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     

Inhomogeneous exercise uptake and accelerated washout of a radioiodinated fatty acid analogue in syndromeX A SPECT study of the left ventricle

Myocardial metabolism in exercise was determined by studying 21 syndromeX patients and 14 healthy volunteers with an aromatic fatty acid analogue IPPA and a gamma camera. We developed criteria for visual semiquantitative assessment of relative segmental radiotracer uptake and washout, and tested a new computer program for quantitative evaluation. One volunteer (7%) and 12 patients (57%) showed visually inhomogeneous uptake (p=0.006, ²-test) in SPECT polar tomograms after a maximal ergometry test. Images in none of the volunteers and seven patients (33%) gave the impression of a slowed regional washout (p=0.057). Only six patients (29%) had a normal radial polarogram. Patients with irregular coronary angiograms (showing slow flow or minor sclerosis) and those with chest pain during the IPPA exercise test had a very low frequency of normalcy, but this was not significant.Total washout was higher in patients than in the reference population, as the exercise to rest activity ratio was 1.36 SD 0.13 versus 1.25 SD 0.11 in computerized quantitation (p=0.015, t-test). Washout did not correlate with age, sex or exercise heart rate. Regarding computerized analysis of uptake and slow washout, the number of deviant segments was not significantly higher in patients than in reference population. Semiquantitative and quantitative analysis correlated in the assessment of uptake, but not in the assessment of washout. Possible reasons for the discrepancy are discussed.Conclusions of this study are not straightforward. SyndromeX was associated with inhomogeneous IPPA uptake, which is not at variance with the theory of microvascular dysfunction. On the other hand, the analysis of washout presumably implies higher fatty acid utilization in patients than in normal controls, which is not a characteristic phenomenon in myocardial ischemia.     

Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats

The anxiolytic profile of dexmedetomidine, a novel, highly-selective ₂-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1–10 µg/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1–10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 µg/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an ₂-adrenergic antagonist, atipamezole, 10–50 µg/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the ₁-adrenergic antagonist, prazosin, 0.1–10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and ₂-agonist responses do not share any molecular component, there does appear to be crosstalk between these two systems. These may involve GABA or noradrenergic downstream effects of either dexmedetomidine or midazolam, respectively.     

High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS: p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.     

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.     

Getting off on the right (or left) foot: perceiving by means of a rod attached to the preferred or non-preferred foot

Behavior is typically organized in terms of a goal one intends to achieve rather than in terms of the anatomical components used in doing so. Similarly, perceptual behavior is typically organized in terms of a property one intends to perceive rather than in terms of the anatomical components used in doing so. Such task-specificity and anatomical independence are manifest in perception of properties of wielded objects. We investigated whether these properties are also manifest in perception of properties by means of wielded objects. Blindfolded participants explored an inclined surface with a rod attached to their preferred or non-preferred foot and reported whether they would be able to stand on that surface. Perception reflected action capabilities, but was unaffected by foot used, highlighting the haptic system as a smart perceptual device.     

First trimester combined screening biochemistry in detection of congenital heart defects

Objective: To evaluate the performance of first trimester biochemical markers, pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (fβ-hCG), and nuchal translucency (NT) in detection of severe congenital heart defects (CHDs).

Methods: During the study period from 1 January 2008 to 31 December 2011, biochemical markers and NT were measured in 31,144 women as part of voluntary first trimester screening program for Down’s syndrome in Northern Finland. Data for 71 severe CHD cases and 762 controls were obtained from the hospital records and from the National Medical Birth Register, which records the birth of all liveborn and stillborn infants, and from the National Register of Congenital Malformations that receives information about all the CHD cases diagnosed in Finland.

Results: Both PAPP-A and fβ-hCG multiple of median (MoM) values were decreased in all severe CHDs: 0.71 and 0.69 in ventricular septal defects (VSDs), 0.58 and 0.88 in tetralogy of Fallot cases (TOFs), 0.82 and 0.89 in hypoplastic left heart syndromes (HLHSs), and 0.88 and 0.96 in multiple defects, respectively. NT was increased in all study groups except of VSD group. ROC AUC was 0.72 for VSD when combining prior risk with PAPP-A and fβ-hCG. Adding NT did not improve the detection rate. With normal NT but decreased (<0.5 MoM) PAPP-A and fβ-hCG odds ratios for VSD and HLHS were 19.5 and 25.6, respectively.

Conclusions: Maternal serum biochemistry improves the detection of CHDs compared to NT measurement only. In cases with normal NT measurement but low concentrations of both PAPP-A and fβ-hCG, an alert for possible CHD, especially VSD, could be given with thorough examination of fetal heart in later ultrasound scans.