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Background Ambitious therapeutic goals in the therapy of inflammatory bowel disease need more stringent individual endpoints. Several definitions for composite endpoints are under evaluation to describe disease control. Most commonly symptomatic (PRO2) remission is combined with endoscopic response, histology and/or biomarker remission. Here we explore the addition of fatigues as a lead problem reported by patients with IBD as part of a composite endpoint. Methods We have conducted an interim analysis of an ongoing open label study of patients with Crohn’s disease (CD) and ulcerative colitis (UC) assigned to anti-TNF therapy, vedolizumab, ustekinumab or tofacitinib. Patients are scheduled for evaluations at start of the respective therapy and at weeks 2, 6, 14, 26 and 52. Endoscopies are conducted before therapy and at weeks 14 and 52. Clinical remission (CR) was defined as CDAI < 150 and reduction of partial Mayo score (pMayo) > 50% vs. baseline at week 14. All patients who are not in CR and/or no improvement in endoscopy at week 14 are assessed for a switch in the mechanism of action and observation schedules after a switch are reset to week 0. FACIT-F scores Results Fatigue was present in 52% patients (39/75) at baseline. 54% (25/46) of the patients achieved CR at week 14 while 46% (21/46) did not meet CR criteria (non-responder). Fatigue at baseline was persistent at week 14 in 12% (3/25) of CR responders, in contrast to 43 % (9/21) of non-responders. 64% (21/33) of all patients reached a combined endpoint of CR and absence of fatigue. If fatigue was present at baseline (n = 25), fatigue response was observed in 52% (13/25) of the patients, while CR was only reached in 40% (10/25) and the combined endpoint of CR and fatigue response in 24% (6/25) of the patients at week 14. In contrast, 71% (15/21) of patients without fatigue at baseline reached CR at week 14. Absence of fatigue at baseline thus increased the chance of CR at week 14, with an OR of 3.75 [1.031 – 11.50] (p = 0.0422 in Fisher’s exact test). Conclusion Fatigue is an important complaint strongly impacting the patients’ quality of life. A composite endpoint including fatigue and clinical remission (based on pMayo and CDAI) can be reached in a significant percentage of patients treated with biological therapies. Presence of fatigue at baseline might serve as a strong marker for clinical non-response at week 14. Further evaluation and replication of this novel composite endpoint will be conducted in our ongoing trial with a particular focus on inclusion of endoscopies and long-term outcome.

Background Currently available disease activity indices for IBD (e.g., CDAI and Mayo score) focus on symptoms directly related to intestinal function, while other relevant health consequences of disease activity including quality of life, neuropsychiatric symptoms like depression, and social functionality, are not captured. With better therapies more stringent definitions of patient health have come into focus. One of the most common patient reported outcomes (PROs) in IBD is fatigue, which can be unrelated to endoscopic disease activity. We have shown earlier a strong degradation of tryptophan in active IBD (Nikolaus et al, 2017, Gastroenterology) and low tryptophan levels have been linked in various chronic disease to high fatigue levels. Here, we aim to study the relationship of fatigue with disease activity in the context of therapy response to a biological treatment. Methods Patients with Crohn’s disease and ulcerative colitis with high disease activity (Mayo score ≥ 6, CDAI ≥ 220) and planned new therapy with a biologic agent were included into a prospective observational protocol. After informed consent, clinical disease activity, inflammatory biomarkers, tryptophan levels in serum and fatigue levels were assessed longitudinally at week 0, 2, 6 and 14 after start of induction therapy. Complete assessments including week 14 were available for 38 patients for this interim analysis of the ingoing study. For fatigue assessment we used the validated German version of the fatigue subscale of the FACIT-F questionnaire. Patients were stratified into therapy responder (clinical remission (CR), reduction of partal Mayo score (pMayo) > 50%, CDAI < 150), non-responders (reduction of Mayo Results In the cross-sectional analysis of all patients (n = 76), the fatigue score strongly (inversely) correlated with pMayo and CDAI and correlated positively with tryptophan levels in serum. In receiver operating characteristic (ROC) analysis, FACIT-F score were able distinguish active vs. non-active disease (p < 0.0001, AUC = 0.7619) with specificity of 0.7103 and sensitivity of 0.7160. We did not observe significant differences in fatigue scores between males and females. In the longitudinal analysis, fatigue score only improved in the CR group (n = 25, median FACIT score 30 at baseline vs. 44 at week 14, p = 0.0221), and was significantly higher in CR vs. non-responder (n = 16, median FACIT score 44 vs. 31.5, p = 0.007). Conclusion Fatigue is strongly related but not completely overlapping with disease activity. Fatigue will be evaluated as a a patient-oriented indicator for therapeutic response. This observation will be extended by increasing the cohort size and independent validation.

