Of Mice and Mucins: Models for studying the role of mucins in the intestine

The small intestine is the major organ for the absorption of nutrients and also secretes enzymes to complete the digestive processes started in the stomach1-5. A 30- 50% loss (remaining length, <75 cm in children and <200 cm in adults) often leads to malabsorption, with resultant severe diarrhea, dehydration, electrolyte imbalances, nutrient deficiencies and weight loss6, 7. The small intestine from proximal to distal is divided into the duodenum, jejunum, and ileum. The lining of the small intestine is a single-layered epithelium. It covers the surface area of the villi that project into the lumen, and lines the crypts that descend into the underlying connective tissue. Dividing stem cells lie protected in the depth of the crypts. These stem cells generate four types of differentiated progeny: (i) enterocytes, with densely packed microvilli on their surfaces to increase their active area, are absorptive in function2; (ii) goblet cells, secreting the mucin Muc28-11 and peptides such as trefoil factor 3 (Tff3)12, both products which serve protective roles in the gut; (iii) Paneth cells, involved in the innate defense system by secreting cryptdins, proteins of the defensin family that kill bacteria13-15, and (iv) enteroendocrine cells, producing peptide hormones that act on neurons and other cell types in the gut wall and regulate growth, proliferation and digestive activities of cells of the gut and other tissues2, 6, 16. All of these cells stem from undifferentiated multipotent stem cells located near the bottoms of the crypts, above the Paneth cells (Fig. 1A). These multipotent stem cells cannot be conclusively identified as they can produce all cell types within the epithelium. The regulatory mechanism behind lineage specification has not yet been fully elucidated as it is complex and specific markers are lacking17. The large intestine, or colon, joins the small intestine at the ileum via a T-shaped junction

The acceptance and voice quality of a new voice prosthesis ‘Vega High performance’:a feasibility study

Background: The Provox Vega High Performance (PVHP) is a newly developed voice prosthesis (VP) with an aim to achieve a longer and more predictable lifetime.Objectives: This feasibility study aims to assess patient acceptance of the PVHP VP, evaluate adverse events, voice quality, and device lifetime. Methods: Laryngectomized patients previously using a Provox Vega or ActiValve Light were included. Acceptance and voice outcomes were evaluated at two-time points with a 2-week interval. Baseline measurements were taken with the standard VP, followed by placement of the PVHP for the 2-week assessment. Results: Fifteen participants completed the study, with thirteen being initial Vega-users. PVHP acceptance was 87% 2 weeks after placement. Median device lifetime for all VPs was 64 d (range 14–370). In the subgroup without periprosthetic leakage, the median device lifetime was 101 d (range 31–370). Acceptance dropped to 40% after device failure. Voice quality did not differ between PVHP and baseline VP. The most reported adverse event was PVHP valve stickiness (46%). Conclusion and significance: Acceptance of the PVHP is largely dependent on device lifetime, decreasing from 87% to 40% after leakage or replacement. Voice quality remains consistent across different VPs. Developing a long-lasting VP remains a challenge.</p

The acceptance and voice quality of a new voice prosthesis ‘Vega High performance’:a feasibility study

Background: The Provox Vega High Performance (PVHP) is a newly developed voice prosthesis (VP) with an aim to achieve a longer and more predictable lifetime.Objectives: This feasibility study aims to assess patient acceptance of the PVHP VP, evaluate adverse events, voice quality, and device lifetime. Methods: Laryngectomized patients previously using a Provox Vega or ActiValve Light were included. Acceptance and voice outcomes were evaluated at two-time points with a 2-week interval. Baseline measurements were taken with the standard VP, followed by placement of the PVHP for the 2-week assessment. Results: Fifteen participants completed the study, with thirteen being initial Vega-users. PVHP acceptance was 87% 2 weeks after placement. Median device lifetime for all VPs was 64 d (range 14–370). In the subgroup without periprosthetic leakage, the median device lifetime was 101 d (range 31–370). Acceptance dropped to 40% after device failure. Voice quality did not differ between PVHP and baseline VP. The most reported adverse event was PVHP valve stickiness (46%). Conclusion and significance: Acceptance of the PVHP is largely dependent on device lifetime, decreasing from 87% to 40% after leakage or replacement. Voice quality remains consistent across different VPs. Developing a long-lasting VP remains a challenge.</p

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment

Active surveillance of oesophageal cancer after response to neoadjuvant chemoradiotherapy:dysphagia is uncommon

