The incidence and outcome of ischemic colitis in a population-based setting.

OBJECTIVE: Population-based studies on patients with ischemic colitis (IC) are limited. We aimed to determine the incidence, risk factors and outcome of patients with IC. METHODS: A retrospective nationwide study was conducted on adult patients with histologically confirmed IC in 2009-2013 in Iceland. IC patients were matched for age and gender with patients hospitalized with lower gastrointestinal bleeding. Data were collected on clinical presentation, comorbidities, smoking habits, management and outcome. RESULTS: Eighty-nine patients, 61 (69%) females and mean age of 65 years (±17), fulfilled the predetermined criteria. Females were older than males, 68 years (±14) vs. 59 years (±20) (p = .0170). The mean cumulative incidence was 7.3 cases per 100,000 inhabitants. A total of 57 (64%) patients presented with abdominal pain, hematochezia and diarrhea. IC was localized in the left colon in 78 (88%) patients. Overall, 62 (70%) patients had cardiovascular disease vs. 53 (60%) of control group (NS) and 55 (62%) had a history of smoking vs. 53 (60%) in control group (NS). Ten (11%) patients required surgery and/or died within 30-days from hospital admission. At the end of follow-up, 7 (9%) patients had experienced recurrence of IC with an estimated 3-year recurrence rate of 15%. CONCLUSIONS: IC is a common clinical phenomenon that affects a wide range of age groups, but is most prominent among elderly women. It typically presents with a clinical triad of abdominal pain, hematochezia and diarrhea. Most cases are mild and self-limiting with a good prognosis.

Health-related quality of life improves during one year of medical and surgical treatment in a European population-based inception cohort of patients with inflammatory bowel disease--an ECCO-EpiCom study.

BACKGROUND & AIMS: Health-related quality of life (HRQoL) is impaired in patients with Inflammatory Bowel Disease (IBD). The aim was prospectively to assess and validate the pattern of HRQoL in an unselected, population-based inception cohort of IBD patients from Eastern and Western Europe. METHODS: The EpiCom inception cohort consists of 1560 IBD patients from 31 European centres covering a background population of approximately 10.1 million. Patients answered the disease specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and generic Short Form 12 (SF-12) questionnaire at diagnosis and after one year of follow-up. RESULTS: In total, 1079 patients were included in this study. Crohn's disease (CD) patients mean SIBDQ scores improved from 45.3 to 55.3 in Eastern Europe and from 44.9 to 53.6 in Western Europe. SIBDQ scores for ulcerative colitis (UC) patients improved from 44.9 to 57.4 and from 48.8 to 55.7, respectively. UC patients needing surgery or biologicals had lower SIBDQ scores before and after compared to the rest, while biological therapy improved SIBDQ scores in CD. CD and UC patients in both regions improved all SF-12 scores. Only Eastern European UC patients achieved SF-12 summary scores equal to or above the normal population. CONCLUSION: Medical and surgical treatment improved HRQoL during the first year of disease. The majority of IBD patients in both Eastern and Western Europe reported a positive perception of disease-specific but not generic HRQoL. Biological therapy improved HRQoL in CD patients, while UC patients in need of surgery or biological therapy experienced lower perceptions of HRQoL than the rest.

Health care and patients' education in a European inflammatory bowel disease inception cohort: an ECCO-EpiCom study.

BACKGROUND AND AIMS: The EpiCom study and inception cohort was initiated in 2010 in 31 centers from 14 Western and 8 Eastern European countries, covering a 10.1million person background population. Our aim was to investigate whether there is a difference between Eastern and Western Europe in health care and education of patients with inflammatory bowel disease (IBD). METHODS: A quality of care (QoC) questionnaire was developed in the EpiCom group consisting of 16 questions covering 5 items: time interval between the onset of symptoms and diagnosis, information, education, empathy and access to health care providers. RESULTS: Of 1,515 patients, 947 (217 east/730 west) answered the QoC questionnaire. Only 23% of all patients had knowledge about IBD before diagnosis. In Eastern Europe, significantly more patients searched out information about IBD themselves (77% vs. 68%, p<0.05), the main source was the Internet (92% vs. 88% p=0.23). In Western Europe, significantly more patients were educated by nurses (19% vs. 1%, p<0.05), while in Eastern Europe, gastroenterologists were easier to contact (80% vs. 68%, p<0.05). CONCLUSION: Health care differed significantly between Eastern and Western Europe in all items, but satisfaction rates were high in both geographic regions. Because of the low awareness and the rising incidence of IBD, general information should be the focus of patient organizations and medical societies. In Western Europe IBD nurses play a very important role in reducing the burden of patient management.

