is a high-affinity binding protein and AGP plasma concentration was found to influence the therapeutic (unbound) plasma concentrations for high-AGP-binding drugs., What This Study Adds: The study actually assessed unbound tamsulosin concentrations in both blood plasma and prostate tissue and reported that the unbound tamsulosin concentrations after multiple dosing in men with BPH, were much higher in prostate than in blood plasma. The assumption is put forward that differential free drug concentrations in prostate and blood plasma may contribute to the relative ‘uroselectivity’ of tamsulosin., Aim: The aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients., Methods: Forty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6-21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (f(u)) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with (14)C-tamsulosin., Results: C(max) in plasma at 4.4 h for total tamsulosin was 15.2 ng ml(-1) and AUC(0,24 h) was 282 ng ml(-1) h, while for prostate C(max) at 11.4 h post-dose was 5.4 ng ml(-1) and AUC(0,24 h) was 120 ng ml(-1) h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). f(u) was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma C(max) concentrations., Conclusions: These data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma., (© 2011 Astellas Pharma Europe B.V. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Introduction: Preoperative work-up in colorectal cancer is comprehensive and can be time consuming. In our institution, the preoperative track for colorectal patients was reorganized in order to reduce the therapeutic delay and the number of outpatient clinic visits. We assessed the impact upon the patient outcomes., Methods: All consecutive patients with colon cancer who entered the reorganized preoperative track between January 2008 and December 2009 (n = 87) were retrospectively compared with a consecutively diagnosed traditionally evaluated patient group diagnosed between January 2005 and December 2006 (n = 108). Time between diagnostic procedures and surgery as well as needed number of preoperative outpatient department visits were calculated. All rectal malignancies, patients who received preoperative chemotherapy and/or radiotherapy and patients who underwent emergency procedures were excluded from analysis., Results: Time between colonoscopy and surgery was reduced from [median (25-75%)] 44 (34-54) to 27 (21-34) days, p < 0.001. The number of outpatient department visits declined from 6 (5-7) to 3 (3-4), p < 0.001. Time between first diagnostic test and colonoscopy was reduced from 44 (11-68) to 9 days (0-30), p < 0.001. Time between first diagnostic test and operation was reduced from 85.5 (56-120.5) to 42 days (28-62), p < 0.001. Before the reorganizations, 7% of colonoscopies were ordered by GPs and went up afterwards to 60%., Conclusion: Reorganization of traditional logistic routes for patients diagnosed with colon cancer reduces therapeutic delay and improves care. Moreover, the surgeon, gastroenterologist and oncologist can focus on the oncologic patient and his/her family instead of having to perform administrative tasks., (Copyright © 2011 S. Karger AG, Basel.)

Objective: The European Panel on the Appropriateness of Crohn's disease Therapy (EPACT) has developed appropriateness criteria. We have applied these criteria retrospectively to the population-based inception cohort of Crohn's disease (CD) patients of the European Collaborative Study Group on Inflammatory Bowel Disease (EC-IBD)., Material and Methods: A total of 426 diagnosed CD patients from 13 European centers were enrolled at the time of diagnosis (first flare, naive patients). We used the EPACT definitions to identify 247 patients with active luminal CD. We then assessed the appropriateness of the initial drug prescription according to the EPACT criteria., Results: Among the cohort patients 163 suffered from mild-to-moderate CD and 84 from severe CD. Among the mild-to-moderate disease group, 96 patients (59%) received an appropriate treatment, whereas for 66 patients (40%) the treatment was uncertain and in one case (1%) inappropriate. Among the severe disease group, 86% were treated medically and 14% required surgery. 59 (70%) were appropriately treated, whereas for one patient (1%) the procedure was considered uncertain and for 24 patients (29%) inappropriate., Conclusion: Initial treatment was appropriate in the majority of cases for non-complicated luminal CD. Inappropriate or uncertain treatment was given in a significant minority of patients, with an increased potential risk of adverse events.

