The aged gut in inflammatory bowel diseases.

Senescence is accompanied by various anatomical and functional alterations starting from mastication and deglutition and consequent modifications of nutrition. In addition, the widespread use of proton pump inhibitors and non-steroidal anti-inflammatory drugs in aged subjects weakens the gastric barrier, thus contributing to easier entry of microbes into the gastrointestinal tract. The microbiota of the elderly is less stable than that of younger adults, therefore, gut dysbiosis is more frequent. Dysbiosis represents a key factor for infections, e.g. Clostridium difficile, especially after antibiotic treatment, but also represents an important step for the development of inflammatory bowel diseases (IBD). IBD onset in the elderly needs careful evaluation in order to distinguish this entity from other pathologies that may affect the gut in senescence. Colitis associated with diverticula, drug-induced, ischemic, and microscopic colitides are among the possible diseases and, therefore, a careful macroscopic and histologic evaluation is mandatory. Finally, late onset IBD represents an important challenge for physicians since it occurs in subjects with frequent comorbidities and relative concomitant treatments. Although there is some evidence that disease course of elderly-onset IBD follows a milder course, overall morbidity, hospitalization rates and even mortality, the latter mostly due to comorbidities, are increased, especially in emergency settings.

[Relevance of personal contextual factors of the ICF for use in practical social medicine and rehabilitation]. / Bedeutung der personbezogenen Faktoren der ICF für die Nutzung in der praktischen Sozialmedizin und Rehabilitation.

Personal contextual factors play an essential part in the model of the International Classification of Functioning, Disability and Health (ICF). The WHO has not yet classified personal factors for global use although they impact on the functioning of persons positively or negatively. In 2010, the ICF working group of the German Society of Social Medicine and Prevention (DGSMP) presented a proposal for the classification of personal factors into 72 categories previously arranged in 6 chapters. Now a positioning paper has been added in order to stimulate a discussion about the fourth component of the ICF, to contribute towards a broader and common understanding about the nature of personal factors and to incite a dialogue among all those involved in health care as well as those people with or with-out health problems in order to gain a comprehensive perspective about a person's condition.

[Measurement of participation in outpatient neurorehabilitation--a pilot study]. / Messung von Teilhabe in der wohnortnahen ambulanten Neurorehabilitation--eine Pilotstudie.

OBJECTIVE: To date there is a lack of tools to measure participation and the already existing measures are not properly used as yet. In 2005 the IMET (Index zur Messung von Einschränkungen der Teilhabe) was developed and is able to measure the ICF associated construct participation as a generic instrument in chronic diseases. IMET and numerous instruments were applied in our own study and results were compared with results of an unpublished study. In addition, to test IMET for its use in neurorehabilitation the effects of outpatient neurorehabilitation were investigated and compared with results obtained in an inpatient setting. METHOD: In a multicentric observational study, consecutively treated patients of 6 outpatient neurorehabilitation centres were asked to fill in a questionnaire at three time points (admission and discharge in the course of rehabilitation and at 4 months follow-up). Additionally, clinical experts were asked to rate the patients' status at admission and discharge. The data were compared with results of a sample of inpatients of an unpublished study. RESULTS: The IMET seems to be the to date best instrument to measure participation in a global, ICF-defined and economic way. Especially participation, general health status and capacity in leisure time and daily routine show the biggest improvements. In comparison, the outpatients show improvements in their participation status. Participation-oriented outpatient neurorehabilitation seems to have a considerable impact on participation status in neurological patients through the course of rehabilitation.

[The German guideline "legal evaluation after closed head injury"]. / Die leitlinie "begutachtung nach gedecktem schädel-hirntrauma".

In 2005, the "Deutsche Gesellschaft für Neurowissenschaftliche Begutachtung" (German Society for Neuroscientific Legal Evaluation) together with other Societies published a guideline for the legal evaluation of patients with closed head injuries. Meanwhile, not only scientific progress in imaging techniques but also in other fields such as neuropsychology has necessitated a revision, which is presented here. In the mean time, the handling of guidelines has been systematised in Germany so that a registration with the Cooperation of German Medical Learned Societies is applied for and publication in the German Guideline Registry is expected.

