Effects of eosinophilic oesophagitis on quality of life in an adult UK population: a case control study.

Eosinophilic oesophagitis (EoE) is a chronic immune-mediated esophageal disease, characterized by symptoms related to esophageal dysfunction and histologically by eosinophil predominant inflammation. Current evidence for an adverse impact on quality of life (QoL) is conflicting and there are no data from a UK population regarding QoL. We conducted a prospective cross-sectional observational study using the Short Form-36 Health Survey, Hospital Dysphagia/Odynophagia Questionnaire, and the EoE Adult Quality of Life Questionnaire to assess QoL and severity of dysphagia in EoE patients, compared to age and gender matched healthy control subjects. Data were also collected on comorbidity and medication use. Eighty-eight subjects were recruited (44 patients). Patients had higher rates of antihistamine and topical (swallowed) corticosteroid use. Physical QoL did not differ between patients and controls, although patients did report a statistically significant lower mental QoL, with small absolute magnitude of difference. Patients reported higher dysphagia scores and these were negatively correlated with both physical and mental QoL. Higher rates of dysphagia and medication use in patients may among other things account for lower mental QoL. However, a higher rate of dysphagia in patients is not associated with a reduced physical QoL. Our findings are of clinical value, particularly when a new diagnosis of EoE is made, as clinicians can reassure patients that their general physical health should not be greatly affected by the diagnosis. Moreover, it may also be useful for patients to be aware that EoE may have an impact on their mental health, but this effect is likely to be small. We therefore advocate education and reassurance in this respect for all patients at diagnosis.

Prevalence and duration of gastrointestinal symptoms before diagnosis of Inflammatory Bowel Disease and predictors of timely specialist review: a population-based study.

BACKGROUND AND AIMS: Lack of timely referral and significant waits for specialist review amongst individuals with unresolved gastrointestinal (GI) symptoms can result in delayed diagnosis of Inflammatory Bowel Disease (IBD). AIMS: To determine the frequency and duration of GI symptoms and predictors of timely specialist review before the diagnosis of both Crohn's Disease (CD) and ulcerative colitis (UC). METHODS: Case-control study of IBD matched 1:4 for age and sex to controls without IBD using the Clinical Practice Research Datalink from 1998-2016. RESULTS: We identified 19,555 cases of IBD, and 78,114 controls. 1 in 4 cases of IBD reported gastrointestinal symptoms to their primary care physician more than 6 months before receiving a diagnosis. There is a significant excess prevalence of GI symptoms in each of the 10 years before IBD diagnosis. GI symptoms were reported by 9.6% and 10.4% at 5 years before CD and UC diagnosis respectively compared to 5.8% of controls. Amongst patients later diagnosed with IBD, <50% received specialist review within 18 months from presenting with chronic GI symptoms. Patients with a previous diagnosis of irritable bowel syndrome or depression were less likely to receive timely specialist review (IBS: HR=0.77, 95%CI 0.60-0.99, depression: HR=0.77, 95%CI 0.60-0.98). CONCLUSIONS: There is an excess of GI symptoms 5 years before diagnosis of IBD compared to the background population which are likely attributable to undiagnosed disease. Previous diagnoses of IBS and depression are associated with delays in specialist review. Enhanced pathways are needed to accelerate specialist referral and timely IBD diagnosis.

RGTA OTR4120, a heparan sulfate mimetic, is a possible long-term active agent to heal burned skin.

Burn-related skin fibrosis leads to loss of tissue function and hypertrophic scar formation with damaging consequences for the patient. There is therefore a great need for an efficient agent to treat burned skin. We report that ReGeneraTing Agent (RGTA) reduces burn-induced skin alteration. The tissue-regenerating effect of RGTA OTR4120 was evaluated after 1-6 days and after 10 months in a rat skin burn model. This effect was also examined in vitro using fibroblasts isolated from control and 6-day-old burned skins. We measured production of dermal collagen I, III, and V and activities of metalloproteinases 2 and 9 (MMP-2 and MMP-9). Ratio of collagen III over collagen I production increased 6 days after the burn, because of a decrease in collagen I production. After 10 months, ratio of collagen III over collagen I in burn sites was still increased compared with control skin, because of an increase in collagen III production. Both abnormalities were corrected by OTR4120. OTR4120 increased pro- and active MMP-2 and MMP-9, compared with healthy and burned controls and therefore accelerated remodeling. Similar data were obtained with cultured fibroblasts from healthy and burned skins. OTR4120 enhanced healing in short- and long-term after burns, reducing the formation of fibrotic tissue, and then represents a potential agent to improve burned skin healing.

Systematic review with meta-analysis: the impact of a depressive state on disease course in adult inflammatory bowel disease.