Background and Aims: Increasing incidence in Inflammatory Bowel Disease (IBD) has been suggested. Recent data on population based incidence rates within Europe are however scarce. Primary aim was to investigate prospectively the incidence of IBD within a well-defined geographical and administrative area of the Netherlands, the South Limburg IBD registry. Secondary aims were to study the duration of symptoms before diagnosis (lag time) and seasonal influences on the incidence of IBD., Methods: The incidence was examined using standardized registration of all newly diagnosed IBD patients, between 1-1-1991 and 1-1-2003. Medical records were reviewed to verify the diagnosis. At inclusion, diagnostic lag time was registered in months., Results: Age standardized incidence rates per 100,000 person-years (p-y) were: Crohn's Disease, male 4.84, female 7.58; Ulcerative Colitis, male 8.51, female 6.92; and Indeterminate Colitis, male 1.05, female 0.93. Incidence rates did not significantly changes over time in either Crohn's Disease, Ulcerative Colitis or Indeterminate Colitis. Lag time was 5 (0-360) months in Crohn's Disease, 3.0 (0-480) months in Ulcerative Colitis and 3.0 (0-180) months in Indeterminate Colitis. Lag time was not significantly different between the periods 1991-1993 and 2000-2002, and no statistical differences in the onset of symptoms per calendar month or season were found., Conclusions: Our results, from the South Limburg region (the Netherlands), show no significant change in incidence rates of IBD. The incidence found is relatively high compared to other European countries. Lag time did not change during the study period, and seasonal influence of incidence rates could not be confirmed.

Objectives: Disease course in inflammatory bowel disease (IBD) is variable and difficult to predict. To optimize prognosis, it is of interest to identify phenotypic characteristics at disease onset and other prognostic factors that predict disease course. The aim of this study was to evaluate such factors in a population-based IBD group., Methods: IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. A follow-up questionnaire was developed and medical records were reviewed. Patients were classified according to phenotype at diagnosis and risk factors were registered. Disease severity, cumulative medication use, and "surgical" and "nonsurgical" recurrence rates were calculated as outcome parameters., Results: In total, 476 Crohn's disease (CD), 630 ulcerative colitis (UC), and 81 indeterminate colitis (IC) patients were diagnosed. In CD (mean follow-up 7.6 years), 50% had undergone resective surgery. In UC (mean follow-up 7 years), colectomy rate was 8.3%. First year cumulative recurrence rates per 100 patient-years for CD, UC, and IC were 53, 44, and 42%, respectively. In CD, small bowel localization and stricturing disease were negative prognostic factors for surgery, as was young age. Overall recurrence rate was increased by young age and current smoking. In UC, extensive colitis increased surgical risk. In UC, older age at diagnosis initially increased recurrence risk but was subsequently protective., Conclusions: This population-based IBD study showed high recurrence rates in the first year. In CD, small bowel localization, stricturing disease, and young age were predictive for disease recurrence. In UC, extensive colitis and older age at diagnosis were negative prognostic predictors.

Objectives: Perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) have been proposed as markers for diagnosis and for subtyping of inflammatory bowel disease (IBD). The aim of this study was to investigate the association of p-ANCA and ASCA with a 10-year disease outcome in terms of cumulative rate of colectomy and relapse in a population-based European inception cohort of ulcerative colitis (UC) patients., Methods: Serum samples from 432 consenting patients were analysed for p-ANCA and ASCA. The results were compared with the cumulative colectomy rate, relapsing disease and total number of relapses. We used multiple regression analyses adjusted for age, sex, residence, disease extent at diagnosis, smoking, familial IBD and drug treatment to study the relationship between serological values and disease course., Results: The relapse rate was higher in the p-ANCA-positive patients: 82% (95% confidence interval [CI] 75-89%) compared with 67% (CI 62-72%, p=0.011) in the p-ANCA-negative patients. The risk of relapsing disease course was higher by a factor of 1.4 (CI 1.1-1.8, p=0.009) for p-ANCA-positive patients than for p-ANCA-negative patients, and the corresponding relative risk (RR) for the total number of relapses was 1.9 (CI 1.7-2.1, p<0.001). In ASCA-positive patients RR for the total number of relapses was 1.8 (CI 1.5-2.1, p<0.001). No significant association with colectomy rate was found for the presence of either p-ANCA or ASCA., Conclusion: UC patients positive for p-ANCA and possibly for ASCA may have a more unfavourable long-term disease outcome in terms of relapse than UC patients without these markers.