European consensus on the histopathology of inflammatory bowel disease.

The histologic examination of endoscopic biopsies or resection specimens remains a key step in the work-up of affected inflammatory bowel disease (IBD) patients and can be used for diagnosis and differential diagnosis, particularly in the differentiation of UC from CD and other non-IBD related colitides. The introduction of new treatment strategies in inflammatory bowel disease (IBD) interfering with the patients' immune system may result in mucosal healing, making the pathologists aware of the impact of treatment upon diagnostic features. The European Crohn's and Colitis Organisation (ECCO) and the European Society of Pathology (ESP) jointly elaborated a consensus to establish standards for histopathology diagnosis in IBD. The consensus endeavors to address: (i) procedures required for a proper diagnosis, (ii) features which can be used for the analysis of endoscopic biopsies, (iii) features which can be used for the analysis of surgical samples, (iv) criteria for diagnosis and differential diagnosis, and (v) special situations including those inherent to therapy. Questions that were addressed include: how many features should be present for a firm diagnosis? What is the role of histology in patient management, including search for dysplasia? Which features if any, can be used for assessment of disease activity? The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas.

Systematic review: macrophage activation syndrome in inflammatory bowel disease.

BACKGROUND: Recently, there have been increasingly frequent reports on the occurrence of macrophage activation syndrome (MAS) in patients with inflammatory bowel disease (IBD). Clinically, MAS is characterized mainly by fever, hepatosplenomegaly, cytopenia, and elevated circulating ferritin and CD25. Mortality, even if diagnosed rapidly, is high. AIM: To identify all reports on MAS in IBD and to establish data on triggering agents, immunosuppression leading to MAS, and mortality. METHODS: A language unrestricted search on Pubmed and Scopus relating to the past 30 years was carried out by matching the following search-terms: h(a)emophagocytic lymphohistiocytosis OR h(a)emophagocytic lymphohistiocytic syndrome OR macrophage activation syndrome OR opportunistic infections OR cytomegalovirus OR Epstein-Barr virus AND Crohn's disease OR ulcerative colitis OR inflammatory bowel disease(s). RESULTS: Fifty cases were identified with an overall mortality of 30%. Virus-related MAS associated with cytomegalovirus or Epstein-Barr virus infections represents the main type of MAS, but in isolated cases bacterial infections precipitated the syndrome. In four cases (8%), a lymphoma was present at the time of MAS diagnosis or developed shortly thereafter. Thiopurine monotherapy was given before MAS onset in 56% of the patients, whereas multiple immunosuppression, including biologics, was administered to 24%. CONCLUSIONS: In IBD patients, the syndrome appears to be triggered by infections, but genetic susceptibility may contribute to its development. Since immunosuppressive therapy represents the backbone of therapeutic interventions in IBD, with the risk of new, or the reactivation of latent infections, even more frequent cases of macrophage activation syndrome may be expected.

Prospective comparison of computed tomography enterography and magnetic resonance enterography for assessment of disease activity and complications in ileocolonic Crohn's disease.

BACKGROUND: Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohn's disease (CD) are scarce. METHODS: The aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16-slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards. RESULTS: No significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02). CONCLUSIONS: MR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD.

Adalimumab in Crohn's disease: tips and tricks after 5 years of clinical experience.

INTRODUCTION: Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home. AIM AND METHODS: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. RESULTS: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. CONCLUSION: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.

New drug delivery systems in inflammatory bowel disease: MMX and tailored delivery to the gut.

