Dysfunctional Extracellular Matrix Remodeling Supports Perianal Fistulizing Crohn's Disease by a Mechanoregulated Activation of the Epithelial-to-Mesenchymal Transition.

BACKGROUND AND AIMS: Perianal fistula represents one of the most disabling manifestations of Crohn's disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation. METHODS: Surgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed. RESULTS: A markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial-mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli. CONCLUSIONS: By mediating changes in the ECM organization, TSG-6 triggers the epithelial-mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula.

Population-based cross-sectional prevalence survey of diabetes and diabetic retinopathy in Sohag-Egypt, 2019.

OBJECTIVES: To determine the prevalence of diabetes mellitus (DM), prevalence of diabetic retinopathy (DR) and sight-threatening conditions among persons with DM aged 50 years and older in Sohag governorate in Upper Egypt. DESIGN: Population-based, cross-sectional survey using the standardised Rapid Assessment of Avoidable Blindness with the addition of the Diabetic Retinopathy module methodology. SETTINGS: Sohag governorate in Egypt where 68 clusters were selected using probability proportional to population size. Households were selected using the compact segment technique. PARTICIPANTS: 4078 people aged 50 years and older in 68 clusters were enrolled, of which 4033 participants had their random blood sugar checked and 843 examined for features of DR. PRIMARY AND SECONDARY OUTCOMES: The prevalence of DM and DR; secondary outcome was the coverage with diabetic eye care. RESULTS: The prevalence of DM was 20.9% (95% CI 19.3% to 22.5%). The prevalence in females (23.8%; 95% CI 21.4% to 26.3%) was significantly higher than in males (18.9%; 95% CI 17.1% to 20.7%) (p=0.0001). Only 38.8% of persons diagnosed with diabetes had good control of DM. The prevalence of DR in the sample was 17.9% (95% CI 14.7% to 21.1%). The prevalence in females was higher (18.9%; 95% CI 14.0% to 23.8%) than in males (17.1%; 95% CI 13.0% to 21.2%). Up to 85.3% of study participants have never had eye examination. Sight-threatening DR (R4 and/or M2) was detected in 5.2% (95% CI 3.4% to 7.0%) with only 2.3% having had laser treatment. CONCLUSION: The prevalence of uncontrolled DM in Sohag governorate in Egypt is higher than the national prevalence. There is a high prevalence of sight-threatening retinopathy and/or maculopathy with few people having access to diabetic eye care. A public health approach is needed for health promotion, early detection and management of DR.

Diagnosis and treatment of HCV heart diseases.

INTRODUCTION: Hepatitis C virus (HCV) infection is an important cause of a variety of otherwise unexplained heart diseases and myocardial injury. A high prevalence of HCV infection has been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy and myocarditis. Various arrhythmias, conduction disturbances and QT prolongation were also associated with HCV infection. A possible role of HCV infection in the pathogenesis of diabetes and atherosclerosis, and the role of immunogenetics of HCV cardiomyopathies is discussed. Recent studies suggest that mononuclear cells may be the major target of HCV, and clinical applications to test this new hypothesis are discussed. AREAS COVERED: In this review, we will evaluate the evidence that HCV causes various cardiovascular diseases, and discuss on the pathogenesis of these disorders. EXPERT OPINION: HCV is the cause of many different forms of heart disease worldwide, but their existence has not been recognized by most of cardiologists. The recognition and diagnosis are indispensable for the early treatment of these diseases. The diverse clinical manifestation of HCV infection and the presence of multiple extrahepatic disease syndromes could be explained by a new hypothesis that the target of HCV is leukocytes.

Fibrotic Strictures in Crohn's Disease: Mechanisms and Predictive Factors.

Fibrotic strictures are one of the most severe complications of Crohn's Disease (CD). They occur in about 50% of patients at five years and in 70% at ten years of the diagnosis. The only treatment available for symptomatic fibrotic strictures is surgical resection and endoscopic dilation. Both strategies are associated with a high rate of recurrence, and with multiple surgical resections, which pose the threat of surgical morbidity and short bowel syndrome. Therefore, it is crucial to identify, early, the patients more prone to develop intestinal fibrosis to intensify follow-ups, switch to more aggressive treatments, and suggest lifestyle modifications. Scarce data are available concerning biomarkers and genetic determinants to predict which patient will develop intestinal fibrosis. Biologic or clinical markers would be useful to determine this subgroup of CD patients and to predict the onset of intestinal fibrosis and, ideally, its severity. Furthermore, the identification of environmental risk factors may suggest lifestyle changes aimed at modifying the natural course, thus decreasing the risk of complicated CD. In this review, we will critically revise clinical, environmental, genetic, and serologic factors that have been associated with a complicated CD course with a particular focus on the fibrostenosing phenotype and their possible implications as predictive factors of intestinal fibrosis.