Background: Population based studies have revealed varying mortality for patients with ulcerative colitis but most have described patients from limited geographical areas who were diagnosed before 1990., Aims: To assess overall mortality in a European cohort of patients with ulcerative colitis, 10 years after diagnosis, and to investigate national ulcerative colitis related mortality across Europe., Methods: Mortality 10 years after diagnosis was recorded in a prospective European-wide population based cohort of patients with ulcerative colitis diagnosed in 1991-1993 from nine centres in seven European countries. Expected mortality was calculated from the sex, age and country specific mortality in the WHO Mortality Database for 1995-1998. Standardised mortality ratios (SMR) and 95% confidence intervals (CI) were calculated., Results: At follow-up, 661 of 775 patients were alive with a median follow-up duration of 123 months (107-144). A total of 73 deaths (median follow-up time 61 months (1-133)) occurred compared with an expected 67. The overall mortality risk was no higher: SMR 1.09 (95% CI 0.86 to 1.37). Mortality by sex was SMR 0.92 (95% CI 0.65 to 1.26) for males and SMR 1.39 (95% CI 0.97 to 1.93) for females. There was a slightly higher risk in older age groups. For disease specific mortality, a higher SMR was found only for pulmonary disease. Mortality by European region was SMR 1.19 (95% CI 0.91 to 1.53) for the north and SMR 0.82 (95% CI 0.45-1.37) for the south., Conclusions: Higher mortality was not found in patients with ulcerative colitis 10 years after disease onset. However, a significant rise in SMR for pulmonary disease, and a trend towards an age related rise in SMR, was observed.

Objective: Geographic differences in disease course of Crohn's disease (CD) might possibly be related to differences in genetic and environmental factors encountered in different parts of the world. The aim of this study was to assess differences in treatment regimens within a European cohort of CD patients as a reflection of disease course, and to identify associated phenotypic risk factors at diagnosis., Material and Methods: A prospective European population-based inception cohort of 380 CD patients was studied. The patients were classified for phenotype according to the Vienna classification. Differences between Northern and Southern European centres in treatment over the first 10 years of disease were analysed using a competing risks survival analysis method., Results: Patients in the North were more likely to have had surgery (p<0.01), whereas patients in the South were more likely to have been treated medically (p<0.01). Phenotype at diagnosis was not predictive of differences in treatment regimens between North and South., Conclusions: In this study, a difference in management of CD was observed between Northern and Southern European centres. This suggests that there may be a North-South disease severity gradient across Europe. Phenotypic differences between patients in the North and South did not explain this observed difference.

Background & Aims: The colectomy rate in ulcerative colitis (UC) is related to morbidity and to treatment decisions made during disease course. The aims of this study were to determine the colectomy risk in UC in the first decade after diagnosis and to identify factors that may influence the choice of surgical treatment., Methods: In 1991-1993, 781 UC patients from 9 centers located in 7 countries in northern and southern Europe and in Israel were included in a prospective inception cohort study. After 10 years of follow-up, 617 patients had complete medical records, 73 had died, and 91 had been lost to follow-up., Results: There were no significant differences in age, sex, or disease extent at diagnosis between patients followed for 10 years and those lost to follow-up. The 10-year cumulative risk of colectomy was 8.7%: 10.4% in the northern and 3.9% in the southern European centers (P < .001). Colectomy was more likely in extensive colitis than in proctitis, with an adjusted hazard ratio (HR) of 4.1 (95% CI: 2.0-8.4). Compared with the southern centers, the adjusted HR was 2.7 (95% CI: 1.3-5.6) for The Netherlands and Norway together and 8.2 (95% CI: 3.6-18.6) for Denmark. Age at diagnosis, sex, and smoking status at diagnosis had no statistically significant influence on colectomy rates., Conclusions: The colectomy rate was found to be lower than that in previous publications, but there was a difference between northern and southern Europe. Colectomy was associated with extensive colitis, but the geographic variations could not be explained.

Background: In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning., Aims: To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis., Methods: A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non-surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease., Results: A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13-2.10)) whereas age >/=40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70-0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21-0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32-7.89))., Conclusions: A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North-South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres.