Environmental factors in a population-based inception cohort of inflammatory bowel disease patients in Europe--an ECCO-EpiCom study.

BACKGROUND AND AIMS: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe possibly due to changes in environmental factors towards a more "westernised" standard of living. The aim of this study was to investigate differences in exposure to environmental factors prior to diagnosis in Eastern and Western European IBD patients. METHODS: The EpiCom cohort is a population-based, prospective inception cohort of 1560 unselected IBD patients from 31 European countries covering a background population of 10.1 million. At the time of diagnosis patients were asked to complete an 87-item questionnaire concerning environmental factors. RESULTS: A total of 1182 patients (76%) answered the questionnaire, 444 (38%) had Crohn's disease (CD), 627 (53%) ulcerative colitis (UC), and 111 (9%) IBD unclassified. No geographic differences regarding smoking status, caffeine intake, use of oral contraceptives, or number of first-degree relatives with IBD were found. Sugar intake was higher in CD and UC patients from Eastern Europe than in Western Europe while fibre intake was lower (p<0.01). Daily consumption of fast food as well as appendectomy before the age of 20 was more frequent in Eastern European than in Western European UC patients (p<0.01). Eastern European CD and UC patients had received more vaccinations and experienced fewer childhood infections than Western European patients (p<0.01). CONCLUSIONS: In this European population-based inception cohort of unselected IBD patients, Eastern and Western European patients differed in environmental factors prior to diagnosis. Eastern European patients exhibited higher occurrences of suspected risk factors for IBD included in the Western lifestyle.

East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Quality control of metoprolol extended-release formulations in the presence of ethanol.

This paper presents in-vitro metoprolol release from four different extended-release (ER) formulations, i.e. Metoprolol GEA® Retard, Logimax® forte, Metoprolol Sandoz® and Seloken ZOC® in the presence of 10 to 40% (v/v%) ethanol at pH 1.2 and pH 6.8. The assay of metoprolol in the dissolution media was performed by reversed phase liquid chromatography (RP-LC) using a mixture of methanol and 100 mM phosphate buffer (pH 3.5) in 40:60 ratio as eluent. The dissolution data showed that the metoprolol contents of Metoprolol Sandoz® and Seloken ZOC® were released fast in the presence of 20% ethanol at the investigated conditions, while the other products demonstrated much more stability against ethanol. Unexpectedly it was discovered that the release of metoprolol from Metoprolol GEA® Retard and to some extent also from Logimax® forte decreased in the ethanol containing media.

Abdominal symptoms and anorectal function in health and irritable bowel syndrome.

BACKGROUND: It is unclear how the quality and quantity of abdominal symptoms and anorectal function differ between irritable bowel syndrome (IBS) patients and healthy controls, and whether different anorectal function in patients is associated with abdominal symptoms in IBS. METHODS: Fifty-two outpatients with IBS and 12 healthy controls kept daily symptom records over 1 week. At the end of the week, anorectal function was assessed by manovolumetry before and after a standard fatty meal. Patients were divided into symptom and manovolumetric subgroups using a cluster analysis and also into those below (hypersensitive) and those within (normosensitive) the 95% confidence interval of the controls' mean for maximal tolerable distension (MTD). RESULTS: Regardless of subgroup, the patients were distinguished from the controls by pain, bloating, straining and incomplete evacuation. Compared with controls, MTD was lower in the pain/bloating subgroup characterized by considerable pain and the bowel habit subgroup characterized by hard stools, variable stool consistency and heavily disturbed stool passage. Preprandial rectal hypersensitivity was highly prevalent in this bowel habit subgroup. No similar association with the pain/bloating subgroup was found. Patients and controls showed a significant and similar postprandial decrease in MTD. CONCLUSIONS: IBS is distinguished from health by pain, bloating, straining and a feeling of incomplete evacuation. Baseline rectal hypersensitivity is associated with constipation-like bowel habit. Increased rectal sensitivity after a meal and/or preceding distension is a normal reaction unimportant in the genesis of symptoms in IBS.