UNLABELLED: Inflammatory bowel diseases are chronic diseases that affect the gastrointestinal tract. Mesalamine, corticosteroids, immunosuppressants and biological agents are currently used to treat these diseases. Due to inadequacies of the currently available delivery systems, a large number of patients do not respond to treatment, especially when they are affected by distal colonic disease. Multimatrix (MMX) technology comprises hydrophilic and lipophilic excipients, enclosed within a gastro-resistant, pH-dependent coating. This new delivery technology has been used to modify some commonly used drugs, including mesalamine and budesonide, as well as heparin, which are now being investigated for their utility in the management of IBD. AIM: The aim of this review is to explore the MMX delivery technology and its efficacy for the treatment of IBD. RESULTS: The results of various studies involving MMX drugs have been published. Mesalamine MMX induces clinical and endoscopic remission in patients with mild to moderate ulcerative colitis (UC) compared with placebo. Positive results have also been observed with MMX budesonide in two phase I studies. In a pilot study involving ten patients with UC, efficacy of heparin-MMX as an IBD therapy was observed. CONCLUSION: MMX is a promising new delivery system that can improve efficacy of current and new drugs, augmenting targeting to the affected tract, thereby increasing response and remission rates for those drugs in patients with IBD.

[Participation limitations following acquired brain damage: a pilot study on the relationship among functional disorders as well as personal and environmental context factors]. / Beeinträchtigungen der Teilhabe nach erworbenen Hirnschädigungen: Zum Verhältnis von Funktionsstörungen, personbezogenen und umweltbezogenen Kontextfaktoren - eine Pilotstudie.

The SGB IX, book 9 of the German social code (Sozialgesetzbuch, SGB), which is the legal basis of rehabilitation in Germany, states "participation and self-determined conduct of life" as the ultimate ambition of rehabilitation. This concept of participation and disability is based on the WHO model expressed in the International Classification of Functioning, Disability and Health (ICF). In this model, participation after the onset of a health problem may not only be infringed by disturbances in body functions and structures and the resulting activity limitations but also by contextual factors such as environmental and personal factors. In an outpatient neurological rehabilitation centre we prospectively rated for 49 patients the influence of these contextual factors as well as of objectively assessed functional/activity limitations on the overall disability. On average, functional/activity limitations were rated as contributing 58.4% (SD=17.2%), personal factors 26.4% (SD=12.7%) and environmental factors 15.1% (SD=11.2%) to the overall disability. The functional/activity limitations closely matched the expected limitations based on the underlying brain lesions. The degree of disability based on contextual factors was not related to activity limitations based on disturbances of body functions and structures. Also, demographic variables such as age, sex or chronicity were not significantly linked to contextual factors. Since contextual factors together contributed 41.6% (SD=17.2%) to the overall disability they have major relevance for the rehabilitation process, because they essentially decide on the extent to which abilities acquired by the rehabilitant during rehabilitation actually be transfered to his everyday life. Therefore, rehabilitation programmes need to include assessment and treatment of contextual factors. It hence is necessary to develop instruments to quantify contextual factors.

Clinical practice in the management of ulcerative colitis--an Italian survey.

OBJECTIVES: To investigate the concordance of medical care of ulcerative colitis (UC) patients in Italy. METHODS: Interviews with responsible physicians in referral centres for inflammatory bowel disease (IBD) regarding the management (e.g. time to referral, time to diagnosis, disease activity at the first visit and after 1 year, treatment algorithm, treatment goals, follow up, etc) of patients with UC. RESULTS: The obtained data showed a correct diagnostic approach, once the patient reached the referral centre, and similar figures for disease activity as reported in studies on epidemiology or on the natural history of UC. Treatment goals for the acute phase of disease and for maintenance therapy were mainly clinically oriented and include only in a minority parameters like quality of life or the regulation of the immune response. CONCLUSIONS: The treatment algorithms were consistent with the established guidelines for the treatment of UC. Major disparity was found for the endoscopic control of treatment success.

Treatment of life-threatening type I refractory coeliac disease with long-term infliximab.