Background Independent assessments of histologic and endoscopic scores are two commonly used parameters as therapeutic endpoints in ulcerative colitis. However, our individual goal for patients is to achieve (long-term) disease-control. It has been recently shown that the individual combination of histologic and endoscopic remission is related to favorable long-term outcomes1. However, real world evidence for the benefit of using combined endoscopic and histologic remission endpoints is scarce. Methods We collected data from a retrospective cohort study of n=398 patients with active UC who underwent clinical assessment and routine colonoscopy. All patients donated data and biomaterials at the University Hospital Schleswig-Holstein (Kiel) using the broad consent2. The patients were observed over a minimum of 6 months and three individual outcomes were pre-defined as outcome-endpoints: i) therapy escalation (systemic steroids/new targeted MoA), ii) long-term hospitalization and iii) IBD-related surgery. Results 398 UC patients (female: n=166, 41.7%, male: n=232, 58.29% with a median age of 47 years at time of routine colonoscopy) were analyzed. We observed therapy escalation in 134 cases (42.27%), hospitalization in 70 cases (21.21%) and IBD-related surgery in 34 cases (10.66%). Remission at the time of colonoscopy was assessed by endoscopic Mayo (eMayo=0) or Nancy-Index (=0) and used for prediction of long-term outcome.We investigated the benefit of combined endoscopic and histologic remission on long-term outcome by comparing a combination of both eMayo=0 and Nancy=0 against eMayo=0 and Nancy>0. Patients with combined histologic and endoscopic remission show a significantly reduced hazard ratio for all three outcome endpoints, such as therapy escalation (HR 0.20, CI 0.10–0.39, p Conclusion We show that the combined assessment of endoscopic and histologic remission substantially increases the identification of patients with favorable long-term outcome in UC. However, even in patients with combined endoscopic and histologic remission approx. 20% underwent therapy escalation within 6-month period. These data highlight the need of combined endpoints using histology, endoscopy and probably other parameters (e.g. inflammatory biomarkers, patient reported outcomes) to define disease control and predict favorable disease trajectories in the future course of patients with UC.