BACKGROUND: Despite a higher prevalence of psychosocial morbidity in Inflammatory Bowel Disease (IBD), the association between depressive state and disease course in IBD is poorly understood. AIM: To investigate the impact of depressive state on disease course in IBD. METHODS: We conducted a systematic review in MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and PsychINFO for prospective studies evaluating the impact of baseline depressive state on subsequent disease course in adult IBD. RESULTS: Eleven studies matched our entry criteria, representing 3194 patients with IBD. Three reported on patients with ulcerative colitis (UC), four included patients with Crohn's disease (CD) exclusively, and four studies included both UC and CD. Five studies reported an association between depressive state and disease course. None of the UC-specific studies found any association. In three of four CD-specific studies, a relationship between depressive state and worsening disease course was found. In four of five studies including patients in remission at baseline, no association between depressive state and disease course was found. Pooled analysis of IBD studies with patients in clinical remission at baseline identified no association between depressive state and disease course (HR 1.04, 95%CI: 0.97-1.12). CONCLUSION: There is limited evidence to support an association between depressive state and subsequent deterioration in disease course in IBD, but what data that exist are more supportive of an association with CD than UC. Baseline disease activity may be an important factor in this relationship. Further studies are needed to understand the relationship between mental health and outcomes in IBD.

Specific RGTA increases collagen V expression by cultured aortic smooth muscle cells via activation and protection of transforming growth factor-beta1.

Regenerating agents (RGTA) are defined as heparan sulfate mimics, which in vivo stimulate tissue repair. RGTA are obtained by controlled grafting of carboxymethyl and sulfate groups on dextran polymers. RGTA are selected in vitro, on their ability to protect heparin binding growth factors such as TGF-beta1 for example, as well as to alter extracellular matrix biosynthesis. We had reported that RGTA were able to modulate smooth muscle cell (SMC) collagen biosynthesis. Here, we demonstrated that a specific RGTA (RG-1503), altered differentially collagen type expression by post-confluent SMC and that this action involves TGF-beta1. RG-1503 decreased, by 50%, collagen I and III biosynthesis and stimulated specifically, by twofold, collagen V biosynthesis. TGF-beta1 stimulated collagen I and V by 1.5- and threefold, respectively. A synergic action for RGTA in association with TGF-beta1 was observed specifically for collagen V expression (eightfold increase). The stimulation of collagen V biosynthesis by RGTA was abolished by TGF-beta1 neutralizing antibodies. These modulations occurred at protein and mRNA levels. RG-1503 did not alter TGF-beta1 mRNA steady state level or total TGF-beta1 protein content (latent+active forms). However, RG-1503 significantly induced an elevated proportion of active TGF-beta1 form, which could result from the selective protection from proteolytic degradation of TGF-beta1 by RG-1503. These data open a rationale for understanding the stimulation of tissue repair induced by RGTA, and also, a new insight for developing drugs adapted to inhibit excess collagen deposition in smooth muscle cells associated vascular disorder, and in fibrotic diseases.

Regulation of the collagen phenotype expression of gamma-irradiated vascular smooth muscle cells by heparan mimetics (RGTA).

Restenosis is characterized by vascular smooth muscle cell (VSMC) proliferation and accumulation of collagen III in a hypertrophic and disorganized extracellular matrix. Restenosis is prevented by antimitotic agents or irradiation but no significant progress has been made to control collagen expression deregulation. Previously, we have shown that a new family of biopolymers named RGTA (heparan mimetics elaborated by grafting on dextran of carboxylate, sulfate, and benzylamide units) stimulate in vivo tissue repair and reduce fibrosis in various models. Using VSMC in vitro (pig aortic VSMC irradiated with a 60Co source and labeled with [3H]Proline), we now show that gamma-irradiation reduced cell survival by 50% and collagen synthesis 6-fold with a major increase in the ratio of collagen III to collagen I biosynthesis taken as a fibrotic index. RGTA added to the cells enhanced their survival up to 80% and reduced collagen III/I ratio back to values found in normal vascular tissues. These results suggest that RGTA combined with gamma-radiation could be an efficient strategy against restenosis.

Perspectives and attitudes of young patients with inflammatory bowel disease: symptoms, burden of disease and communication with their healthcare professionals.

INTRODUCTION: Inflammatory bowel disease (IBD) affects a significant proportion of young patients in the UK. The role of the healthcare professional, and their relationship with the young patient is particularly important at this difficult stage of their life, when education, social integration and career planning, can be dramatically affected by this consuming condition. OBJECTIVES: To address the attitudes, experiences and erspectives of young patients suffering from IBD, focusing particularly on the relationship between sufferer and healthcare provider. METHODS: Crohn's and Colitis UK invited its young members to respond to a detailed internet based questionnaire addressing various aspects of patients' disease and their relationship with respective healthcare workers. RESULTS: 1081 patients aged 29 years or less responded. Self reported burden of illness was high with only 12% respondents free from a disease flare in the previous 12 months with almost half being hospitalised in the same period. Quality of ommunication with healthcare providers was generally high, with three-quarters of patients feeling appropriately empowered in their healthcare decisions. The IBD nurse specialist was highlighted as a particularly valuable member of the team, scoring the highest of the professional groups in communication comfort scores, as well as being nominated by the patients as the preferred professional group to discuss their disease with. CONCLUSIONS: The results emphasize the considerable impact of the disease that this group is encumbered with, and identifies areas in the patient-professional relationship that can be augmented to improve the overall healthcare of this complex and fragile subgroup of patients.