[Irritable bowel syndrome. Survey of definitions, differential diagnosis and pathogenesis]. / Irriterade tarmens syndrom. Oversikt över definitioner, differentialdiagnostik och patogenes.

Abdominal pain/discomfort, bloating, need to rush to the toilet, straining, feeling of incomplete bowel emptying and alternating periods of diarrhea and constipation is the clinical definition of the irritable bowel syndrome. The internationally used syndrome definition is based on expert opinions and answers to patient questionnaires. When symptoms are registered prospectively, abdominal pain starts or worsens after meals and is not relieved by defecation. As in the general population patients with the syndrome define diarrhea as loose stools and constipation as hard stools regardless of stool frequencies. Variation in defecatory symptoms and discrepancies between these symptoms and stool consistency are the hallmarks of the syndrome, and the degree of variation per fortnight is relatively stable in the individual patient. Fermentation of carbohydrates by colonic bacteria, increased sensitivity to bowel distention by gas, gas-producing food, increased secretion of cholecystokinin after fatty meals and/or increased sympathetic nerve tone at stress can give rise to symptoms. Symptoms can start after a single period of bacterial gastroenteritis. Although patients seeking medical care for the syndrome are more often anxious, the syndrome itself is not psychosomatic. Symptoms are possibly mediated through partial degranulation of mast cells in bowel mucosa, but this does not make it an allergic disease. If bowel dysmotility can be measured, early stage or a mild case of intestinal pseudoobstruction should be considered. Hyperreactivity in the enteric nervous system and/or in the brain is the likely main cause of the symptoms. More widespread activity in the brain after exposure to stimuli originating from bowel nerves or less inhibition of this stimulation in the brain are possible mechanisms.

Intracellular Fas ligand in normal and malignant breast epithelium does not induce apoptosis in Fas-sensitive cells.

Fas ligand (FasL) is expressed on some cancers and may play a role in the immune evasion of the tumour. We used immuno-histochemistry to study the expression of Fas and FasL in tissue samples from breast cancer patients, as well as normal breast tissue. Our results show that Fas and FasL are co-expressed both in normal tissue and in breast tumours. Fas and FasL mRNA were expressed in fresh normal and malignant breast tissue, as well as cultured breast epithelium and breast cancer cell lines. Flow cytometry analysis of live cells failed to detect FasL on the surface of normal or malignant breast cells; however, both stained positive for FasL after permeabilization. Fas was detected on the surface of normal breast cells and T47D and MCF-10A cell lines but only intracellularly in other breast cell lines tested. Neither normal breast epithelium nor breast cell lines induced Fas-dependent apoptosis in Jurkat cells. Finally, 20 tumour samples were stained for apoptosis. Few apoptotic cells were detected and there was no increase in apoptotic cells on the borders between tumour cells and lymphocytes. We conclude that FasL is expressed intracellularly in both normal and malignant breast epithelium and unlikely to be important for the immune evasion of breast tumours.

Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.

Chromosomal losses involving the short arm of chromosome 8 are frequent in a variety of tumour types, including breast cancer, suggesting the presence of one or more tumour suppressor genes in this region. In this study, we have used 11 microsatellite markers to analyse loss of heterozygosity (LOH) at chromosome 8p in 151 sporadic breast tumours and 50 tumours from subjects carrying the BRCA2 999del5 mutation. Fifty percent of sporadic tumours compared to 78% of BRCA2 linked tumours exhibit LOH at one or more markers at 8p showing that chromosome 8p alterations in breast tumours from BRCA2 999del5 carriers are more pronounced than in sporadic breast tumours. The pattern of LOH is different in the two groups and a higher proportion of BRCA2 tumours have LOH in a large region of chromosome 8p. In the total patient material, LOH of 8p is associated with LOH at other chromosome regions, for example, 1p, 3p, 6q, 7q, 9p, 11p, 13q, 17p, and 20q, but no association is found between LOH at 8p and chromosome regions 11q, 16q, 17q, and 18q. Furthermore, an association is detected between LOH at 8p and positive node status, large tumour size, aneuploidy, and high S phase fraction. Breast cancer patients with LOH at chromosome 8p have a worse prognosis than patients without this defect. Multivariate analysis suggests that LOH at 8p is an independent prognostic factor. We conclude that chromosome 8p carries a tumour suppressor gene or genes, the loss of which results in growth advantage of breast tumour cells, especially in carriers of the BRCA2 999del5 mutation.