Background Histological disease severity assessment in ulcerative colitis has become a mainstay in clinical endpoints definition (“histologic remission”) in clinical trials of ulcerative colitis (UC). Among the several scores that were developed for the microscopical assessment of disease activity, the Nancy index (NI) stands out for the least amount of work load due to the lowest number of scoring items. To which extent histologic assessment using NI is affected by interobserver reliability in the real word setting, is poorly understood. We therefore performed a single-center retrospective analysis of NI assessment in patients with ulcerative colitis. Methods We retrospectively evaluated in two independent cohorts with a total of n=1085 of biopsy samples (sigmoid, rectum) taken from 547 clinically diagnosed UC patients, who underwent colonoscopy between 2007 and 2020. Cohort #1 consisted of 637 biopsies from 312 patients, Cohort #2 consisted of 448 biopsies from 235 patients. The NI of these samples were assessed by two blinded pathologists with a different amount of pathological experience. After each cohort a consensus conference was held where samples that were rated with different NI grades were re-assessed, and a consensual score was given by both observers. We evaluated interobserver reliability and differences in the amount of the several grades of the NI rated by the observers. Results The interobserver-agreement of the NI was very-good after the assessment of the 1085 samples (κ = 0,687 [95%-CI: 0,653-0,720]). An improvement of the interobserver-agreement was found with growing numbers of samples evaluated by both observers (1st cohort: κ = 0,659 [95%-CI: 0,615-0,704]; 2nd cohort: κ = 0,726 [95%-CI: 0,675-0,776]). The biggest number of differences were in NI grade 1 (observer 1: n=128; observer 2: n=236). The smallest number of differences were in NI grades 0 (observer 1: n=504; observer 2: n=479) and 3 (observer 1: n=71; observer 2: n=66). After a consensual score was given the largest part of grades were NI grade 0 (n=504) followed by NI grade 2 (n=309). The least number of samples were given NI grade 3 (n=62). Average time for scoring was less than 2 minutes. Conclusion The NI represents an easy-to-use index with very high interobserver reliability to assess the histological disease activity of UC patients in a real-world setting. Though further improvements of the NI regarding stricter classifications of the several grades need to be done to improve the practicability of the index. While NI grades 0 and 3 having a very high level of agreement between the observers, NI grade 1 has a lower agreement-level. This highlights the clinical need to specify histological characteristic leading to NI grade 1.

Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence.A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence.Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels.Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.

Objective The Checklist Individual Strength (CIS) measures four dimensions of fatigue: Fatigue severity, concentration problems, reduced motivation and activity. On the fatigue severity subscale, a cut-off score of 35 is used. This study 1) investigated the psychometric qualities of the CIS; 2) validated the cut-off score for severe fatigue and 3) provided norms. Methods Representatives of the Dutch general population ( n = 2288) completed the CIS. The factor structure was investigated using an exploratory factor analysis. Internal consistency and test-retest reliability were determined. Concurrent validity was assessed in two additional samples by correlating the CIS with other fatigue scales (Chalder Fatigue Questionnaire, MOS Short form-36 Vitality subscale, EORTC QLQ-C30 fatigue subscale). To validate the fatigue severity cut-off score, a Receiver Operating Characteristics analysis was performed with patients referred to a chronic fatigue treatment centre ( n = 5243) and a healthy group ( n = 1906). Norm scores for CIS subscales were calculated for the general population, patients with chronic fatigue syndrome (CFS; n = 1407) and eight groups with other medical conditions ( n = 1411). Results The original four-factor structure of the CIS was replicated. Internal consistency (α = 0.84–0.95) and test-retest reliability ( r = 0.74–0.86) of the subscales were high. Correlations with other fatigue scales were moderate to high. The 35 points cut-off score for severe fatigue is appropriate, but, given the 17% false positive rate, should be adjusted to 40 for research in CFS. Conclusion The CIS is a valid and reliable tool for the assessment of fatigue, with a validated cut-off score for severe fatigue that can be used in clinical practice.

Background: Subjects with Chronic inflammatory diseases (CID) exhibit a profound increase of cardiovascular risk (CVR) resulting in reduced life expectancy. At the same time LDL-cholesterol serum levels seem to be low in these patients suggesting a special type of “rheumatic dyslipidemia”.[for full text, please go to the a.m. URL], 44. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 30. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 26. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Die Therapie mit Infliximab fur den komplizierten Verlauf des M. Crohn und der Colitis ulcerosa wurde durch grose prospektive Therapiestudien in den letzten 10 Jahren etabliert. Mit der Zulassung von Adalimumab besteht nun die Wahl zwischen 2 verschiedenen Biologika fur die Anti-Tumor-Nekrose-Faktor- (TNF-)Therapie. Neben der Unterdruckung der Entzundungsaktivitat ist die Beendigung einer chronischen Glukokortikoidtherapie ein wichtiger Grund fur den Einsatz der Anti-TNF-Therapie geworden. Als neue Indikation zeichnet sich ein fruher Einsatz im Krankheitsverlauf ab. Die zunehmend kritische Beobachtung der vorwiegend infektiosen Nebenwirkungen hat einen klaren Trend zur Monotherapie mit Biologika gesetzt.