Whereas medical approach to coeliac disease is well defined, treatment of patients who fail to respond to a gluten-free diet remains still problematic. We describe the case of a 68 years DQ-2 positive male who lost response to a strict gluten-free diet after an initial response over a 3-year period. His conditions became critical despite high dose prednisone treatment. After a careful differential diagnosis, the patient was classified as having a type I refractory coeliac disease and a single infusion of infliximab at 5mg/kg was given with excellent clinical results. However, clinical response was lost despite background therapy with azathioprine. Six months after the single infusion an induction therapy with infliximab and, thereafter, maintenance every 8 weeks was administered with excellent clinical results. Since small bowel histology recovered very slowly treatment was continued over the following 2 years with a return to near normal architecture. This case shows that anti-tumour necrosis factor treatment may be used in carefully selected patients with type I refractory coeliac disease.

Incidence of Crohn's disease and CARD15 mutation in a small township in Sicily.

BACKGROUND: The incidence of Crohn's disease (CD) has been shown to be lower in Southern than in Northern Europe. Data on the frequency of the NOD2/CARD15 mutations for Mediterranean area are very scant. AIM: To determine the incidence of CD from 1979 to 2002 in a township in Sicily together with the allele frequency of NOD2/CARD15 mutations in patients, family members and controls, and to determine the allele frequency of these mutations in sporadic CD from other areas of Sicily in comparison with a control population. METHODS: Casteltermini is a small town close to Agrigento (Sicily) with a population of 9,130 inhabitants. All the diagnoses of inflammatory bowel disease (IBD) made from 1979 to 2002 were obtained through the local health authority. NOD2/CARD15 mutations were studied in 23 out of the 29 patients with CD in Casteltermini, in 60 family members and in 64 controls. NOD2/CARD15 was also studied in 80 sporadic cases of CD disease among Sicilians outside Casteltermini and 118 healthy controls. RESULTS: From 1979 to 2002, 29 patients with CD and 13 patients with ulcerative colitis (UC) were registered. The 6-year mean incidence of CD ranged from 8.0 to 17 new cases for every 100,000 inhabitants, whereas the mean incidence of UC ranged from five new cases to 7.8 for every 100,000 inhabitants. The allele frequencies of NOD2/CARD15 mutations (L1007finsC, G908R, R702W) were 8.7, 4.3 and 8.7%, respectively, in CD cases; 5.0, 4.2 and 3.1% in family members; 1.6, 2.3 and 3.1% in controls. In sporadic Sicilian CD patients outside Casteltermini the allele frequency was 7.5, 8.1, 6.2% whereas in control population it was 3.3, 1.6, 1.6%. CONCLUSIONS: A high incidence of CD compared with UC was observed in this small town in Southern Italy. The frequency of NOD2/CARD15 mutations in CD is similar to other Caucasian population studied so far.

Hepatic osteodystrophy: does the osteoprotegerin/receptor activator of nuclear factor-kB ligand system play a role?

Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease (CLD). Recently, two new cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor-kB ligand (RANKL), have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases. Therefore, the aim of our study was to evaluate bone metabolism, bone mineral density (BMD) and OPG/RANKL system in 65 male patients with CLD and in 65 healthy controls. Our patients showed lower BMD values than controls both at lumbar and femoral levels. Moreover, they had an unbalanced bone turnover with an increased resorption phase, as shown by high levels of urinary deoxypyridinoline and a decreased formation phase, as shown by the slightly, but significant, low levels of bone-alkaline phosphatase. Patients showed lower plasma levels of free-testosterone than controls and higher - although not significantly so - plasma levels of 17 beta-estradiol. Furthermore, patients with CLD had higher levels of sex hormone-binding globulin and OPG, and lower levels of 25-hydroxyvitamin D (25-HOD) and IGF-I than the control group, while RANKL levels were similar in the two groups. In conclusion, our data do not confirm the hypothesis that the OPG/RANKL system could exert a key role in the pathogenesis of hepatic osteodystrophy, but rather that the observed increase in OPG levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption.

Effects of iron deprivation or chelation on DNA damage in experimental colitis.