Population-based rapid assessment of avoidable blindness survey in Sohag governorate in Egypt.

OBJECTIVES: To determine the prevalence and causes of blindness and vision impairment, and the coverage and quality of cataract surgical services, among population aged 50 years and older in Sohag governorate in Egypt. DESIGN: A population-based cross-sectional survey using two-stage cluster random sampling following the rapid assessment of avoidable blindness methodology. SETTING: A community-based survey conducted by six teams of ophthalmologists, assistants and local guides. Enrolment and examination were door-to-door in selected clusters. PARTICIPANTS: Using 2016 census data, 68 population units were randomly selected as clusters (of 60 people) with probability proportionate to population size. Anyone aged 50 years and older, residing in a non-institutional setting in a cluster for at least 6 months, was eligible to participate. PRIMARY AND SECONDARY OUTCOME MEASURES: The prevalence and causes of blindness and vision impairment. Secondary outcomes were CSC and effectiveness and participant-reported barriers to cataract surgery. RESULTS: Of 4078 participants enrolled, 4033 (98.9%) were examined. The age-adjusted and sex-adjusted prevalence of blindness, severe vision impairment and moderate vision impairment were 5.9% (95% CI 4.8% to 6.9%), 4.7% (95% CI 3.8% to 5.7%) and 18.9% (95% CI 16.8% to 21.0%), respectively. Cataract caused most of blindness (41.6%), followed by non-trachomatous corneal opacity (15.7%) and posterior segment diseases (14.5%). Cataract surgical coverage (CSC) for persons for visual acuity <3/60 was 86.8%, the proportion of cataract surgeries with poor visual outcome was 29.5% and effective CSC (eCSC) was 44.9%. eCSC was lower in women than men. The most frequently reported barrier to surgery was cost (51.5%). CONCLUSIONS: The prevalence of blindness in Sohag governorate is higher than districts in other middle-income countries in the region. CSC was high; however, women suffer worse quality-corrected CSC than men. The quality of cataract surgery needs to be addressed, while health system strengthening across government and private settings could alleviate financial barriers.

Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6.

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which this polysaccharide exerts its beneficial effects are unclear. Here, we demonstrated that HA treatment in vitro and in vivo improved mucosal healing by accelerating intestinal epithelial regeneration. Indeed, mice treated with HA showed a faster recovery from colitis and reduced endoscopic signs of mucosal inflammation compared to those receiving saline. Furthermore, histological analysis revealed less ulcerated mucosa in mice treated with HA, characterized by re-epithelialized areas. TSG-6, the secreted product of TNF-stimulated gene-6, is an HA-binding protein shown previously to have tissue-protective properties and promote wound healing. Mucosal levels of TSG-6 increased in UC patients compared to the healthy controls and also after wounding in mice. TSG-6 deletion prevented the beneficial properties of HA in mucosal wound repair, suggesting that the interaction of HA with TSG-6 is crucial for intestinal epithelial regeneration. Overall these results are consistent with HA having a therapeutic effect via the promotion of mucosal healing in patients with ulcerative colitis.

Prevalence of trachoma in four marakez of Elmenia and Bani Suef Governorates, Egypt.

PURPOSE: In 2015, to determine where interventions are needed to eliminate trachoma as a public health problem from Egypt, we initiated population-based prevalence surveys using the Global Trachoma Mapping Project platform in four suspected-endemic marakez (districts; singular: markaz) of the governorates of Elmenia and Bani Suef. METHODS: In each markaz, 30 households were selected in each of 25 villages. Certified graders examined a total of 3682 children aged 1-9 years in 2993 households, noting the presence or absence of trachomatous inflammation-follicular (TF) and trachomatous inflammation-intense (TI) in each eye. A total of 5582 adults aged ≥15 years living in the same households were examined for trachomatous trichiasis (TT). Household-level access to water and sanitation was recorded. RESULTS: Three of four marakez had age-adjusted TF prevalence estimates in 1-9-year olds of >10%; the other markaz had a TF prevalence estimate of 5-9.9%. Estimates of the age- and gender-adjusted prevalence of unmanaged TT in adults ranged from 0.7% to 2.3%. Household-level access to water and sanitation was high. (We did not, however, measure use of water or sanitation facilities.) Conclusions: Each of the four marakez surveyed has trachoma as a public health problem, with a need for implementation of the SAFE (surgery, antibiotics, facial cleanliness, environmental improvement) strategy. Further mapping is also required to determine the need for interventions in other areas of Egypt.