The complex microbiome of the human gut contains an excessive amount of genetic information that is more than 100-fold larger than the human genome. In patients with inflammatory bowel disease diversity of the gut microbiome is significantly reduced and moreover specific phyla are overrepresented or underrepresented. However, the functional capacity of the microflora to generate certain metabolic products containing lipids or amino acids- and more complex regulatory substances is more important that the mere annotation of the microorganisms. Modern pharmacological approaches target the functional capacity and constitution of the microbiome. An important strategy is the development of controlled release formulations that deliver defined lipid, carbohydrate or amino acid products derived from nutritional components targeting gut areas distal to the absorption zones of the upper gastrointestinal tract.

The neuropeptide substance P is known to have mnemogenic and reinforcing actions and can exert neurotrophic and regenerative effectsin vitroas well asin vivo. Furthermore, our previous work in the rat showed that either pre- or post-lesion treatment with substance P can promote functional recovery in cases of partial nigrostriatal dopamine lesions. Other work has provided evidence that the effects of substance P might be differentially encoded by its C- and N-terminal fragments. The C-terminal fragment was found to be reinforcing, whereas the mnemogenic as well as neurotrophic properties have been ascribed to the N-terminal sequences. Given these relations, we asked here whether pre-lesion treatment with either a C- or an N-terminal fragment of substance P might differentially affect the behavioral and neurochemical outcome of nigrostriatal dopamine lesions. Therefore, either substanceP1−7or substanceP5−11(37 nmol/kg each) was administered intraperitoneally daily for eight consecutive days before unilateral 6-hydroxy-dopamine lesions of the substantia nigra. Control rats received prelesion treatment with vehicle. Furthermore, we investigated the effects of pre-treatment with Boc-cholecystokinin-4 (0.91 nmol/kg), as we had found an increase in dopamine metabolism in animals that were pre-treated with cholecystokinin-8 in a former study. In accordance with our previous work, drug treatment effects were observed when excluding animals with most severe dopamine lesions: In animals with partial lesions (residual neostriatal dopamine levels of more than 10%), lesion-dependent asymmetries in turning behavior were observed in animals that were pre-treated with vehicle-, substanceP1−7, or Boc-cholecysto-kinin–4,. whereas turning after pre-treatment with substanceP5−11was not significantly asymmetrical. Furthermore, the ipsi- and contra-lateral neostriatal dopamine levels did not differ significantly in this group. Moreover, pre treatment with substanceP5−11affected dopamine metabolism in the neostriatum and in the venral striatum, as indicated by increased ratios of dihydroxyphenyllic acid to dopamine. The data provide the first evidence that the promotive effects of substance-P treatment in the unilateral dopamine lesion model might be mediated by its C-terminal and might depend on actions on residual dopamine mechanisms.

Evaluating fatigue items from traditional questionnaires and a new scale (BRAF-MDQ) by experts in rheumatoid arthritis (RA). This evaluation was part of a study to select fatigue items to develop an item bank for a Dutch computer-adaptive test (CAT) for RA. Experts' opinions were incorporated since they are essential for content validity of measurement instruments.The 60 items of the SF-36 subscale vitality, FACIT-F, POMS subscale fatigue/inertia, MAF and the recently developed BRAF-MDQ were evaluated by rheumatologists, nurses and RA patients in a Delphi procedure. Items were selected for development of the item bank/CAT if rated as adequate by at least 80% of the participants (when 50% or less they were excluded). On the basis of participants' comments, remaining items were re-worded and re-evaluated in the following round. The procedure stopped when all items were selected or rejected.Ten rheumatologists, 20 nurses and 15 RA patients participated. After the first round, 40% of the traditional items and 60% of the BRAF-MDQ items were directly selected and 3 items of the traditional questionnaires and 1 item of the BRAF-MDQ were directly excluded. Remaining items were re-worded, eight of which were presented for re-evaluation in the second round. Finally, 90% of the items from the traditional questionnaires and 95% of the items from the new BRAF-MDQ were included in our item pool.Fifty-five of the 60 items (92%) from fatigue questionnaires proved to have good content validity and were feasible for use in the Netherlands, some after adaptation.