Division of the irritable bowel syndrome into subgroups on the basis of daily recorded symptoms in two outpatients samples.

BACKGROUND: If subgroups exist in a sample of patients with irritable bowel syndrome (IBS), they may represent different etiologic and pathophysiologic entities. Our aim was to identify subgroups on the basis of symptoms in IBS. METHODS: Two independent groups of 56 (sample I) and 52 (sample II) outpatients recorded their abdominal symptoms daily for 6 weeks and 1 week, respectively. The daily records were assessed by using cluster analysis. RESULTS: Similar subgroups appeared in both samples. Three bowel habit subgroups were identified. The first was distinguished by hard stools, varying stool consistency, and highly disturbed stool passage, the second by loose stools and urgency, and the third by normal stools and the least disturbed stool passage. Two pain/bloating subgroups were identified, one distinguished by little and the other by considerable pain and bloating. No relation was found between pain/bloating and bowel habit subgroup membership. Most patients had stool frequency within the normal range regardless of subgroup. In sample I the subgroups had stable symptoms during the study, and subgroup placement was not related to the presence of dyspepsia, smoking habits, or use of bulk agent and/or sporadic intake of loperamide. The degree of pain and bloating was inversely related to illness duration. CONCLUSIONS: Subgroups exist in IBS. Division of IBS into bowel habit subgroups should be based on stool consistency, not frequency. Mechanisms mediating pain and bloating may be different from those mediating symptoms at defecation.

Replication error in colorectal carcinoma: association with loss of heterozygosity at mismatch repair loci and clinicopathological variables.

Instability of microsatellite DNA or replication error (RER) is characteristic of tumours caused by mismatch repair (MMR) deficiency. Germline mutations in MMR genes are associated with Hereditary non-polyposis colorectal carcinoma (HNPCC) and somatic mutations in these genes are also found in a substantial fraction of colorectal cancers (CRC). In this study we concurrently screened colorectal tumours for the RER phenotype and loss of heterozygosity (LOH) at MMR gene loci. The RER phenotype was evident in 47/197 (24%) tumours. RER was more commonly detected in young patients (< 50 years) and in tumours located in the proximal colon. RER was positively associated with LOH at the hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the younger patients (< 50 years). RER was not associated with clinicopathological parameters, such as Duke's stage and tumour differentiation (grade). The RER phenotype was associated with better overall survival, but there was a trend towards significance when multivariate analysis was used. This indicates that loss of MMR genes generate a less aggressive phenotype, and raises the question about RER being a useful indicator of prognosis for CRC patients.

Abdominal symptoms are not related to anorectal function in the irritable bowel syndrome.

BACKGROUND: The pathophysiologic significance of altered intestinal motility and perception in irritable bowel syndrome (IBS) is unclear, as a consistent association with abdominal symptoms has not been proved. Our aim was to investigate the association between abdominal symptoms and anorectal function in IBS. METHODS: Fifty-two patients recorded their symptoms daily for I week. At the end of the week anorectal function was investigated by manovolumetry before and after a standardized fatty meal. Cluster analysis of daily recorded symptoms and both pre- and postprandial manovolumetric data was performed to identify symptom and physiologic subgroups. RESULTS: Symptom subgroups did not differ with regard to anorectal function. Physiologic subgroups did not differ with regard to daily recorded symptoms. Postprandially, the thresholds eliciting maximal tolerable distention were decreased in 22 of the patients. This increase in rectal sensitivity was not related to symptoms and may have been caused by the preprandial anorectal measurement, since thresholds for maximal tolerable distention decreased significantly in nine patients retested without an intervening meal. CONCLUSIONS: Abdominal symptoms and anorectal function are not related in IBS.

Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival.

The distal half of chromosome 1p was analysed with 15 polymorphic microsatellite markers in 683 human solid tumours at different locations. Loss of heterozygosity (LOH) was observed at least at one site in 369 cases or 54% of the tumours. LOHs detected ranged from 30-64%, depending on tumour location. The major results regarding LOH at different tumour locations were as follows: stomach, 20/38 (53%); colon and rectum, 60/109 (55%); lung, 38/63 (60%); breast, 145/238 (61%); endometrium, 18/25 (72%); ovary, 17/31 (55%); testis, 11/30 (37%); kidney, 22/73 (30%); thyroid, 4/14 (29%); and sarcomas, 9/14 (64%). High percentages of LOH were seen in the 1p36.3, 1p36.1, 1p35-p34.3, 1p32 and 1p31 regions, suggesting the presence of tumour-suppressor genes. All these regions on chromosome 1p show high LOH in more than one tumour type. However, distinct patterns of LOH were detected at different tumour locations. There was a significant separation of survival curves, with and without LOH at chromosome 1p, in the breast cancer patients. Multivariate analysis showed that LOH at 1p in breast tumours is a better indicator for prognosis than the other variables tested in our model, including nodal metastasis.