Background: No previous correlation between phenotype at diagnosis of Crohn's disease (CD) and mortality has been performed. We assessed the predictive value of phenotype at diagnosis on overall and disease related mortality in a European cohort of CD patients., Methods: Overall and disease related mortality were recorded 10 years after diagnosis in a prospectively assembled, uniformly diagnosed European population based inception cohort of 380 CD patients diagnosed between 1991 and 1993. Standardised mortality ratios (SMRs) were calculated for geographic and phenotypic subgroups at diagnosis., Results: Thirty seven deaths were observed in the entire cohort whereas 21.5 deaths were expected (SMR 1.85 (95% CI 1.30-2.55)). Mortality risk was significantly increased in both females (SMR 1.93 (95% CI 1.10-3.14)) and males (SMR 1.79 (95% CI 1.11-2.73)). Patients from northern European centres had a significant overall increased mortality risk (SMR 2.04 (95% CI 1.32-3.01)) whereas a tendency towards increased overall mortality risk was also observed in the south (SMR 1.55 (95% CI 0.80-2.70)). Mortality risk was increased in patients with colonic disease location and with inflammatory disease behaviour at diagnosis. Mortality risk was also increased in the age group above 40 years at diagnosis for both total and CD related causes. Excess mortality was mainly due to gastrointestinal causes that were related to CD., Conclusions: This European multinational population based study revealed an increased overall mortality risk in CD patients 10 years after diagnosis, and age above 40 years at diagnosis was found to be the sole factor associated with increased mortality risk.

Objective: To give a general outline of a 10-year clinical follow-up study of a population-based European cohort of inflammatory bowel disease (IBD) patients and to present the first results in terms of clinical outcome parameters and risk factors., Materials and Methods: A population-based cohort of newly, prospectively, diagnosed cases was initiated between 1991 and 1993. The 2201 patients with IBD (706 had Crohn's disease (CD), 1379 had ulcerative colitis (UC) and 116 had indeterminate colitis) originated from 20 different areas in 11 different European countries and Israel. For the 10-year follow-up of this cohort, electronic data-collecting instruments were made available through an Internet-based website. Data concerning vital status, disease activity, medication use, surgical events, cancer, pregnancy, fertility, quality of life and health-care costs were gathered. A blood sample was obtained from patients and controls to perform genotypic characterization., Results: Thirteen centres from eight European countries and Israel participated. In 958 (316 CD and 642 UC) out of a total of 1505 IBD patients (64%) from these 13 centres, a complete dataset was obtained at follow-up. Even though an increased mortality risk was observed in CD patients 10 years after diagnosis, a benign disease course was observed in this patient group in terms of disease recurrence. A correlation between ASCA and CARD15 variants in CD patients and complicated disease course was observed. A north-south gradient was observed regarding colectomy rates in UC patients. Direct costs were found to be highest in the first year after diagnosis and greater in CD patients than in UC patients, with marked differences between participating countries., Conclusions: This 10-year clinical follow-up study of a population-based European cohort of IBD patients provides updated information on disease outcome of these patient groups.

Aim: To describe an Internet-based data acquisition facility for a European 10-year clinical follow-up study project of a population-based cohort of inflammatory bowel disease (IBD) patients and to investigate the influence of demographic and disease related patient characteristics on response rates., Methods: Thirteen years ago, the European Collaborative study group of IBD (EC-IBD) initiated a population-based prospective inception cohort of 2 201 uniformly diagnosed IBD patients within 20 well-described geographical areas in 11 European countries and Israel. For the 10-year follow-up of this cohort, an electronic patient questionnaire (ePQ) and electronic physician per patient follow-up form (ePpPFU) were designed as two separate data collecting instruments and made available through an Internet-based website. Independent demographic and clinical determinants of ePQ participation were analyzed using multivariate logistic regression., Results: In 958 (316 CD and 642 UC) out of a total number of 1 505 (64%) available IBD patients, originating from 13 participating centers from nine different countries, both ePQ and ePpPFU were completed. Patients older than 40 years at ePQ completion (OR: 1.53 (95%CI: 1.14-2.05)) and those with active disease during the 3 mo previous to ePQ completion (OR: 3.32 (95%CI: 1.57-7.03)) were significantly more likely to respond., Conclusion: An Internet-based data acquisition tool appeared successful in sustaining a unique Western-European and Israelian multi-center 10-year clinical follow-up study project in patients afflicted with IBD.