We studied the effect of poly(ethylene glycol) (PEG) on the extrusion of large, multilamellar nanocapsules (also called liposomes or vesicles) through nanochannels with a length of 6 microm. For the generation of the nanocapsules, we used a lipid mixture with lecithin consisting of saturated and unsaturated fatty acids (dipalmitoylphosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC)), cholesterol, and 2-8 mol % PEG linked to a lipid anchor (distearoylphosphatidylethanolamine (DSPE)) or the plain lipid anchor without PEG. An increase in PEG leads to a decrease of the critical tension for nanocapsule rupture (lysis tension) between 20-30%, whereas the pure lipid anchor does not produce any differences. We interpret these findings to be produced by a partial intrusion of the polymeric chain into the phospholipid bilayer of the nanocapsule which weakens its tensile strength. We evaluate statistically the discrepancies of lysis tensions found for different channels widths (50-100 nm) and two or four channels in series. Comparing our results on the flow resistance of either nanocapsules or pure water with lubrication theory, we find that the calculated viscous forces are not sufficient to account for the measured friction of nanocapsules. This shows that the nanocapsules are decelerated in the nanochannels by van der Waals interactions between channel and capsule walls and the intermediate water layer. The strength of these forces is 24 times higher for PEG and 94 times higher for the pure lipid anchor than the respective calculated viscous forces alone, showing that nanocapsule flow in nanochannels cannot be considered under the classical continuum assumption of the intermediate water layer.

During the recent years, in vivo imaging of small animals using SPECT has become of growing relevance. Along with the development of dedicated high-resolution small animal SPECT cameras, an increasing number of conventional clinical scanners has been equipped with single or multipinhole collimators. This paper reviews the small animal tomographs, which are operating at present and compares their performance characteristics. Furthermore, we describe the in vivo imaging studies, which have been performed so far with the individual scanners and survey current approaches to optimize molecular imaging with small animal SPECT.

A retrospective image fusion method is presented for the quantitation of receptor and transporter binding in cerebral regions using small animal SPECT and PET. To obtain images of bone metabolism, tissue perfusion and brain perfusion rats were injected /sup 99m/Tc-labeled DPD, tetrofosmin (TF) or HMPAO. Further rats were applied dopamine transporter (DAT) or D/sub 2/ receptor ligands (/sup 123/I-FP-CIT, /sup 123/I-IBZM, /sup 18/F-FMB). DAT or D/sub 2/ blockade was induced by methylphenidate (MP) and haloperidol (HAL), respectively. Scanning was performed with small animal SPECT or PEL Striatal, cortical and cerebellar regions were defined on sets of fusion images allowing the localization of the target regions relative to the sites of specific accumulation of metabolism and perfusion markers. For validation, mean striato- and corticocerebellar ratios were computed for blocked and unblocked DAT and D/sub 2/ binding. DPD, TF and HMPAO scans provided quasi-anatomical information, which facilitated the identification of striatum, cortex and cerebellum relative to the localization of cranium and orbitae with Harder's glands. This was crucial in MP- and HAL-treated rats with reduced intracerebral radioactivity accumulations. Quantitative data obtained with this method lay within the order of magnitude previously reported in literature. The study shows the feasibility of fusing receptor and transporter with bone metabolism and perfusion scans. Our method represents a nuclear medical alternative to morphological coregistration with dedicated CT or MRT.