BACKGROUND AND AIMS: In inflammatory bowel diseases iron contributes to the formation of DNA adducts through the production of hydroxyl radicals. The aim of our study was to evaluate the effects of dietary or pharmacological iron deprivation in an experimental model of colitis in the rat and its potential protective effect against DNA damage. METHODS: Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulphonic acid. Rats were assigned to an iron-deprived diet or to desferrioxamine preceding the induction of colitis. The severity of colitis was assessed by the presence of bloody diarrhea, colonic macroscopic damage score, body-weight variations and the amount of DNA colonic adducts. Hepatic and colonic iron concentrations were measured. RESULTS: Treated rats experienced less diarrhea and did not lose weight in comparison to untreated animals. The macroscopic damage score was significantly reduced in the iron-deprived diet for the 5-week group (P=0.03). Liver and colonic iron levels were significantly more reduced in the iron-deprived groups than in the standard diet group (P<0.03 and P<0.01 after a 3- and 5-week iron-deprived diet, respectively). DNA adduct formation was significantly reduced in the groups deprived of iron for 5 weeks (P<0.001) or treated with desferrioxamine (P<0.01). CONCLUSIONS: The degree of colitis caused by DNBS is macroscopically improved by dietary iron deprivation and to a lesser extent by pharmacological chelation; genomic damage is reduced by dietary iron deprivation or chelation, and this may have clinical implications on cancer prevention.

Effect of stress on the paracellular barrier in the rat ileum.

BACKGROUND: Restraint stress induces permeability changes in the rat small intestine but little is known of the ultrastructural events leading to defects of the paracellular sealing or of the short term evolution of these alterations. METHODS: In the present study, we performed transmission electron microscopy in the terminal ileum perfused with lanthanum after two hours of immobilisation stress and in non-stressed control rats. Moreover, immunohistochemistry of the tight junction (TJ) associated proteins, occludin and zonula occludens 1 (ZO-1), was carried out together with western blot analysis of the transmembrane protein occludin. TJ morphology was also assessed after a 22 hour recovery period. RESULTS: Immobilisation stress induced a significant increase in epithelial permeability to the lanthanum tracer (p<0.005) which recovered completely after 22 hours. Compared with unstressed controls, in stressed rats no differences were found on freeze fracture analysis. The TJ related immunofluorescence signals of occludin and of ZO-1 were irregularly distributed in stressed rats after two hours but returned to a normal pattern at 24 hours although with minor intensity. No quantitative alterations in occludin were detectable in stressed rats by immunoblot whereas a perinuclear concentration of occludin was observed by immunolocalisation. CONCLUSIONS: Immobilisation stress induced an increase in TJ permeability in the rat terminal ileum. These changes were mainly due to modifications and redistribution of the TJ transmembrane protein occludin and of the plaque protein ZO-1 whereas protein synthesis, at least that of occludin, was not affected by stress.

[Evaluation of olfactory stimuli by depressed patients]. / Bewertung von Geruchsreizen bei depressiv Erkrankten.

Anhedonia, a cardinal sign of depression, is discussed to originate from a transmitter dysbalance in the central dopaminergic reward system. This system involves neuroanatomically many structures of the olfactory system. Hence the question arises whether anhedonia can be quantified when depressive patients judge smells hedonically. Sensory evaluation of olfactory stimuli by 16 depressive patients was compared that of an age-matched control group. In the group comparison, mono- and birhinal sensory thresholds as well as judgment of intensity were not significantly different. For four of the eight smells, the hedonic judgements were found to be identical between the group of depressives and controls, with the remaining smells not significantly different. There were no differences in the consistency of ranking of smells. In a longitudinal (test-retest) assessment there were again no differences in intensity, familiarity, and hedonic quality of the smells. The findings suggest that changes in the dopaminergic transmitter balance during the state of depression causing anhedonia affect neither olfactory perception nor the hedonic judgement of smells. Contrary to the clinical picture, anhedonia thus seems not to arise at the level of sensory perception yet but should be considered a more complex construct of disturbed central processing.