Precision of cerebrovascular reactivity assessment with use of different quantification methods for hypercapnia functional MR imaging.

BACKGROUND AND PURPOSE: Tools for noninvasive mapping of hemodynamic function including cerebrovascular reactivity are emerging and may become clinically useful to predict tissue at hemodynamic risk. One such technique assesses blood oxygen level-dependent (BOLD) MR imaging contrast in response to hypercapnia, but the reliability of its quantification is uncertain. The aim of this study was to prospectively investigate the intersubject and interhemispheric variability and short-term reproducibility of hypercapnia functional MR imaging (fMRI) in healthy volunteers and to assess the effects of different methods of quantification and normalization. MATERIALS AND METHODS: Sixteen healthy volunteers, (7 women and 9 men) underwent hypercapnia fMRI with a clinical 1.5T scanner; 8 underwent scanning twice. We determined BOLD amplitude changes using a visually defined block design or automated regression to end-tidal (ET) carbon dioxide (CO2). Absolute percent signal intensity changes (PSC) were extracted for whole-brain, gray matter, and middle cerebral artery territory, and also normalized to ETCO2 change. Intersubject and intrasubject (between hemispheres and sessions) coefficients of variation (COV) were derived. We assessed the effects of different quantification methods on reproducibility indices using the t test and U tests. RESULTS: The mean change in ETCO2 was 7.8 +/- 3.3 mm Hg. Averaged BOLD increases varied from 2.54% to 2.92%. Short-term reproducibility was good for absolute PSC (4.8% to 10%) but poor for normalized PSC (range, 24% to 27% COV). Intersubject reproducibility varied between 11% and 23% for absolute PSC and, again, was poorer for normalized data (32% to 39%). Interhemispheric reproducibility of absolute PSC was excellent ranging between 1.24 and 2.16% COV. CONCLUSIONS: In conclusion, quantification of cerebrovascular reactivity with use of hypercapnia fMRI was found to have good between-session and very good interhemispheric reproducibility. The technique holds promise as a diagnostic tool, especially for sensitive detection of unilateral disease.

Reversal of abnormal collagen production in Crohn's disease intestinal biopsies treated with regenerating agents.

BACKGROUND: Crohn's disease (CD) is characterised by inflammation, muscle layer overgrowth, and collagenous fibrosis of the intestinal tract, with no effective therapy against collagen accumulation. AIMS: We quantified production of collagen in resection specimens from normal and CD patients and investigated the effect of regenerating agents (RGTAs) on collagen production. RGTAs are chemically substituted dextrans engineered to mimic the growth factor protecting effects of heparan sulphates. RGTAs have been shown to enhance tissue repair in various in vivo models and to modulate in vitro collagen phenotype differentially according to their structure. PATIENTS: We studied intestinal biopsies from two groups of CD patients: treated with glucocorticoids (CD-GC group: 10 patients) or not treated (CD group: seven patients), and from seven control patients. METHODS: After 24 hours of ex vivo incubation with (3H) proline, collagen I, III, and V were extracted by pepsin and quantitatively separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Biosynthesis of each collagen type was quantified on radiolabelled isolated collagen. RESULTS: Total intestinal collagen production in CD patients compared with controls was increased up to 3.5-fold overall (p<0.001). In particular, collagen III biosynthesis was enhanced by 6.2-fold (p<0.001) in CD patients. In the CD-GC group, collagen production abnormalities were less marked. RGTAs added to the incubation medium in the CD group decreased total collagen production by 50% and decreased collagen III synthesis by 76%. CONCLUSION: This finding offers a rationale for using RGTAs in the treatment of intestinal fibrosis in CD, thus opening up a potential new therapeutic field for this family of drugs.

Heparan mimetic regulates collagen expression and TGF-beta1 distribution in gamma-irradiated human intestinal smooth muscle cells.

Radiation-induced intestinal fibrosis is characterized by collagen accumulation, a process in which TGF-beta1 plays a key role. We analyzed the effects of gamma radiation on collagen expression and TGF-beta1 distribution in human intestinal smooth muscle cells (HISM). We investigated the activity of a carboxymethylated and sulfated dextran (RG-1503), exhibiting antifibrotic properties and promoting in vivo intestinal tissue repair, on irradiated HISM. After (60)Co irradiation (10 Gy), HISM were labeled with [(3)H] proline (+/-RG-1503). Radiolabeled collagen I, III, and V were quantified by SDS-PAGE. TGF-beta1 was quantified by ELISA in culture medium, pericellular and intracellular compartments. Irradiation induced a specific 2.85-fold increase in collagen III production by HISM. Collagen V decreased by 80% 72 h after irradiation. Pericellular TGF-beta1 was increased (up to twofold) in irradiated HISM. RG-1503 added before or after irradiation reversed both mRNA and protein levels of collagen III and V to control values. RG-1503 decreased the amount of TGF-beta1 in the cell layer below the control values. Irradiation of HISM induced the development of a fibrotic phenotype in terms of collagen production and TGF-beta1 distribution. The antifibrotic RG-1503 restored HISM physiological characteristics and may represent a promising therapeutic approach for radiation-induced intestinal fibrosis.