Compromised duodenal mucosal integrity in children with short bowel syndrome after adaptation to enteral autonomy

BackgroundIntestinal adaptation has been extensively studied experimentally, but very limited data is available on human subjects. In this study we assessed intestinal adaption in humans with short bowel syndrome (SBS).MethodsWe comparatively evaluated mucosal hyperplasia, inflammation, barrier function and nutrient transport using histology, immunohistochemistry and qPCR for selected 52 key genes in duodenal biopsies obtained from children with SBS after weaning off parenteral nutrition (n = 33), and matched controls without intestinal pathology (n = 12). Small bowel dilatation was assessed from contrast small bowel series.ResultsDuodenal mucosa of SBS children showed increased histologic inflammation of lamina propria (p = 0.033) and mucosal mRNA expression of tumor necrosis factor (p = 0.027), transforming growth factor (TGF)-β2 (p = 0.006) and caveolin-1 (CAV1; p = 0.001). Villus height, crypt depth, enterocyte proliferation, apoptosis and expression of proliferation and nutrient transport genes remained unchanged. Pathologic small bowel dilatation reduced crypt depth (p = 0.045) and downregulated mRNA expression of interleukin (IL)-6 by three-fold (p = 0.008), while correlating negatively with IL6 (r = -0.609, p = 0.004). Loss of ileocecal valve (ICV) upregulated mRNA expression of toll-like receptor 4 (TLR4), TGF-β1, CAV1, several apoptosis regulating genes, and mRNA expression of zonulin (p < 0.05 for all).ConclusionsDespite successful adaptation to enteral autonomy, duodenal mucosa of SBS children displayed histologic and molecular signs of abnormal inflammation and regulation of epithelial permeability, whereas no structural or molecular signs of adaptive hyperplasia or enhanced nutrient transport were observed. Excessive dilatation of the remaining small bowel paralleled impaired duodenal crypt homeostasis, while absence of ICV modified regulation of mucosal inflammation, regeneration and permeability.Level of evidenceII     

Colonic methanogenesis in vivo and in vitro and fecal pH after resection of colorectal cancer and in healthy intact colon

Purpose  

We compared colonic methanogenesis in vivo and in vitro as well as fecal pH in healthy subjects and in patients with resected colorectal cancer thus without the possible confounding effects of the tumor.     

High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids

AIM: To investigate whether high-fat-feeding is associated with increased intestinal permeability via alterations in bile acid metabolism.METHODS: Male C57Bl/6J mice were fed on a high-fat (n = 26) or low-fat diet (n = 24) for 15 wk. Intestinal permeability was measured from duodenum, jejunum, ileum and colon in an Ussing chamber system using 4 kDa FITC-labeled dextran as an indicator. Fecal bile acids were analyzed with gas chromatography. Segments of jejunum and colon were analyzed for the expression of farnesoid X receptor (FXR) and tumor necrosis factor (TNF).RESULTS: Intestinal permeability was significantly increased by high-fat feeding in jejunum (median 0.334 for control vs 0.393 for high-fat, P = 0.03) and colon (0.335 for control vs 0.433 for high-fat, P = 0.01), but not in duodenum or ileum. The concentration of nearly all identified bile acids was significantly increased by high-fat feeding (P < 0.001). The proportion of ursodeoxycholic acid (UDCA) in all bile acids was decreased (1.4% ± 0.1% in high-fat vs 2.8% ± 0.3% in controls, P < 0.01) and correlated inversely with intestinal permeability (r = -0.72, P = 0.01). High-fat feeding also increased jejunal FXR expression, as well as TNF expression along the intestine, especially in the colon.CONCLUSION: High-fat-feeding increased intestinal permeability, perhaps by a mechanism related to bile acid metabolism, namely a decreased proportion of fecal UDCA and increased FXR expression.     

Crafts as Memory Triggers in Reminiscence: A Case Study of Older Women with Dementia

This case study explored the benefits of crafts as memory triggers in reminiscence sessions with older women in residential care who had severe symptoms of dementia and had enjoyed crafting as a leisure activity during their lifetime. Three structured reminiscence sessions, involving different kinds of handicrafts, craft material, and craft tools, were used to trigger memories and offer multisensory stimuli. Thematization, quantification, and theory-based reasoning were employed for content analysis. Multisensory triggers activated nonverbal and verbal reactions, sustaining attention and prompting interaction and nonverbal communication. The most interesting triggers stimulated recall of forgotten, pleasing craft experiences.     

Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized,placebo‐controlled trials

Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial‐onset seizures (POS). Methods: Two identical, randomized, placebo‐controlled, double‐blind studies were conducted in adults with POS uncontrolled for ≥1 year. Therapy‐refractory epilepsy patients (≥16 years) remained on stable doses of prescribed antiepileptic drugs (≤2) for an 8‐week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12‐week double‐blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with ≥50% reduction in POS frequency) during the double‐blind phase compared with the prospective baseline phase. Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16–75 years) and 36 years (study 2, range 16–74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment‐emergent adverse events (≥5% in any group), those with an incidence exceeding placebo (≥3%) were dizziness (400 mg/day group) and somnolence. Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial‐onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well‐tolerated in both studies.     

Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations

A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected 'hidden' MMR gene defects in 42% of such families, leaving the remaining 58% 'truly' mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among 31 tumors from MMR gene mutation positive families, 25 (81%) had active Wnt signaling as indicated by aberrant beta-catenin localization with or without CTNNB1 mutations, compared to only 7/18 tumors from MMR gene mutation negative families (39%; P=0.005). CGH studies revealed stable profiles in 9/16 (56%) of MMR gene mutation negative tumors, which was significantly associated with membranous beta-catenin (P=0.005). Tumors with membranous beta-catenin from the MMR gene mutation negative group also showed low frequency of TP53 mutations compared to those with nuclear beta-catenin. Thus, a majority of the MMR gene mutation negative cases exhibited a novel molecular pattern characterized by the paucity of changes in common pathways to colorectal carcinogenesis. This feature distinguishes the MMR gene mutation negative families from both HNPCC families linked to MMR defects and sporadic cases, suggesting the involvement of novel predisposition genes and pathways in such families.     

Carotid stenosis degree in CT angiography: assessment based on luminal area versus luminal diameter measurements

The aim of this study was to investigate CT angiography (CTA) luminal area measurements in the assessment of carotid artery stenosis compared with the current clinically used criteria based on lumen diameter measurements. Seventy-two vessels in 36 patients were evaluated by CTA and digital subtraction angiography (DSA). Two observers measured area and diameter stenosis degrees using automated 3D CTA analysis software. The ratio of the largest/smallest luminal diameter at the level of maximal stenosis (L/S ratio) was used to describe lumen morphology. Diagnostic agreement between CTA and DSA was calculated. For the assessment of area stenosis, interobserver and intraobserver correlation coefficients were 0.898 and 0.906 (p<0.001). The correlation coefficient between the diameter stenosis and area stenosis was lower in stenoses with extremely noncircular lumen (L/S ratio 1.5) (r=0.797, p<0.001) compared with stenoses with circular lumen (LS ratio <1.2) (r=0.978, p<0.001). Only satisfactory agreement ( 0.54-0.77, p<0.001) was obtained between area stenosis on CTA and diameter stenosis on DSA. Assessment of stenosis degree with area measurements on 3D CTA proved to be reproducible. Area stenosis provides a less-severe estimate of the degree of carotid stenosis but might theoretically express the real hemodynamic significance of the lesion better than diameter stenosis, especially in stenoses with noncircular lumen.