Background: Disease outcome in Crohn's disease might have changed during the last four decades. Disease outcome measurement in Crohn's disease has methodological difficulties because of patient selection and lack of proper definition of diagnostic and outcome measurement criteria., Aim: To assess possible changes in disease outcome in Crohn's disease during the last four decades., Methods: A systematic literature search was performed using the MEDLINE search engine and major international conference libraries. Articles and abstracts were selected according to stringent inclusion criteria., Results: Forty articles and nine abstracts complied with the inclusion criteria. Seven studies with a median follow-up time between 11.1 and 17 years showed standard mortality ratios in Crohn's disease ranging between 2.16 and 0.72 with a tendency of decline during the last four decades. One study with 11.4 years mean follow-up time showed a statistically significant increased relative risk for colorectal cancer that was not confirmed by three others. Sixteen publications applied in the disease recurrence category. Probability of first resective surgery ranged between 38 and 96% during the first 15 years after diagnosis. The overall recurrence and surgical recurrence rates after first resective surgery ranged between 50 and 60, and 28 and 45% respectively during the following 15 years without an apparent time trend., Conclusion: This structured literature review provides no hard evidence for change in disease outcome in Crohn's disease during the last four decades., (Copyright 2004 Blackwell Publishing Ltd)

It has previously been demonstrated that ototoxicity induced by systemic administration of cisplatin is reduced by concomitant systemic administration of alpha-melanocyte stimulating hormone (alpha-MSH). In this study we investigated the effects of cochlear, perilymphatic application of alpha-MSH during intraperitoneal administration of cisplatin. Guinea pigs, implanted with a round-window electrode, allowing daily monitoring of the compound action potential (CAP), and also implanted with a mini-osmotic pump, pumping at a rate of 0.25 microl/h either physiological saline or alpha-MSH solution (0.02, 2, and 20 microg/ml), were treated daily with a bolus injection of cisplatin (2 mg/kg) until the electrocochleogram showed a persistent decrease in CAP amplitude (> or = 40 dB threshold shift at 8 kHz). Then, cisplatin treatment was stopped, but intracochlear perfusion of alpha-MSH or physiological saline was continued for 10 days to evaluate possible effects of alpha-MSH on the expected recovery. On day 10, the animals were killed and the cochleas were fixed and processed for histological analysis. All groups required 6-7 days of cisplatin to reach the criterion CAP threshold shift. Ten days after cessation of the cisplatin treatment, recovery of the CAP was observed in all groups and at all frequencies, although it was more pronounced at the lower frequencies. With respect to recovery, small statistically significant differences were found between the saline and the alpha-MSH co-treated groups. Histological results showed significantly less outer hair cell (OHC) loss in the group co-treated with 2 microg/ml alpha-MSH as compared to the group co-treated with saline. Since alpha-MSH was directly delivered to the cochlea, the ameliorating effect of alpha-MSH on OHC survival is likely to involve a cochlear target.

