[Sweden can again take the lead in clincal research - if we want to!] / Sverige kan ta täten i klinisk forskning igen ­ om vi vill!

The support systems for Swedish clinical research have been evaluated by the Swedish Research Council and here we summarize some key issues. The shift towards precision medicine and rising requirements for post-registration ¼real world data« is expected to affect the system for clinical studies. The emerging requirements regarding demonstration of patient value for medical devices need to be better defined. There is a need for more meeting-places between the entrepreneurial system and the health-care system. Since research/development is often not considered to be a ¼core activity« in the Swedish health care system, it is frequently given a lower priority. Changing this may necessitate legislation. All interviewed, including patient organizations, were positive toward participation in research and development.

Associations among neurophysiology measures in irritable bowel syndrome (IBS) and their relevance for IBS symptoms.

Abnormal gut-brain interactions are common in irritable bowel syndrome (IBS), but the associations between neurophysiological measures and their relation to gastrointestinal (GI) symptoms are poorly understood. Our aim was to explore these relationships and define the most relevant neurophysiology measures for GI symptom severity in IBS. IBS patients underwent small intestinal motility (manometry; fasted and fed contraction frequency, phase III time) and secretion (transmural potential difference), rectal sensorimotor (barostat; sensory thresholds, tone response, compliance), autonomic nervous system (baroreceptor sensitivity and effectiveness), and colonic motor function (transit time) examinations. GI symptom severity (GSRS-IBS), and anxiety and depression (HAD) as a proxy measure of central nervous system (CNS) dysfunction, were assessed. In total 281 IBS patients (Rome II criteria) were included (74% females, median age 36 [interquartile range 28-50] years). Significant correlations between neurophysiology measures were stronger within, rather than between, different neurophysiological examinations. The strongest neurophysiology-symptom correlations occurred between a combination of CNS and visceral sensitivity parameters, and GSRS-IBS total score and pain domain (ρ = 0.40, p < 0.001, and ρ = 0.38, p < 0.001). Associations between GI symptoms in IBS and individual and combinations of neurophysiological factors occurred, primarily in CNS and visceral sensitivity measures, providing new insights into the clinical presentation of IBS.

Pretreatment Tumor DNA Sequencing of KIT and PDGFRA in Endosonography-Guided Biopsies Optimizes the Preoperative Management of Gastrointestinal Stromal Tumors.

BACKGROUND: Neoadjuvant tyrosine kinase inhibitor (TKI) therapy increases the chance of organ-preserving, radical resection in selected patients with gastrointestinal stromal tumors (GISTs). We aimed to evaluate systematic, immediate DNA sequencing of KIT and PDGFRA in pretreatment GIST tissue to guide neoadjuvant TKI therapy and optimize preoperative tumor response. METHODS: All patients who were candidates for neoadjuvant therapy of a suspected GIST [the study cohort (SC)] were prospectively included from January 2014 to March 2018. Patients were subjected to pretreatment endosonography-guided fine-needle biopsy (EUS-FNB) or transabdominal ultrasound-guided needle biopsy (TUS-NB), followed by immediate tumor DNA sequencing (< 2 weeks). A historic (2006-2013) reference cohort (RC) underwent work-up without sequencing before neoadjuvant imatinib (n = 42). The rate of optimal neoadjuvant therapy (TherapyOPTIMAL) was calculated, and the induced tumor size reduction (Tumor RegressionMAX, %) was evaluated by computed tomography (CT) scan. RESULTS: The success rate of pretreatment tumor DNA sequencing in the SC (n = 81) was 77/81 (95%) [EUS-FNB 71/74 (96%); TUS-NB 6/7 (86%)], with mutations localized in KIT (n = 58), PDGFRA (n = 18), or neither gene, wild type (n = 5). In patients with a final indication for neoadjuvant therapy, the TherapyOPTIMAL was higher in the SC compared with the RC [61/63 (97%) versus 33/42 (79%), p = 0.006], leading to a significantly higher Tumor RegressionMAX in patients treated with TKI (27% vs. 19%, p = 0.015). CONCLUSIONS: Pretreatment endosonography-guided biopsy sampling followed by immediate tumor DNA sequencing of KIT and PDGFRA is highly accurate and valuable in guiding neoadjuvant TKI therapy in GIST. This approach minimizes maltreatment with inappropriate regimens and leads to improved tumor size reduction before surgery.