Der Altersgipfel in der Erstmanifestation chronisch entzundlicher Darmerkrankungen (M. Crohn, Colitis ulcerosa) liegt im Adoleszenz- und fruhen Erwachsenenalter. Auf Grund des lebenslangen, chronisch rezidivierenden Charakters der Erkrankung ist eine langfristige Therapieplanung unumganglich. Das gegenwartige Stufenschema der Therapie (Aminosalizylate, Glukokortikoide, Immunsuppressiva, biologische Therapien wie Infliximab) ist durch eine Eskalation der Wirkungsstarke, aber auch der Nebenwirkungen gekennzeichnet. Auf Grund der noch fehlenden therapeutischen Option, die Krankheit in einer dauerhaften Remission zu halten, ist die fruhe Identifikation komplizierter Verlaufe wichtig, in denen die geeignete Koordination langfristig angelegter medikamentoser und chirurgischer Therapieverfahren den Betroffenen eine optimale Lebensqualitat sichert. Es ist zu hoffen, dass das rapide Verstandnis der genetischen Grundlagen der Erkrankung in Zukunft die Identifikation von Patientensubgruppen mit unterschiedlichen Verlaufen erleichtert und zu einer individuellen Adaptation der Therapie fuhrt.

Because the etiology of inflammatory bowel diseases is unclear, no causative therapy is available. However, pathophysiology of the disease offers a lot of possibilities to disrupt the inflammatory cascade that maintains the inflammatory process. The aim of every therapy is to maintain remission as long as possible and to amend the natural course of the disease. Pharmacotherapy includes 5-Aminosalicylates, glucocorticoids, immunosupressants (methotrexate, azathioprine) as well as specific pharmacologic interventions like monoclonal antibodies directed against TNF-alpha (Infliximab). Important supportive tools are available to improve symptoms like diarrhea and pain. Dietetic treatment and surgical procedures represent important alternatives or supplement pharmacotherapeutic interventions.

Previous studies on hypothyroid subjects have indicated serious psychiatric symptoms affecting the patients' quality of life. The present prospective cross-sectional study's aim was to examine these symptoms in thyroid patients with different functional states. A total of 254 patients (age: 56 +/- 14 years [mean +/- standard deviation], 181 female, 73 male) referred to a hospital for radioiodine treatment of hyperthyroidism or for follow-up of differentiated thyroid cancer, respectively, were included. All patients underwent the twelve-item general health questionnaire, which is an instrument for detecting mood disturbances. Euthyroid and hyperthyroid patients did not differ significantly in their general health questionnaire score (11 +/- 5 vs. 11 +/- 7), nor did subclinical hyperthyroid (11 +/- 6) or subclinical hypothyroid subjects (12 +/- 5). In contrast, hypothyroid patients showed a significantly higher mean score (17 +/- 7, p < 0.001, ANOVA). Binary logistic regression revealed that hypothyroidism increases age and gender-adjusted risk for critical mood deterioration by seven-fold. Thus, hypothyroidism represents a widely underestimated functional condition that may severely affect mental health.

Genomic technologies offer new approaches to the investigation of the aetiology and pathophysiology of inflammatory bowel disease. An important field relevant to inflammatory bowel disease therapy is the pharmacogenetic investigation of gene variations that may predict responses to certain medications in order to target these therapeutic interventions more precisely. To date, only about 12,000 of the estimated 30,000-50,000 human genes have been characterized. Therefore, the use of techniques for a global analysis of gene expression may allow the identification of new pathways or molecules in the therapeutic mechanisms of drugs. Recently, NOD2 has been identified as the first disease gene in inflammatory bowel disease. DLGS and OCTN-1 have been named as further disease genes. Although the detection of disease-associated variants has greatly advanced our understanding of the primary events that lead to the development of inflammatory bowel disease in a subgroup of patients with Crohn's disease, the implications of the findings for diagnostic and therapeutic algorithms are less clear. However, it appears that there is a clear association between certain subphenotypes of Crohn's disease and the disease-associated variants in the NOD2 gene. It can be anticipated that genomic findings will profoundly influence the future therapy of inflammatory bowel disease.