It has been shown that alphaMSH and the nonmelanotropic ACTH/MSH(4-9) analog ORG 2766 can ameliorate cisplatin-induced neurotoxicity and ototoxicity. Here, we investigated whether these peptides delay the occurrence of the cisplatin-induced shift in auditory threshold, and whether they affect the subsequent recovery of cochlear potentials. Chronically implanted round window electrodes were used to obtain daily recordings of auditory nerve compound action potentials (CAP) and cochlear microphonics at frequencies ranging from 2 to 16 kHz. Cisplatin (1.5 mg/kg i.p.) plus alphaMSH, ORG 2766 (75 mug/kg s.c.), or saline were injected daily until the 40-dB CAP threshold shift at 8 kHz was reached. Endocochlear potential (EP) was measured either 1-2 days or 28 days later, followed by morphometric analysis of the cochlea. Peptide cotreatment did not consistently delay the threshold shift; however, the CAP threshold recovered faster and to a greater extent, with the potency order being alphaMSH > ORG 2766 > saline. Significant recovery at the 2 highest frequencies was seen in the alphaMSH-treated animals only. CAP amplitude at high sound pressures, which depends more on nerve function than on outer hair cell (OHC) function, decreased severely in all groups but recovered significantly in the alphaMSH- and completely in the ORG-2766-cotreated group. EP was significantly lower in the first days after the threshold shift but had completely recovered at 28 days. Morphometric analysis of the spiral ganglion also indicated involvement of ganglion cells. OHC loss was most severe in the basal turn of saline-cotreated animals. These data suggest that the cisplatin-induced acute threshold shift might be due to reversible strial failure, whereas subsequent OHC survival determines the final degree of functional recovery. Both OHC loss and neuronal function were ameliorated by peptide cotreatment., (Copyright 2003 S. Karger AG, Basel)

It has previously been demonstrated that ototoxicity induced by systemic administration of cisplatin is reduced by concomitant administration of melanocortins, like alpha-melanocyte stimulating hormone (alpha-MSH). However, these experiments were hampered by large interanimal variability. Therefore, we re-investigated the effects of systemically administered alpha-MSH during local (intracochlear) administration of cisplatin. Guinea pigs, implanted with a round-window electrode, allowing daily monitoring of the compound action potentials (CAPs), and a mini-osmotic pump, pumping either 0.5 microl/h physiological saline or cisplatin solution (15 microg/ml), were co-treated daily with a subcutaneous bolus injection of either alpha-MSH (75 microg/kg) or physiological saline for 1 week or until the electrocochleogram showed a persistent decrease in CAP amplitude (40 dB threshold shift at 8 kHz). Next, the animals were sacrificed and the cochleas were processed for histology. After 2-3 days, cisplatin alone caused a threshold shift at all frequencies (2-16 kHz). Co-administration with alpha-MSH consistently delayed the criterion threshold shift by 1 day. When the 40 dB criterion had been reached, similar outer hair cell losses in both the cisplatin/alpha-MSH- and cisplatin/saline-treated groups were observed. This experiment confirms that direct administration of cisplatin into the cochlea results in considerably less interanimal variability than systemic administration and that co-treatment with alpha-MSH delays cisplatin ototoxicity. Since cisplatin was delivered directly to the cochlea, the ameliorating effect of alpha-MSH probably involves a cochlear target.

Zolpidem is a nonbenzodiazepine GABA(A) receptor modulator that binds in vitro with high affinity to GABA(A) receptors expressing alpha(1) subunits but with relatively low affinity to receptors expressing alpha(2), alpha(3), and alpha(5) subunits. In the present study, it was investigated whether this subtype selectivity could be detected and quantified in vivo. Three doses (1.25, 5, and 25 mg) of zolpidem were administered to rats in an intravenous infusion over 5 min. The time course of the plasma concentrations was determined in conjunction with the change in the beta-frequency range of the EEG as pharmacodynamic endpoint. The concentration-effect relationship of the three doses showed a dose-dependent maximum effect and a dose-dependent potency. The data were analyzed for one- or two-site binding using two pharmacodynamic models based on 1) the descriptive model and 2) a novel mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for GABA(A) receptor modulators that aims to separates drug- and system-specific properties, thereby allowing the estimation of in vivo affinity and efficacy. The application of two-site models significantly improved the fits compared with one-site models. Furthermore, in contrast to the descriptive model, the mechanism-based PK/PD model yielded dose-independent estimates for affinity (97 +/- 40 and 33,100 +/- 14,800 ng x ml(-1)). In conclusion, the mechanism-based PK/PD model is able to describe and explain the observed dose-dependent EEG effects of zolpidem and suggests the subtype selectivity of zolpidem in vivo.