Anxiety and depression in irritable bowel syndrome: Exploring the interaction with other symptoms and pathophysiology using multivariate analyses.

BACKGROUND: Anxiety or depression, in other words, psychological distress, are common comorbidities in patients with irritable bowel syndrome (IBS), but their interaction with pathophysiological factors and other symptoms are unclear. METHODS: Patients with IBS (Rome III criteria), thoroughly characterized regarding pathophysiology (colonic transit time, visceral sensitivity, and autonomic nervous system [ANS] function), symptom profile (IBS severity, somatic symptoms, gastrointestinal [GI]-specific anxiety and fatigue), and quality of life, were explored for differences regarding pathophysiology and symptoms between patients with and without reported psychological distress in univariate and multivariate analyses (Principal Component Analysis [PCA] with Hotelling's T2 and Orthogonal Partial Least Squares-Discriminant Analysis [OPLS-DA]). KEY RESULTS: When using Hospital Anxiety and Depression Scale score ≥8 as cut-off score, including both borderline and clinically significant cases, 345 (44.9%) out of 769 IBS patients reported anxiety, and 198 (25.7%) depression. In univariate analyses, patients reporting psychological distress demonstrated more severe GI and non-GI symptoms, fatigue, GI-specific anxiety and lower quality of life, and differences for some pathophysiological measures. IBS patients with and without reported psychological distress showed significant differences between the multivariate means in symptom reporting (PCA; both P < 0.001), and in pathophysiological measures in patients with and without anxiety (P = 0.018). Visceral hypersensitivity, altered ANS function, more severe GI-specific anxiety, fatigue, and higher somatic non-GI symptoms were the factors that most strongly separated patients with and without psychological distress (OPLS-DA). CONCLUSIONS AND INFERENCES: Reported anxiety and depression are common in IBS patients, and our study demonstrates that they are interwoven in the complex pathophysiological and clinical picture of IBS.

Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis.

OBJECTIVE: The colonic inner mucus layer protects us from pathogens and commensal-induced inflammation, and has been shown to be defective in active UC. The aim of this study was to determine the underlying compositional alterations, their molecular background and potential contribution to UC pathogenesis. DESIGN: In this single-centre case-control study, sigmoid colon biopsies were obtained from patients with UC with ongoing inflammation (n=36) or in remission (n=28), and from 47 patients without colonic disease. Mucus samples were collected from biopsies ex vivo, and their protein composition analysed by nanoliquid chromatography-tandem mass spectrometry. Mucus penetrability and goblet cell responses to microbial stimulus were assessed in a subset of patients. RESULTS: The core mucus proteome was found to consist of a small set of 29 secreted/transmembrane proteins. In active UC, major structural mucus components including the mucin MUC2 (p<0.0001) were reduced, also in non-inflamed segments. Active UC was associated with decreased numbers of sentinel goblet cells and attenuation of the goblet cell secretory response to microbial challenge. Abnormal penetrability of the inner mucus layer was observed in a subset of patients with UC (12/40; 30%). Proteomic alterations in penetrable mucus samples included a reduction of the SLC26A3 apical membrane anion exchanger, which supplies bicarbonate required for colonic mucin barrier formation. CONCLUSION: Core mucus structural components were reduced in active UC. These alterations were associated with attenuation of the goblet cell secretory response to microbial challenge, but occurred independent of local inflammation. Thus, mucus abnormalities are likely to contribute to UC pathogenesis.

[Robot-assisted surgery on a broad front--without evidence for being cost-effective]. / Robotkirurgi på bred front ­ utan evidensbaserad grund - Tekniken används allt mer, trots att den är dyr och att vetenskapliga bevis för patientnytta saknas.