The study presented here firstly compares the distribution of the binding potential of the serotonin-5HT2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated.Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT2A ligand 18F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature.The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p0.0001). A difference in the receptor density between two regions could be detected with p0.05 when it amounted at least to 18%.This study demonstrates a good agreement between in vivo data obtained with 18F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%.

Interleukin (IL)-10 is a cytokine with potent anti-inflammatory properties. We investigated the safety and efficacy of different doses of human recombinant (rhu)IL-10 in patients with Crohn's disease (CD).A prospective, multicenter, double-blind, placebo-controlled study was conducted in 329 therapy-refractory patients with CD. Clinical improvement was defined by a reduction of the Crohn's Disease Activity Index (CDAI) by 100 points or more and clinical remission by a decrease of the CDAI to150 points. At selected centers, patients underwent ileocolonoscopies and activation of the nuclear factor-kappa B (NF-kappa B) system was assessed in biopsy specimens.Subcutaneous treatment with rhuIL-10 over 28 days induced a fully reversible, dose-dependent decrease in hemoglobin and thrombocyte counts but no clinically significant side effects. No differences in the induction of remission were observed between rhuIL-10 groups (1 microg, 18% [9.6-29.2]; 4 microg, 20% [11.3-32.2]; 8 microg, 20% [11.1-31.8]; 20 microg, 28% [18-40.7]; and placebo, 18% [9.6-29.6]). Clinical improvement was observed in 46% (33.7-59) in the 8-microg/kg rhuIL-10 group in comparison with 27% (17-39.6) in patients taking placebo. Responders to rhuIL-10 showed inhibition of NF-kappaB p65 activation in contrast to nonresponders.Up to 8 microg/kg of rhuIL-10 was well tolerated. A tendency toward clinical improvement but not remission was observed in the 8-microg/kg dose group. Further studies should delineate which subgroups of patients with CD benefit from rhuIL-10 therapy.

Glucocorticoids as well as 5-aminosalicylic acid have been used successfully in different formulations during the past 40 years for the treatment of both acute and chronic inflammation in inflammatory bowel disease. The mechanism by which the drugs exert their actions are only partially known. Recent studies of the immunoregulation in the lamina propria provide evidence that numerous therapeutic mechanisms contribute to the efficacy of these drugs including the inhibition of arachidonic acid metabolism, a decrease in radical formation by oxygen radical scavenging, an inhibition of both in vivo and in vitro activation of peripheral and intestinal lymphocytes. Moreover direct immunoregulatory effects exerted by the drug may be important in influencing the complex balance of pro-inflammatory mechanisms during active intestinal inflammation. Such effects are the inhibition of both peripheral and intestinal B lymphocyte immunoglobulin secretion as well as the inhibition of pro-inflammatory cytokine production and their binding to receptors. Some of these immunoregulatory effects appear to be mediated by an inhibition of the activation of the nuclear factor kappa B transcription factor family by steroids and (less potent) aminosalicylic acid. Activation of nuclear factor kappa B appears to be pivotal for the sustained upregulation of inflammation molecule expression in many inflammatory diseases. It seems, therefore, most likely that the enormous therapeutic potency of steroids, as well as the anti-inflammatory properties of 5-aminosalicylic acid, are not achieved by a single action of the drug. The complex orchestration of numerous inhibitory interactions with pro-inflammatory principles will add to the therapeutic potential of steroids and of 5-aminosalicylic acid in the treatment of both acute and chronic intestinal inflammation.

