Progenitor Cell Therapy for Sensorineural Hearing Loss in Infants

Typical language development requires typical hearing. With sensorineural hearing loss (SNHL), the damaged hair cells of the organ of Corti within the cochlea interfere with typical hearing and, as a result, cause impaired language development. Untreated SNHL causes significant neurocognitive differences in affected children. SNHL is a permanent sensory disorder affecting more than 270 million people worldwide. Congenital SNHL is found in 4 of 1000 newborns. Approximately half of congenital SNHL is hereditary and is the result of genetic mutations causing improper development of cochlear hair cells. Non-genetic congenital SNHL is thought to be the result of an injury to the cochlea typically from premature birth, infection, or exposure to ototoxic medications or noise. In mammals, the cochlea is postmitotic at birth, and no spontaneous repair occurs thereafter. Existing treatments for SNHL (hearing aids and cochlear implants) function by augmenting the damaged organ of Corti. No reparative treatments currently exist. In preclinical and clinical studies, progenitor cell therapy (cord blood and mesenchymal stem cells) has shown promise in reversing the underlying pathology of SNHL, the loss of cochlear sensory hair cells. Progenitor cell therapy may also allow functional reorganization of the auditory pathways including primary auditory cortex (Heschl’s gyrus). We will present a summary of the effect of hearing loss on auditory development, existing preclinical and clinical data on progenitor cell therapy, and its potential role in the (re)habilitation of non-genetic SNHL

Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice

BACKGROUND: Hnf4alpha, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4alpha in the maintenance of gut inflammatory homeostasis in mice. METHODOLOGY/PRINCIPAL FINDINGS: We show here that specific epithelial deletion of Hnf4alpha in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4alpha null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4alpha mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4alpha gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease. CONCLUSION: Our results highlight the critical role of Hnf4alpha to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4alpha in the regulation of claudin-15 expression. This establishes Hnf4alpha as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis

Особенности учета заработной платы на примере УФПС "Почта России"

Исследование системы учета труда и заработной платы в ФГУП "Почта России".Research of the system of account of labour and salary in ФГУП "Mail of Russia"

letter to tHe eDitor

Bhat M, Lu Y, Marcil V, et al. Tumour necrosis factor-alpha polymorphism increases the risk for nonvariceal upper gastrointestinal bleeding in patients taking proton pump inhibitors. Can J Gastroenterol Hepatol 2014;28(9):488. To the Editor: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is associated with significant morbidity, affecting 50 to 150 per 100,000 adults annually (1). Patients with NVUGIB may present with melena, hematochezia or coffee-ground emesis, often accompanied by a decrease in hemoglobin levels and even hemodynamic instability. Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori infection are the principal risk factors for NVUGIB, accounting for >95% of cases. Taking proton pump inhibitors (PPIs) is a known protective factor against NVUGIB. There has recently been growing interest in a possible genetic predisposition to NVUGIB, with investigation of single nucleotide polymorphisms (SNPs) associated with bleeding events. Of particular interest have been mutations in proinflammatory genes or genes that regulate NSAID/PPI metabolism, which may contribute to excessive inflammation and ulceration in the context of H pylori infection and NSAID use. A recent pharmacogenomic study The above literature describing a genetic predisposition for bleeding events applies principally to East Asian patient populations. Therefore, we decided to study whether such genetic associations could be elicited in the Canadian context. We performed a pilot study to assess the association of SNPs involved in NSAID metabolism (CYP2C9) and inflammatory response (TNF-α) with NVUGIB events. Patients who were part of the REASON-II NVUGIB study population at the McGill University Health Centre (Montreal, Quebec) were recruited (5). Study controls were asymptomatic patients undergoing screening colonoscopy, and excluded if there was any history of NVUGIB. DNA extracted from serum was genotyped for SNPs in the proinflammatory TNF-α (rs1799724, rs1800630, rs1799964) and NSAID-metabolizing CYP2C9 genes (rs1799853, rs1057910). Using STATA version 10, we assessed for any association between SNPs and NVUGIB events using logistic regression analysis and stratifying according to H pylori status, NSAID and PPI use. Our study included 23 patients and 46 controls of comparable age and sex, with NSAID (26.1% versus 6.7%) and PPI use (21.7% versus 13.0%) being more prevalent among patients. The TNFα1031C SNP, a proinflammatory cytokine polymorphism, was more common among patients with NVUGIB (OR 2.2 [95% CI 0.9 to 5.1]; P=0.084), particularly among those using PPIs (OR 20.0 [95% CI 0.9 to 429.9]; P=0.056) or not taking NSAIDs (OR 3.2 [95% CI 1.1 to 9.0]; P=0.027) at the time of the bleeding event. There was a trend in association of the TNF-α863A SNP with NVUGIB in patients not taking NSAIDs (OR 2.7 [95% CI 0.9 to 8.6]; P=0.071). We did not detect an association between CYP2C9 polymorphisms and NVUGIB, a result similar to that obtained in the study by Musumba et al (2). In conclusion, our pilot study demonstrates that TNF-α1031C SNP confers a risk for NVUGIB events among patients taking PPIs, a finding compatible with previous studies showing increased risk for peptic ulceration with this particular SNP (3