Robot-assisted surgery on a broad front - without evidence for being cost-effective Robot-assisted surgery is currently heavily marketed. The HTA centre in Region Västra Götaland has produced five HTA reports regarding use of robot-assisted surgery in different clinical situations (prostatic cancer, benign gynaecological surgery, pediatric pyeloplasty and fundoplication, and rectal cancer), finding weak evidence for a patient value. The current report by Per Carlsson et al confirms that robot-assisted surgery indeed leads to increased costs that are not balanced by augmented patient value, i.e. robot-assisted surgery cannot be regarded as cost efficient. We comment critically on the capricious introduction of new techniques/devices, a procedure that stands in sharp contrast to the strictly formalized system for approval of new drugs.

An Antibody Against Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Dampens Proinflammatory Cytokine Secretion by Lamina Propria Cells from Patients with IBD.

BACKGROUND: Triggering receptor expressed on myeloid cells 1 (TREM-1) is a potent amplifier of inflammation. Recently, the antimicrobial peptide PGLYRP-1 was shown to be the ligand of TREM-1. Here, the ability of an anti-TREM-1 antibody to dampen the release of proinflammatory cytokines by colon lamina propria cells (LPCs) from patients with IBD was investigated and correlated with PGLYRP-1 levels. METHODS: Biopsies from patients with ulcerative colitis (UC, n = 45) or Crohn's disease (CD, n = 26) were compared with those from individuals undergoing colonoscopy for other reasons (n = 17). TREM-1 expression was analyzed on myeloid cells by flow cytometry. Cell culture experiments with LPCs were used to analyze PGLYRP-1 and inflammatory cytokine levels and assess the effect of anti-TREM-1 on cytokine secretion. RESULTS: The frequency of TREM-1-expressing neutrophils and recruited macrophages was higher in inflamed than in noninflamed biopsies. The PGLYRP-1 level in inflamed tissue was higher than in noninflamed tissue; it was produced primarily by neutrophils, and its level correlated with the secretion of proinflammatory cytokines. Secretion of myeloperoxidase, tumor necrosis factor-α, interleukin-1ß, and interleukin-8 by LPCs stimulated with the potent TREM-1 agonist consisting of PGLYRP-1 complexed with peptidoglycan was reduced in the presence of anti-TREM-1. Moreover, a blocking effect of anti-TREM-1 was apparent when LPCs from a subset of inflamed individuals with elevated PGLYRP-1 were stimulated with killed bacteria. CONCLUSIONS: An anti-TREM-1 antibody can dampen secretion of proinflammatory cytokines in inflamed patients with elevated PGLYRP-1. Moreover, PGLYRP-1 + myeloperoxidase is a potential biomarker for predicting the effect of anti-TREM-1 therapy.

[Better regulatory framework needed for medical devices]. / Bättre regelverk behövs för medicintekniska produkter - HTA-utredning av läkemedelsavgivande stentar och ballonger vid benartärsjukdom visar på bristerna.

We summarize an HTA report regarding patient values of drug-eluting stents and balloons for treatment of atherosclerotic disease in the lower extremities. We found 17 randomized controlled trials, 4 cohort studies and 13 case series. The total number of studied patients was substantial (about 3,000) but there was a strong heterogeneity regarding site of lesion, symptom pattern, device, drug used and outcome measures, making the analysis difficult and based on relatively small subgroups. We found low certainty of evidence (GRADE ++) for a reduced risk of restenosis in patients with critical ischemia and lesions below the knee, and also a modest beneficial effect on ischemic symptoms in a mixed patient population. However, we also identified a worrying safety signal, with increased risk for amputation in a group of patients with below-the-knee disease and critical ischemia. The results highlight the need for a structured system for validation of medical devices, a system analogous to that currently used for evaluation of new pharmacological products.

Are the definitions for chronic diarrhoea adequate? Evaluation of two different definitions in patients with chronic diarrhoea.