A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model for neuroactive steroids, comprising a separate characterization of 1) the receptor activation process and 2) the stimulus-response relationship, was applied to various nonsteroidal GABAA receptor modulators. The EEG effects of nine prototypical GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one beta-carboline) were determined in rats in conjunction with plasma concentrations. Population PK/PD modeling revealed monophasic concentration-EEG effect relationships with large differences in potency (EC50) and intrinsic activity between the compounds. The data were analyzed on the basis of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the assumption of a single and unique stimulus-response relationship. The model converged yielding estimates of both the apparent in vivo receptor affinity (KPD) and the in vivo intrinsic efficacy (ePD). The values of KPD ranged from 0.41 +/- 0 ng.ml(-1) for bretazenil to 436 +/- 72 ng.ml(-1) for clobazam and the values for e(PD) from -0.27 +/- 0 for methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate to 0.54 +/- 0.02 for diazepam. Significant linear correlations were observed between KPD for unbound concentrations and the affinity in an in vitro receptor bioassay (r = 0.93) and between e(PD) and the GABA-shift in vitro (r = 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABAA receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABAA receptor modulators behave as partial agonists relative to neuroactive steroids.

Cisplatin, an important chemotherapeutic agent, has severe dose-limiting side effects including peripheral neurotoxicity and ototoxicity. Peripheral neurotoxicity can be delayed or prevented by simultaneous treatment with a class of neuropeptides known as melanocortins. Examples are ORG 2766, alpha-melanocyte stimulating hormone (alpha-MSH) and melanotan-II (MT-II). In albino guinea pigs, our group has found that ORG 2766 and alpha-MSH can also reduce cisplatin-induced ototoxicity. In this study we investigated the possibly protective effects of MT-II upon cisplatin ototoxicity. Guinea pigs, equipped with a permanent round-window electrode for electrocochleography, were treated with cisplatin (1.5 mg/kg/day intraperitoneal) and simultaneously with MT-II (30 or 3 microg/kg/day subcutaneous) or saline until a 40 dB suppression of the compound action potential (CAP) threshold (3 microV criterion) at 8 kHz occurred. This -40 dB criterion was reached after 5-18 days. Thereafter, the treatment was stopped, but electrocochleography was continued for another 4 weeks. The number of days in which the -40 dB criterion was reached in the MT-II co-treated group did not differ from the period in the saline group. Ten days after the end of the treatment a spontaneous recovery of the CAP was observed in all groups and at all frequencies, although it was more pronounced at lower frequencies. Also with respect to recovery, no differences were found between the saline and the MT-II co-treated group. Thus, in contrast with the otoprotective properties of other melanocortins, MT-II has no protective properties against cisplatin-induced ototoxicity, at least not with the doses applied here.

Background: Infusion of anti-tumour necrosis factor-alpha appears to be highly effective in patients with Crohn's disease., Aim: To assess the effect of infliximab on the quality of life in patients with active or fistulizing disease, as measured by the inflammatory bowel disease questionnaire, and to examine the impact on its four dimensions., Methods: An observational study was conducted in 65 patients. An infusion of 5 mg/kg infliximab was given at week 0 in patients with active disease and at week 0, 2 and 6 in fistulizing disease. Changes from baseline in the total and dimensional inflammatory bowel disease questionnaire scores were calculated and compared between the patient groups. Potential predictors of change in the quality of life were identified., Results: In the active disease group, at week 4, the mean total and dimensional inflammatory bowel disease questionnaire scores improved compared to baseline (P < 0.001). In the fistulizing group, at week 6, all scores changed from baseline (P < 0.05). Improvement in the total inflammatory bowel disease questionnaire score correlated well with the improvement of the Crohn's disease activity index. Systemic and social scores improved more than bowel and emotional scores. Inflammatory Crohn's disease and a young age at diagnosis were predictors for a better response to infliximab therapy., Conclusions: Infliximab therapy improves all dimensions of the quality of life in patients with Crohn's disease.

Zambian under-fives with malaria were selected on a positive thick blood smear for Plasmodium falciparum of at least 1000 parasites/microliter on the day of admission. During a chloroquine course, daily follow-up of parasitaemia was performed. Bloodsamples were taken on day 0 and day 3 to measure chloroquine levels before admission and after treatment. Eighty four patients were evaluated in this study. Forty eight patients did not meet all criteria. Thirty six patients met all criteria, of which 16 (44.5%) patients were infected with sensitive strains (S) and 20 (55.5%) with resistant strains (R) of P.falciparum.