Safety of Autologous Umbilical Cord Blood Therapy for Acquired Sensorineural Hearing Loss in Children

This article presents the results of a phase 1 clinical trial to evaluate the intravenous administration of human umbilical cord blood (hUCB) mononuclear fraction in infants and children with acquired sensorineural hearing loss (SNHL)

Allied Health Professional Support in Pediatric Inflammatory Bowel Disease: A Survey from the Canadian Children Inflammatory Bowel Disease Network—A Joint Partnership of CIHR and the CH.I.L.D. Foundation

Objectives. The current number of healthcare providers (HCP) caring for children with inflammatory bowel disease (IBD) across Canadian tertiary-care centres is underinvestigated. The aim of this survey was to assess the number of healthcare providers (HCP) in ambulatory pediatric IBD care across Canadian tertiary-care centres. Methods. Using a self-administered questionnaire, we examined available resources in academic pediatric centres within the Canadian Children IBD Network. The survey evaluated the number of HCP providing ambulatory care for children with IBD. Results. All 12 tertiary pediatric gastroenterology centres participating in the network responded. Median full-time equivalent (FTE) of allied health professionals providing IBD care at each site was 1.0 (interquartile range (IQR) 0.6–1.0) nurse, 0.5 (IQR 0.2–0.8) dietitian, 0.3 (IQR 0.2–0.8) social worker, and 0.1 (IQR 0.02–0.3) clinical psychologists. The ratio of IBD patients to IBD physicians was 114 : 1 (range 31 : 1–537 : 1), patients to nurses/physician assistants 324 : 1 (range 150 : 1–900 : 1), dieticians 670 : 1 (range 250 : 1–4500 : 1), social workers 1558 : 1 (range 250 : 1–16000 : 1), and clinical psychologists 2910 : 1 (range 626 : 1–3200 : 1). Conclusions. There was a wide variation in HCP support among Canadian centres. Future work will examine variation in care including patients’ outcomes and satisfaction across Canadian centres

Diagnostic Delay Is Associated with Complicated Disease and Growth Impairment in Paediatric Crohn\u27s Disease

Background: Paediatric data on the association between diagnostic delay and inflammatory bowel disease [IBD] complications are lacking. We aimed to determine the effect of diagnostic delay on stricturing/fistulising complications, surgery, and growth impairment in a large paediatric cohort, and to identify predictors of diagnostic delay. Methods: We conducted a national, prospective, multicentre IBD inception cohort study including 1399 children. Diagnostic delay was defined as time from symptom onset to diagnosis \u3e75th percentile. Multivariable proportional hazards [PH] regression was used to examine the association between diagnostic delay and stricturing/fistulising complications and surgery, and multivariable linear regression to examine the association between diagnostic delay and growth. Predictors of diagnostic delay were identified using Cox PH regression. Results: Overall (64% Crohn\u27s disease [CD]; 36% ulcerative colitis/IBD unclassified [UC/IBD-U]; 57% male]), median time to diagnosis was 4.2 (interquartile range [IQR] 2.0-9.2) months. For the overall cohort, diagnostic delay was \u3e9.2 months; in CD, \u3e10.8 months and in UC/IBD-U, \u3e6.6 months. In CD, diagnostic delay was associated with a 2.5-fold higher rate of strictures/internal fistulae (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.41-4.56). Every additional month of diagnostic delay was associated with a decrease in height-for-age z-score of 0.013 standard deviations [95% CI 0.005-0.021]. Associations persisted after adjusting for disease location and therapy. No independent association was observed between diagnostic delay and surgery in CD or UC/IBD-U. Diagnostic delay was more common in CD, particularly small bowel CD. Abdominal pain, including isolated abdominal pain in CD, was associated with diagnostic delay. Conclusions: Diagnostic delay represents a risk factor for stricturing/internal fistulising complications and growth impairment in paediatric CD