BACKGROUND: The classical definition of chronic diarrhoea is ≥3 defecations/day, with a stool weight of more than 200 g and duration of ≥4 weeks. However, with this definition many patients with substantial symptoms and pathology will be excluded from further investigations. As a consequence other definitions have been proposed, mainly based on evaluation of the stool form. OBJECTIVE: To evaluate the accuracy of the classic criteria for diarrhoea in comparison with a definition based on stool consistency, using the Bristol Stool Form Scale. METHODS: All patients were investigated with laboratory tests, upper and lower gastrointestinal endoscopy with biopsies, and SeHCAT test. They were asked to complete a diary recording stool frequency and consistency during a week, as well as other gastrointestinal symptoms (pain, bloating and gas). RESULTS: One hundred and thirty-nine subjects were eligible for analysis. Ninety-one had an organic cause of diarrhoea. Fifty-three patients had ≥3 loose stools/day, whereas 86 reported <3 stools/day. Ninety had a median stool consistency that was mushy or loose and 49 had harder stools. A higher proportion of subjects with an organic cause of their diarrhoea compared with subjects with a functional bowel disorder had ≥3 loose stools/day, 43/91 (47%) vs. 10/48 (21%) (p < 0.01). Similarly, more subjects with an organic cause of their diarrhoea versus patients with a functional bowel disorder had a median stool consistency that was mushy or watery, 73/91 (80%) vs. 17/48 (35%), p < 0.0001. When diarrhoea was defined according to stool form, more patients were classified correctly as having a functional disorder or organic disorder, compared with the classical definition (p < 0.05). CONCLUSION: Loose stools defined according to the Bristol Stool Form scale seem to be the best predictor of having an organic cause of the diarrhoea.

Carbachol-induced colonic mucus formation requires transport via NKCC1, K⁺ channels and CFTR.

The colonic mucosa protects itself from the luminal content by secreting mucus that keeps the bacteria at a distance from the epithelium. For this barrier to be effective, the mucus has to be constantly replenished which involves exocytosis and expansion of the secreted mucins. Mechanisms involved in regulation of mucus exocytosis and expansion are poorly understood, and the aim of this study was to investigate whether epithelial anion secretion regulates mucus formation in the colon. The muscarinic agonist carbachol was used to induce parallel secretion of anions and mucus, and by using established inhibitors of ion transport, we studied how inhibition of epithelial transport affected mucus formation in mouse colon. Anion secretion and mucin exocytosis were measured by changes in membrane current and epithelial capacitance, respectively. Mucus thickness measurements were used to determine the carbachol effect on mucus growth. The results showed that the carbachol-induced increase in membrane current was dependent on NKCC1 co-transport, basolateral K(+) channels and Cftr activity. In contrast, the carbachol-induced increase in capacitance was partially dependent on NKCC1 and K(+) channel activity, but did not require Cftr activity. Carbachol also induced an increase in mucus thickness that was inhibited by the NKCC1 blocker bumetanide. However, mice that lacked a functional Cftr channel did not respond to carbachol with an increase in mucus thickness, suggesting that carbachol-induced mucin expansion requires Cftr channel activity. In conclusion, these findings suggest that colonic epithelial transport regulates mucus formation by affecting both exocytosis and expansion of the mucin molecules.

Spontaneous colitis in Muc2-deficient mice reflects clinical and cellular features of active ulcerative colitis.