High incidence of loss of heterozygosity in breast tumors from carriers of the BRCA2 999del5 mutation.

Germ-line mutation in the BRCA2 gene confers an increased risk of breast cancer. An elevation of additional genetic defects in tumors of patients with germ-line mutation in the BRCA2 gene compared with sporadic breast tumors has been reported. To evaluate the nature of the difference, we did detailed mapping of chromosomes 1p, 3p, 6q, 11, 13q, 16q, 17, and 20q, using microsatellite markers. We found that the frequency of loss of heterozygosity was similar at some chromosomal regions in the BRCA2 999del5 and sporadic tumors but significantly different at others. These others include chromosomal arms 3p, 6q, 11p, 11q, 13q, and 17p. Loss of heterozygosity mapping suggests that the same chromosome regions are involved in both tumor groups but at elevated frequencies in BRCA2 999del5 tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to the BRCA2 999del5 germ-line mutation. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals.

Pain is temporally related to eating but not to defaecation in the irritable bowel syndrome (IBS). Patients' description of diarrhea, constipation and symptom variation during a prospective 6-week study.

OBJECTIVES: To study the intensity and variation of pain and its temporal relation to eating and defaecation. Furthermore, what irritable bowel (IBS) patients mean by constipation and diarrhea and how bowel symptoms vary. DESIGN: Prospective daily symptom recording over 6 weeks. SETTING: The primary catchment area of University Hospital of Linköping. PARTICIPANTS: Eighty consecutive patients fulfilling the Rome criteria; 63 finished the study. RESULTS: Fifty-nine of 63 patients recorded an average of 29 pain periods and 24 days with pain during the 6 weeks. Over-all pain burden decreased slightly over the study period. At inclusion 38 (64%) patients claimed that pain was relieved by defaecation. However, on average, only 10% of each patient's recorded pain periods were relieved by defaecation. At inclusion 29 (49%) patients claimed postprandial worsening of pain. On average, 50% of each patient's recorded pain periods worsened postprandially. The patients defined constipation as hard stools and diarrhea as loose stools and urgency. Stool frequency did not differ. Bowel symptoms varied within, but not between, fortnightly periods. CONCLUSIONS: Postprandial worsening of pain should be included as a criterion in the clinical definition of IBS while the criterion 'pain relieved by defaecation' should be re-evaluated. IBS patients can probably be divided into subgroups based on stool consistency, not frequency. Daily records are superior to structured clinical interviews or questionnaires for a detailed study of symptoms in IBS.

Loss of heterozygosity at chromosome 7q in human breast cancer: association with clinical variables.

In this study 238 human primary breast cancers were analysed with 9 polymorphic microsatellite markers specific to region 7q21-q35 on chromosome 7. LOH was observed at one or more marker in 82 cases or (34%). The deletions were evenly distributed throughout the region. Patients were divided into two groups according to whether LOH was observed in their tumours or not, and tested for association with overall survival, the clinicopathological features: steroid receptor content, tumour size, node status, DNA ploidy and S-phase fraction, and LOH at other chromosomal regions. An association was found between 7q LOH and high S-phase fraction. An association was found between LOH at 7q and LOH at 1p, 3p, 9p, 13q and 17q. These results suggest the location of a putative tumour suppressor gene at chromosome 7q21-q35 that, in combination with other deletions, might enhance tumour growth.

Review article: Targeted drug delivery in treatment of intestinal diseases.

Topical therapy within the treatment of intestinal diseases presents realistic formulation challenges for targeted drug delivery. Some relevant oral formulation concepts are reviewed. The basic principles employed are based mainly on differences in pH and metabolic activity between the different parts of the gastrointestinal tract. A successful example of targeted drug delivery within the treatment of Crohn's disease is presented. Topical therapy for the treatment of ulcerative colitis is also discussed. Physiological variations and influence of the disease and disease status present major challenges when deciding upon a suitable formulation principle.