Genes Involved in the Metabolism of Poly-Unsaturated Fatty-Acids (PUFA) and Risk for Crohn's Disease in Children & Young Adults

Epidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn's disease (CD) is unclear, although the key metabolite leucotriene B4 (LTB(4)) is closely linked to the inflammatory process. We hypothesized that inherited variation in key PUFA metabolic enzymes may modify susceptibility for CD.A case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children ≤20 yrs diagnosed with CD and controls were recruited. 19 single nucleotide polymorphisms (SNPs) across the ALOX5 (4) CYP4F3 (5) and CYP4F2 (10) genes, were genotyped. Associations between SNPs/haplotypes and CD were examined. A total of 431 cases and 507 controls were studied. The mean (±SD) age of the cases was 12.4 (±3.3) years. Most cases were male (56.4%), had ileo-colonic disease (L3±L4, 52.7%) and inflammatory behavior (B1±p, 87%) at diagnosis. One genotyped CYP4F3 SNP (rs2683037) not in Hardy-Weinberg Equilibrium was excluded. No associations with the remaining 4 CYP4F3 SNPs with CD were evident. However haplotype analysis revealed associations with a two-marker haplotype (TG) (rs3794987 & rs1290617) (p = 0.02; permuted p = 0.08). CYP4F2 SNPs, rs3093158 (OR (recessive) = 0.56, 95% CI = 0.35-0.89; p = 0.01), rs2074902 (OR (trend) = 1.26, 95% CI = 1.00-1.60; p = 0.05), and rs2108622 (OR (recessive) = 1.6, 95% CI = 1.00-2.57; p = 0.05) were significantly associated whereas rs1272 (OR (recessive) = 0.58, 95% CI = 0.30-1.13; p = 0.10) showed suggestions for associations with CD. A haplotype comprising these 4 SNPs was significantly associated (p = 0.007, permuted p = 0.02) with CD. Associations with SNP rs3780901 in the ALOX5 gene were borderline non-significant (OR (dominant) = 1.29, 95% CI = 0.99-1.67; p = 0.056). A haplotype comprising the 4 ALOX5 SNPs (TCAA, p = 0.036) was associated with CD, but did not withstand corrections for multiple comparisons (permuted p = 0.14).Inherited variation in enzymes involved in the synthesis/metabolism of LTB(4) may be associated with CD. These findings implicate PUFA metabolism as a important pathway in the CD pathogenesis

Oxidative Stress and Mitochondrial Functions in the Intestinal Caco-2/15 Cell Line

Although mitochondrial dysfunction and oxidative stress are central mechanisms in various pathological conditions, they have not been extensively studied in the gastrointestinal tract, which is known to be constantly exposed to luminal oxidants from ingested foods. Key among these is the simultaneous consumption of iron salts and ascorbic acid, which can cause oxidative damage to biomolecules.The objective of the present work was to evaluate how iron-ascorbate (FE/ASC)-mediated lipid peroxidation affects mitochondrion functioning in Caco-2/15 cells. Our results show that treatment of Caco-2/15 cells with FE/ASC (0.2 mM/2 mM) (1) increased malondialdehyde levels assessed by HPLC; (2) reduced ATP production noted by luminescence assay; (3) provoked dysregulation of mitochondrial calcium homeostasis as evidenced by confocal fluorescence microscopy; (4) upregulated the protein expression of cytochrome C and apoptotic inducing factor, indicating exaggerated apoptosis; (5) affected mitochondrial respiratory chain complexes I, II, III and IV; (6) elicited mtDNA lesions as illustrated by the raised levels of 8-OHdG; (7) lowered DNA glycosylase, one of the first lines of defense against 8-OHdG mutagenicity; and (8) altered the gene expression and protein mass of mitochondrial transcription factors (mtTFA, mtTFB1, mtTFB2) without any effects on RNA Polymerase. The presence of the powerful antioxidant BHT (50 microM) prevented the occurrence of oxidative stress and most of the mitochondrial abnormalities.Collectively, our findings indicate that acute exposure of Caco-2/15 cells to FE/ASC-catalyzed peroxidation produces harmful effects on mitochondrial functions and DNA integrity, which are abrogated by the powerful exogenous BHT antioxidant. Functional derangements of mitochondria may have implications in oxidative stress-related disorders such as inflammatory bowel diseases