BACKGROUND: The colonic mucus layer plays a critical role in intestinal homeostasis by limiting contact between luminal bacteria and the mucosal immune system. A defective mucus barrier in animal models allows bacterial contact with the intestinal epithelium and results in spontaneous colitis. A defective mucus barrier is also a key feature of active ulcerative colitis (UC). Alterations in the immune compartment due to intestinal bacterial breach in mice lacking the colon mucus barrier have not been characterized and correlated to active UC. AIMS: To characterize alterations in the immune compartment due to intestinal bacterial breach in Muc2-/- mice, which lack the colon mucus barrier, and correlate the findings to active UC. METHODS: Bacterial contact with colon epithelium and penetration into colon tissue was examined in Muc2-/- mice and colon biopsies from patients with active UC using fluorescence microscopy and qPCR. Neutrophils, lymphocytes, CD103+ dendritic cell subsets and macrophages in colon from Muc2-/- mice and biopsies from UC patients were quantitated by flow cytometry. RESULTS: Inflamed UC patients and Muc2-/- mice had bacteria in contact with the colon epithelium. Bacterial rRNA was present in colonic mucosa in humans and Muc2-/- mice and in the draining lymph nodes of mice. Inflamed Muc2-/- mice and UC patients had elevated colon neutrophils, T cells and macrophages while a reduced frequency of CD103+ DCs was present in the inflamed colon of both mice and humans. CONCLUSIONS: The parallel features of the colon immune cell compartment in Muc2-/- mice and UC patients supports the usefulness of this model to understand the early phase of spontaneous colitis and will provide insight into novel strategies to treat UC.

Proteomic mucin profiling for the identification of cystic precursors of pancreatic cancer.

BACKGROUND: Pancreatic cystic lesions (PCLs) are increasingly frequent radiological incidentalomas, with a considerable proportion representing precursors of pancreatic cancer. Better diagnostic tools are required for patients to benefit from this development. METHODS: To evaluate whether cyst fluid mucin expression could predict malignant potential and/or transformation in PCLs, a proteomic method was devised and prospectively evaluated in consecutive patients referred to our tertiary center for endoscopic ultrasound-guided aspiration of cystic lesions from May 2007 through November 2008 (discovery cohort) and from December 2008 through October 2012 (validation cohort). Cytology and cyst fluid carcinoembryonic antigen (CEA; premalignancy > 192 ng/mL, malignancy > 1000 ng/mL) were routinely analyzed, and samples were further processed as follows: one-dimensional gel electrophoresis, excision of high-mass areas, tryptic digestion and nano-liquid chromatography-tandem mass spectrometry, with peptide identification by Mascot software and an in-house mucin database. All diagnostic evaluations were blinded to proteomics results. Histology was required to confirm the presence/absence of malignant transformation. All statistical tests were two-sided. RESULTS: Proteomic mucin profiling proved statistically significantly more accurate (97.5%; 95% confidence interval [CI] = 90.3% to 99.6%) than cytology (71.4%; 95% CI = 59.8% to 80.9%; P < .001) and cyst fluid CEA (78.0%; 95% CI = 65.0% to 87.3%; P < .001) in identifying the 37 (out of 79; 46.8%) lesions with malignant potential (ie, premalignant or malignant tumors). The accuracy of proteomics was nearly identical (96.6% vs 98.0%) between the discovery (n = 29) and validation (n = 50) cohorts. Furthermore, mucin profiling predicted malignant transformation, present in 16 out of 29 (discovery cohort: 9, validation cohort: 20) lesions with available histology, with 89.7% accuracy (95% CI = 71.5% to 97.3%) (for the validation cohort only: 95.0%; 95% CI = 73.1% to 99.7%). This markedly exceeded corresponding results for cytology (51.7%; 95% CI = 32.9% to 70.1%; P = .003) and CEA (57.1%; 95% CI = 34.4% to 77.4%; P = .02). CONCLUSIONS: Proteomic cyst fluid mucin profiling robustly discriminates benign, premalignant, and malignant PCLs. Consequently, it may improve pancreatic cancer prevention and reduce the morbidity burden of unwarranted pancreatic surgery.

Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis.