BACKGROUND: Active surveillance is being investigated as an alternative to standard surgery after neoadjuvant chemoradiotherapy for oesophageal cancer. It is unknown whether dysphagia persists or develops when the oesophagus is preserved after neoadjuvant chemoradiotherapy. The aim of this study was to assess the prevalence and severity of dysphagia during active surveillance in patients with an ongoing response. METHODS: Patients who underwent active surveillance were identified from the Surgery As Needed for Oesophageal cancer ('SANO') trial. Patients without evidence of residual oesophageal cancer until at least 6 months after neoadjuvant chemoradiotherapy were included. Study endpoints were assessed at time points that patients were cancer-free and remained cancer-free for the next 4 months. Dysphagia scores were evaluated at 6, 9, 12, and 16 months after neoadjuvant chemoradiotherapy. Scores were based on the European Organisation for Research and Treatment of Cancer oesophago-gastric quality-of-life questionnaire 25 (EORTC QLQ-OG25) (range 0-100; no to severe dysphagia). The rate of patients with a (non-)traversable stenosis was determined based on all available endoscopy reports. RESULTS: In total, 131 patients were included, of whom 93 (71.0 per cent) had adenocarcinoma, 93 (71.0 per cent) had a cT3-4a tumour, and 33 (25.2 per cent) had a tumour circumference of greater than 75 per cent at endoscopy; 60.8 to 71.0 per cent of patients completed questionnaires per time point after neoadjuvant chemoradiotherapy. At all time points after neoadjuvant chemoradiotherapy, median dysphagia scores were 0 (interquartile range 0-0). Two patients (1.5 per cent) underwent an intervention for a stenosis: one underwent successful endoscopic dilatation; and the other patient required temporary tube feeding. Notably, these patients did not participate in questionnaires. CONCLUSION: Dysphagia and clinically relevant stenosis are uncommon during active surveillance.</p

Active surveillance of oesophageal cancer after response to neoadjuvant chemoradiotherapy:dysphagia is uncommon

BACKGROUND: Active surveillance is being investigated as an alternative to standard surgery after neoadjuvant chemoradiotherapy for oesophageal cancer. It is unknown whether dysphagia persists or develops when the oesophagus is preserved after neoadjuvant chemoradiotherapy. The aim of this study was to assess the prevalence and severity of dysphagia during active surveillance in patients with an ongoing response. METHODS: Patients who underwent active surveillance were identified from the Surgery As Needed for Oesophageal cancer ('SANO') trial. Patients without evidence of residual oesophageal cancer until at least 6 months after neoadjuvant chemoradiotherapy were included. Study endpoints were assessed at time points that patients were cancer-free and remained cancer-free for the next 4 months. Dysphagia scores were evaluated at 6, 9, 12, and 16 months after neoadjuvant chemoradiotherapy. Scores were based on the European Organisation for Research and Treatment of Cancer oesophago-gastric quality-of-life questionnaire 25 (EORTC QLQ-OG25) (range 0-100; no to severe dysphagia). The rate of patients with a (non-)traversable stenosis was determined based on all available endoscopy reports. RESULTS: In total, 131 patients were included, of whom 93 (71.0 per cent) had adenocarcinoma, 93 (71.0 per cent) had a cT3-4a tumour, and 33 (25.2 per cent) had a tumour circumference of greater than 75 per cent at endoscopy; 60.8 to 71.0 per cent of patients completed questionnaires per time point after neoadjuvant chemoradiotherapy. At all time points after neoadjuvant chemoradiotherapy, median dysphagia scores were 0 (interquartile range 0-0). Two patients (1.5 per cent) underwent an intervention for a stenosis: one underwent successful endoscopic dilatation; and the other patient required temporary tube feeding. Notably, these patients did not participate in questionnaires. CONCLUSION: Dysphagia and clinically relevant stenosis are uncommon during active surveillance.</p

Mucin Muc2 Deficiency and Weaning Influences the Expression of the Innate Defense Genes Reg3β, Reg3γ and Angiogenin-4

Background Mucin Muc2 is the structural component of the intestinal mucus layer. Absence of Muc2 leads to loss of this layer allowing direct bacterial-epithelial interactions. We hypothesized that absence of the mucus layer leads to increased expression of innate defense peptides. Specifically, we aimed to study the consequence of Muc2 deficiency (Muc2-/-) on the expression of regenerating islet-derived protein 3 beta (Reg3ß), regenerating islet-derived protein 3 gamma (Reg3¿), and angiogenin-4 (Ang4) in the intestine shortly before and after weaning. Methods Intestinal tissues of Muc2-/- and wild-type (WT) mice were collected at postnatal day 14 (P14, i.e. pre-weaning) and P28 (i.e. post-weaning). Reg3ß, Reg3¿, and Ang4 expression was studied by quantitative real-time PCR, Western-blot, in situ hybridization, and immunohistochemistry. Results Reg3ß and Reg3¿ were expressed by diverging epithelial cell types; namely enterocytes, Paneth cells, and goblet cells. Additionally, Ang4 expression was confined to Paneth cells and goblet cells. Expression of Reg3ß, Reg3¿, and Ang4 differed between WT and Muc2-/- mice before and after weaning. Interestingly, absence of Muc2 strongly increased Reg3ß and Reg3¿ expression in the small intestine and colon. Finally, morphological signs of colitis were only observed in the distal colon of Muc2-/- mice at P28, where and when expression levels of Reg3ß, Reg3¿, and Ang4 were the lowest. Conclusions Expression of Reg3 proteins and Ang4 by goblet cells point to an important role for goblet cells in innate defense. Absence of Muc2 results in up-regulation of Reg3ß and Reg3¿ expression, suggesting altered bacterial-epithelial signaling and an innate defense response in Muc2-/- mice. The inverse correlation between colitis development and Reg3ß, Reg3¿, and Ang4 expression levels might point toward a role for these innate defense peptides in regulating intestinal inflammatio