Dress Up

Dress Up (Performance, 40 minutes) is a dress that functions as a floor, blanket, tablecloth, book and walls. It tells a visual story about domestic care giving rituals, referencing different times and places

A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity.

Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred

Colon cancer associated transcript-1 (CCAT1) expression in adenocarcinoma of the stomach

Background: Long non-coding RNAs (lncRNAs) have been shown to have functional roles in cancer biology and are dys-regulated in many tumors. Colon Cancer Associated Transcript -1 (CCAT1) is a lncRNA, previously shown to be significantly up-regulated in colon cancer. The aim of this study is to determine expression levels of CCAT1 in gastric carcinoma (GC). Methods: Tissue samples were obtained from patients undergoing resection for gastric carcinoma (n=19). For each patient, tumor tissue and normal appearing gastric mucosa were taken. Normal gastric tissues obtained from morbidly obese patients, undergoing laparoscopic sleeve gastrectomy served as normal controls (n=19). A human gastric carcinoma cell line (AGS) served as positive control. RNA was extracted from all tissue samples and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR). Results: Low expression of CCAT1 was identified in normal gastric mucosa samples obtained from morbidly obese patients [mean Relative Quantity (RQ) = 1.95±0.4]. AGS human gastric carcinoma cell line showed an elevated level of CCAT1 expression (RQ=8.02). Expression levels of CCAT1 were approximately 10.8 fold higher in GC samples than in samples taken from the negative control group (RQ=21.1±5 vs. RQ=1.95±0.4, respectively, p<0.001). Interestingly, CCAT1 expression was significantly overexpressed in adjacent normal tissues when compared to the negative control group (RQ = 15.25±2 vs. RQ=1.95±0.4, respectively, p<0.001). Tissues obtained from recurrent GC cases showed the highest expression levels (RQ = 88.8±31; p<0.001). Expression levels increased with tumor stage (T4- 36.4±15, T3- 16.1±6, T2- 4.7±1), however this did not reach statistical significance (p=0.2). There was no difference in CCAT1 expression between intestinal and diffuse type GC (RQ=22.4±7 vs. 22.4±16, respectively, p=0.9). Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients (RQ= 2.4±0.9 vs. 0.93±0.2, respectively, p=0.13). Conclusion: CCAT1 is up-regulated in gastric cancer, and may serve as a potential bio-marker for early detection and surveillance. © Ivyspring International Publisher

The Use of Fecal Calprotectin Testing in Paediatric Disorders : A Position Paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee

Objectives: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children. Methods: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors. Results: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9. Conclusions: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schonlein purpura. FC measurement is of little value in Cow's Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps.Peer reviewe

Aminoglycoside antibiotics and autism: a speculative hypothesis

BACKGROUND: Recently, it has been suspected that there is a relationship between therapy with some antibiotics and the onset of autism; but even more curious, some children benefited transiently from a subsequent treatment with a different antibiotic. Here, we speculate how aminoglycoside antibiotics might be associated with autism. PRESENTATION: We hypothesize that aminoglycoside antibiotics could a) trigger the autism syndrome in susceptible infants by causing the stop codon readthrough, i.e., a misreading of the genetic code of a hypothetical critical gene, and/or b) improve autism symptoms by correcting the premature stop codon mutation in a hypothetical polymorphic gene linked to autism. TESTING: Investigate, retrospectively, whether a link exists between aminoglycoside use (which is not extensive in children) and the onset of autism symptoms (hypothesis "a"), or between amino glycoside use and improvement of these symptoms (hypothesis "b"). Whereas a prospective study to test hypothesis "a" is not ethically justifiable, a study could be designed to test hypothesis "b". IMPLICATIONS: It should be stressed that at this stage no direct evidence supports our speculative hypothesis and that its main purpose is to initiate development of new ideas that, eventually, would improve our understanding of the pathobiology of autism

Cystic fibrosis presenting as recurrent pancreatitis in a young child with a normal sweat test and pancreas divisum: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pancreatitis is a rare manifestation of cystic fibrosis (CF) and may rarely be the presenting symptom in adolescent or adult patients with CF. We report a case of a 4 year-old female who initially presented with recurrent pancreatitis, a normal sweat test, and a diagnosis of pancreas divisum. She was subsequently diagnosed with cystic fibrosis at the age of 6 years, despite normal growth and no pulmonary symptoms, after nasal potential difference measurements suggested possible CF and two known CF-causing mutations (ΔF508 and L997F) were detected.</p> <p>Case Presentation</p> <p>An otherwise healthy 4 year-old female developed chronic pancreatitis and was diagnosed with pancreas divisum. Sphincterotomy was performed without resolution of her pancreatitis. Sweat test was negative for cystic fibrosis, but measurement of nasal potential differences suggested possible cystic fibrosis. These results prompted extended Cystic Fibrosis Transmembrane Regulator Conductance (CFTR) mutational analysis that revealed a compound heterozygous mutation: ΔF508 and L997F.</p> <p>Conclusion</p> <p>CFTR mutations should be considered in cases of chronic or recurrent pancreatitis despite a negative sweat test and the presence of pancreas divisum. Children with CFTR mutations may present with recurrent pancreatitis, lacking any other signs or symptoms of cystic fibrosis. It is possible that the combination of pancreas divisum and abnormal CFTR function may contribute to the severity and frequency of recurrent pancreatitis.</p

Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis

Cystic fibrosis (CF) is the commonest inherited life‐shortening illness in white populations, caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation mainly affects the airways where excess salt absorption dehydrates the airway lining leading to impaired mucociliary clearance. Consequently, thick, sticky mucus accumulates making the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Other complications include malnutrition, diabetes and subfertility. Increased understanding of the condition has allowed pharmaceutical companies to design mutation‐specific therapies targeting the underlying molecular defect. CFTR potentiators target mutation classes III and IV and aim to normalise airway surface liquid and mucociliary clearance, which in turn impacts on the chronic infection and inflammation. This is an update of a previously published review. Objectives To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with CF. Search methods We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles, reviews and online clinical trial registries. Last search: 21 November 2018. Selection criteria Randomised controlled trials (RCTs) of parallel design comparing CFTR potentiators to placebo in people with CF. A separate review examines trials combining CFTR potentiators with other mutation‐specific therapies. Data collection and analysis The authors independently extracted data, assessed the risk of bias in included trials and used GRADE to assess evidence quality. Trial authors were contacted for additional data. Main results We included five RCTs (447 participants with different mutations) lasting from 28 days to 48 weeks, all assessing the CFTR potentiator ivacaftor. The quality of the evidence was moderate to low, mainly due to risk of bias (incomplete outcome data and selective reporting) and imprecision of results, particularly where few individuals experienced adverse events. Trial design was generally well‐documented. All trials were industry‐sponsored and supported by other non‐pharmaceutical funding bodies. F508del (class II) (140 participants) One 16‐week trial reported no deaths, or changes in quality of life (QoL) or lung function (either relative or absolute change in forced expiratory volume in one second (FEV1) (moderate‐quality evidence). Pulmonary exacerbations and cough were the most reported adverse events in ivacaftor and placebo groups, but there was no difference between groups (low‐quality evidence); there was also no difference between groups in participants interrupting or discontinuing treatment (low‐quality evidence). Number of days until the first exacerbation was not reported, but there was no difference between groups in how many participants developed pulmonary exacerbations. There was also no difference in weight. Sweat chloride concentration decreased, mean difference (MD) ‐2.90 mmol/L (95% confidence interval (CI) ‐5.60 to ‐0.20). G551D (class III) (238 participants) The 28‐day phase 2 trial (19 participants) and two 48‐week phase 3 trials (adult trial (167 adults), paediatric trial (52 children)) reported no deaths. QoL scores (respiratory domain) were higher with ivacaftor in the adult trial at 24 weeks, MD 8.10 (95% CI 4.77 to 11.43) and 48 weeks, MD 8.60 (95% CI 5.27 to 11.93 (moderate‐quality evidence). The adult trial reported a higher relative change in FEV1 with ivacaftor at 24 weeks, MD 16.90% (95% CI 13.60 to 20.20) and 48 weeks, MD 16.80% (95% CI 13.50 to 20.10); the paediatric trial reported this at 24 weeks, MD 17.4% (P < 0.0001)) (moderate‐quality evidence). These trials demonstrated absolute improvements in FEV1 (% predicted) at 24 weeks, MD 10.80% (95% CI 8.91 to 12.69) and 48 weeks, MD 10.44% (95% CI 8.56 to 12.32). The phase 3 trials reported increased cough, odds ratio (OR) 0.57 (95% CI 0.33 to 1.00) and episodes of decreased pulmonary function, OR 0.29 (95% CI 0.10 to 0.82) in the placebo group; ivacaftor led to increased dizziness in adults, OR 10.55 (95% CI 1.32 to 84.47). There was no difference between groups in participants interrupting or discontinuing treatment (low‐quality evidence). Fewer participants taking ivacaftor developed serious pulmonary exacerbations; adults taking ivacaftor developed fewer exacerbations (serious or not), OR 0.54 (95% CI 0.29 to 1.01). A higher proportion of participants were exacerbation‐free at 24 weeks with ivacaftor (moderate‐quality evidence). Ivacaftor led to a greater absolute change from baseline in FEV1 (% predicted) at 24 weeks, MD 10.80% (95% CI 8.91 to 12.69) and 48 weeks, MD 10.44% (95% CI 8.56 to 12.32); weight also increased at 24 weeks, MD 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, MD 2.75 kg (95% CI 1.74 to 3.75). Sweat chloride concentration decreased at 24 weeks, MD ‐48.98 mmol/L (95% CI ‐52.07 to ‐45.89) and 48 weeks, MD ‐49.03 mmol/L (95% CI ‐52.11 to ‐45.94). R117H (class IV) (69 participants) One 24‐week trial reported no deaths. QoL scores (respiratory domain) were higher with ivacaftor at 24 weeks, MD 8.40 (95% CI 2.17 to 14.63), but no relative changes in lung function were reported (moderate‐quality evidence). Pulmonary exacerbations and cough were the most reported adverse events in both groups, but there was no difference between groups; there was no difference between groups in participants interrupting or discontinuing treatment (low‐quality evidence). Number of days until the first exacerbation was not reported, but there was no difference between groups in how many participants developed pulmonary exacerbations. No changes in absolute change in FEV1 or weight were reported. Sweat chloride concentration decreased, MD ‐24.00 mmol/L (CI 95% ‐24.69 to ‐23.31). Authors' conclusions There is no evidence supporting the use of ivacaftor in people with the F508del mutation. Both G551D phase 3 trials demonstrated a clinically relevant impact of ivacaftor on outcomes at 24 and 48 weeks in adults and children (over six years of age) with CF. The R117H trial demonstrated an improvement in the respiratory QoL score, but no improvement in respiratory function. As new mutation‐specific therapies emerge, it is important that trials examine outcomes relevant to people with CF and their families and that adverse events are reported robustly and consistently. Post‐market surveillance is essential and ongoing health economic evaluations are required