OBJECTIVE: The inner mucus layer in mouse colon normally separates bacteria from the epithelium. Do humans have a similar inner mucus layer and are defects in this mucus layer a common denominator for spontaneous colitis in mice models and ulcerative colitis (UC)? METHODS AND RESULTS: The colon mucus layer from mice deficient in Muc2 mucin, Core 1 O-glycans, Tlr5, interleukin 10 (IL-10) and Slc9a3 (Nhe3) together with that from dextran sodium sulfate-treated mice was immunostained for Muc2, and bacterial localisation in the mucus was analysed. All murine colitis models revealed bacteria in contact with the epithelium. Additional analysis of the less inflamed IL-10(-/-) mice revealed a thicker mucus layer than wild-type, but the properties were different, as the inner mucus layer could be penetrated both by bacteria in vivo and by fluorescent beads the size of bacteria ex vivo. Clear separation between bacteria or fluorescent beads and the epithelium mediated by the inner mucus layer was also evident in normal human sigmoid colon biopsy samples. In contrast, mucus on colon biopsy specimens from patients with UC with acute inflammation was highly penetrable. Most patients with UC in remission had an impenetrable mucus layer similar to that of controls. CONCLUSIONS: Normal human sigmoid colon has an inner mucus layer that is impenetrable to bacteria. The colon mucus in animal models that spontaneously develop colitis and in patients with active UC allows bacteria to penetrate and reach the epithelium. Thus colon mucus properties can be modulated, and this suggests a novel model of UC pathophysiology.

The importance of a person-centered approach in diagnostic workups of patients with irritable bowel syndrome: a qualitative study.

The aim of this study was to explore experiences of undergoing a diagnostic workup in patients with irritable bowel syndrome (IBS) at a unit for functional gastrointestinal disorders. Research has been sparse in addressing such experiences and the impact on well-being. Patients with IBS were invited to perform a workup of gastrointestinal tests. Of 120 patients who completed the tests, 20 were invited for an interview. Analysis of interviews was conducted through interpretative phenomenological analysis. One master theme emerged: validation of IBS experience inferred from three subthemes: the duality of suffering in IBS, coping with inflicted discomfort and pain, and capacity for resilience.Patients reported long-term suffering from symptoms including poor management within the healthcare organization. Despite inconvenience associated with the tests, patients expressed appreciation for professional attributes such as attentiveness that were perceived as a sense of being cared for and seen as a "person." During the workup, patients acquired greater knowledge of what IBS means, including knowledge about their own body functions and experienced relief that symptoms were not caused by any "dangerous" disease. Validation of IBS experience surfaced in the data implying that in such context, patients with IBS appear to find personal solutions to cope with everyday experiences and enhance autonomy.

Transcriptome signatures in Helicobacter pylori-infected mucosa identifies acidic mammalian chitinase loss as a corpus atrophy marker.

BACKGROUND: The majority of gastric cancer cases are believed to be caused by chronic infection with the bacterium Helicobacter pylori, and atrophic corpus gastritis is a predisposing condition to gastric cancer development. We aimed to increase understanding of the molecular details of atrophy by performing a global transcriptome analysis of stomach tissue. METHODS: Biopsies from patients with different stages of H. pylori infection were taken from both the antrum and corpus mucosa and analyzed on microarrays. The stages included patients without current H. pylori infection, H. pylori-infected without corpus atrophy and patients with current or past H. pylori-infection with corpus-predominant atrophic gastritis. RESULTS: Using clustering and integrated analysis, we found firm evidence for antralization of the corpus mucosa of atrophy patients. This antralization harbored gain of gastrin expression, as well as loss of expression of corpus-related genes, such as genes associated with acid production, energy metabolism and blood clotting. The analyses provided detailed molecular evidence for simultaneous intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM) in atrophic corpus tissue. Finally, acidic mammalian chitinase, a chitin-degrading enzyme produced by chief cells, was shown to be strongly down-regulated in corpus atrophy. CONCLUSIONS: Transcriptome analysis revealed several gene groups which are related to development of corpus atrophy, some of which were increased also in H. pylori-infected non-atrophic patients. Furthermore, loss of acidic chitinase expression is a promising marker for corpus atrophy.

How patients with long-term experience of living with irritable bowel syndrome manage illness in daily life: a qualitative study.

OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic, disabling and functional gastrointestinal disorder. Effective treatments are lacking. Self-care and coping with symptoms are considered important but little is known about what patients with IBS actually do to manage their illness. The aim of this study was to explore how patients with long-term experience of living with IBS perceive their situation and manage illness in daily life. PATIENTS AND METHODS: The study adopted a qualitative approach - an interpretative phenomenological analysis. Twenty patients with IBS (16 women) with a mean age of 46 (27-74) years were interviewed. The mean IBS duration was 24 (7-65) years. RESULTS: Two themes emerged from the analysis: Healed but not cured and Take control of daily life. Healed but not cured is about mastering IBS. Even though the patients feel there has been an improvement, their abdomen is constantly present. The patients live with intermittent interaction between well-being and illness and construct explanations for the cause of the IBS symptoms. Taking control of daily life is about the activities the patients perform to master IBS symptoms: self-centredness, disciplined self-care, control over daily routines and finding social support. CONCLUSION: These results suggest that the negative impact of IBS on daily life can be reduced. Over time, the patients had found effective strategies for symptom improvement, although this is a long-term learning process. The healthcare system could be more effective in supporting patients to find solutions to problems caused by IBS that are consistent with person-centred care and could be adopted as part of different supportive/educational interventions.

Serum IL-17A in newly diagnosed treatment-naive patients with ulcerative colitis reflects clinical disease severity and predicts the course of disease.

BACKGROUND: The clinical course of ulcerative colitis (UC) is unpredictable. The need for reliable biomarkers to reflect disease severity and predict disease course is therefore large. We investigated whether cytokines in mucosal tissue and serum reflect clinical disease severity at the onset of UC and predict the future disease course. METHODS: We prospectively monitored 102 patients from the onset of UC during 3 years, and they were followed up yearly for clinical and biochemical disease severity. Rectal biopsies were obtained from healthy controls and patients with UC. Serum and stool samples were obtained from patients with UC. Total mRNA from biopsies was analyzed with real-time PCR. Cytokine levels in serum were determined using Luminex or ELISA. RESULTS: Mucosal mRNA expression of IL-17A was 99.8 times higher while IFN-γ and IL-13 expression was increased 12.4 and 6.7 times, respectively, in patients relative to controls. Serum IL-17A correlated with clinical disease severity at the onset. Also, contrary to a number of other parameters, serum IL-17A at the onset predicted the clinical and biochemical course of the disease, as reflected by the Mayo score, number × severity of flares, and fecal calprotectin levels, respectively, during 3 years after the onset of the disease. None of these associations were found with mucosal cytokines at the onset. CONCLUSIONS: Serum IL-17A levels of treatment-naive patients with UC reflect clinical disease severity at the onset of the disease and also predicted the disease course over the following 3 years. Thus, serum IL-17A may be valuable in the clinical management of patients with UC at the onset of the disease.

The gastrointestinal mucus system in health and disease.

Mucins--large, highly glycosylated proteins--are important for the luminal protection of the gastrointestinal tract. Enterocytes have their apical surface covered by transmembrane mucins and goblet cells produce the secreted gel-forming mucins that form mucus. The small intestine has a single unattached mucus layer, which in cystic fibrosis becomes attached, accounting for the intestinal manifestations of this disease. The stomach and colon have two layers of mucus; the inner layer is attached and the outer layer is less dense and unattached. In the colon, the outer mucus layer is the habitat for commensal bacteria. The inner mucus layer is impervious to bacteria and is renewed every hour by surface goblet cells. The crypt goblet cells have the ability to restitute the mucus layer by secretion, for example after an ischaemic challenge. Proteases of certain parasites and some bacteria can cleave mucins and dissolve the mucus as part of their pathogenicity. The inner mucus layer can, however, also become penetrable to bacteria by several other mechanisms, including aberrations in the immune system. When bacteria reach the epithelial surface, the immune system is activated and inflammation is triggered. This mechanism might occur in some types of ulcerative colitis.