Expression of pro-inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease (IBD). Nuclear factor kappa B (NF kappa B) controls transcription of inflammation genes. On activation, NF kappa B is rapidly released from its cytoplasmic inhibitor (I kappa B), transmigrates into the nucleus, and binds to DNA response elements in gene promoter regions.To investigate whether increased activation of NF kappa B is important in IBD and may be down-regulated by anti-inflammatory treatment.Activation of NF kappa B was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells.Nuclear levels of NF kappa B p65 are increased in lamina propria biopsy specimens from patients with Crohn's disease in comparison with patients with ulcerative colitis and controls. Increased activation of NF kappa B was detected in lamina propria mononuclear cells from patients with active IBD. Corticosteroids strongly inhibit intestinal NF kappa B activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor I kappa B alpha against activation induced degradation.In both IBDs, but particularly Crohn's disease, increased activation of NF kappa B may be involved in the regulation of the inflammatory response. Inhibition of NF kappa B activation may represent a mechanism by which steroids exert an anti-inflammatory effect in IBD.

Background —Concentrations of pro-inflammatory cytokines are increased in the intestinal mucosa of patients with active inflammatory bowel disease (IBD). Polymorphonuclear neutrophil granulocytes (PMN) are the most abundant cell type in intestinal lesions in IBD. Interleukin 10 (IL-10) is an important contra-inflammatory cytokine which induces downregulation of pro-inflammatory cytokines. Aims —To investigate whether PMN from patients with IBD or infectious colitis, respectively, secrete increased amounts of pro-inflammatory cytokines and can be regulated by IL-10. Methods —Secretion (ELISA) as well as corresponding mRNA levels (semiquantitative RT-PCR) of pro-inflammatory cytokines (IL-1β, TNF-α) and of IL-1 receptor antagonist were assessed in peripheral PMN. Results —PMN from patients with IBD are primed to secrete enhanced amounts of pro-inflammatory cytokines accompanied by detection of corresponding mRNAs in comparison with normal controls. This finding is not specific for IBD but rather reflects intestinal inflammation in general. IL-10 markedly inhibited pro-inflammatory cytokine secretion as well as corresponding mRNA concentrations. Conclusions —PMN are an important source of pro-inflammatory cytokines in patients with intestinal inflammation and can be downregulated by IL-10.

Nikolaus, S., J. P. Huston, B. KORber, C. Thiel and R. K. W. Schwarting. Pretreatment with neurokinin substance P but not with cholecystokinin-8S can alleviate functional deficits of partial nigrostriatal 6-hydroxydopamine lesion. Peptides 18(8) 1161–1168, 1997.—The neuropeptide substance P (SP) has been implicated in the control of various neuro-behavioral functions including reinforcement and learning processes. It also exerts neurotrophic and regenerating effects in vitro and in vivo. A previous study indicated a potential therapeutic effect of SP in rats with partial 6-hydroxydopamine lesions of the nigrostriatal dopamine system when SP was administered after the lesion. The purpose of the present study was to determine whether prelesion treatment with SP would also interact with the effects of unilateral 6-hydroxydopamine lesion of the substantia nigra. Thus, SP (50 μg/kg) was administered i.p. on 8 consecutive days prior to unilateral lesion of the substantia nigra. Furthermore, we investigated the effects of prelesion treatment with cholecystokinin-8S (CCK; 1 μg/kg), another neuropeptide, which is closely related to dopaminergic neurons, and which also can have neurotrophic and neuroprotective functions. Our results show that animals with partial neostriatal dopamine depletions (residual dopamine levels of more than 10%) did not show turning asymmetries when pretreated with SP, whereas animals pretreated with vehicle exhibited an initial ipsiversive asymmetry from which they recovered. In contrast, behavioral asymmetries were most pronounced in animals which had been pretreated with CCK. These peptide treatments did not affect the degree of neostriatal dopamine depletion; however, dihydroxyphenylacetic acid/dopamine ratios were enhanced in the neurostriatum of animals with partial dopamine damage after SP- and CCK-pretreatment, and in the ventral striatum of SP-pretreated animals. These data provide evidence that prelesion treatment with SP, but not with CCK, can alleviate functional deficits induced by a partial nigro-striatal dopamine lesion. This effect may be related to enhanced ventral striatal dopamine activity and/or to the peptide’s known effects on learning, motivation, and emotion.