Heterogeneous phenotypes of platelet and plasma von Willebrand factor in obligatory heterozygotes for severe von Willebrand disease

To characterize the heterogeneity of severe (type III) von Willebrand disease (vWD), plasma and platelet von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activity (Ricof) were measured in 28 obligatory heterozygotes (ie, parents or children of probands from 15 different kindreds with severe vWD). On the average, heterozygotes had low levels of vWF in both platelets and plasma. There was, however, considerable heterogeneity, with four distinct patterns. Eleven heterozygotes had concordant reduction of vWF:Ag and Ricof in both plasma and platelets; five had low levels of vWF:Ag and Ricof in plasma contrasting with normal levels in platelets; eight had a peculiar pattern, the reverse of the above (ie, low levels in platelets and normal levels in plasma); and in one, both vWF measurements were normal in plasma and platelets. These patterns were genetically determined: they were consistent in four couples of consanguineous heterozygotes and in two couples carrying the same gene deletion. Only the remaining three heterozygotes had no clearly identifiable pattern. Other findings of this study were that although most of the heterozygotes had normal bleeding times, the 7 of 28 who had prolonged bleeding times had concordantly low levels of vWF measurements in both plasma and platelets. In conclusion, this large series of obligatory heterozygotes provides evidence for phenotypic and genotypic heterogeneity of severe vWD.     

Gene expression in colon cancer: A focus on tumor site and molecular phenotype

Hundreds to thousands of genes are differentially expressed in tumors when compared to nontumor colonic tissue samples. We evaluated gene expression patterns to better understand differences in colon cancer by tumor site and tumor molecular phenotype. We analyzed RNA‐seq data from tumor/normal paired samples from 175 colon cancer patients. We implemented a cross validation strategy with nonparametric tests to identify genes which displayed varying expression characteristics related to paired tumor/nontumor tissue across proximal and distal colon sites and by tumor molecular phenotypes, that is, TP53, KRAS, CpG Island Methylator Phenotype (CIMP), and microsatellite instability (MSI). We used Ingenuity Pathway Analysis (IPA) to determine networks associated with deregulated genes in our data. Genes showed significant differences in expression characteristics at the 0.01 level in both validation groups between tumor subsite (116 genes), CIMP high versus CIMP low (79 genes), MSI versus microsatellite stable (MSS) (49 genes), TP53‐mutated versus not mutated (17genes), and KRAS‐mutated versus not mutated (1 gene). Deregulated genes for CIMP high and MSI tumors were often down‐regulated. In contrast to CIMP high and MSI tumors, genes that were deregulated in TP53 were likely to be up‐regulated. ERK1, WNT, growth factors and inflammation‐related factors were focal points of both CIMP and MSI IPA networks. The MUC family of genes was up‐regulated MSI networks. Numerous genes showed differences in expression between proximal and distal tumors, nontumor proximal and distal tissue, and tumor molecular phenotype. Deregulated mucin genes appear to play an important role in MSI tumors. © 2015 Wiley Periodixzcals, Inc.     

Powerful Set‐Based Gene‐Environment Interaction Testing Framework for Complex Diseases

Identification of gene‐environment interaction (G × E) is important in understanding the etiology of complex diseases. Based on our previously developed Set Based gene EnviRonment InterAction test (SBERIA), in this paper we propose a powerful framework for enhanced set‐based G × E testing (eSBERIA). The major challenge of signal aggregation within a set is how to tell signals from noise. eSBERIA tackles this challenge by adaptively aggregating the interaction signals within a set weighted by the strength of the marginal and correlation screening signals. eSBERIA then combines the screening‐informed aggregate test with a variance component test to account for the residual signals. Additionally, we develop a case‐only extension for eSBERIA (coSBERIA) and an existing set‐based method, which boosts the power not only by exploiting the G‐E independence assumption but also by avoiding the need to specify main effects for a large number of variants in the set. Through extensive simulation, we show that coSBERIA and eSBERIA are considerably more powerful than existing methods within the case‐only and the case‐control method categories across a wide range of scenarios. We conduct a genome‐wide G × E search by applying our methods to Illumina HumanExome Beadchip data of 10,446 colorectal cancer cases and 10,191 controls and identify two novel interactions between nonsteroidal anti‐inflammatory drugs (NSAIDs) and MINK1 and PTCHD3.     

Artificial intelligence in gastroenterology: A state-of-the-art review

The development of artificial intelligence (AI) has increased dramatically in the last 20 years, with clinical applications progressively being explored for most of the medical specialties. The field of gastroenterology and hepatology, substantially reliant on vast amounts of imaging studies, is not an exception. The clinical applications of AI systems in this field include the identification of premalignant or malignant lesions (e.g., identification of dysplasia or esophageal adenocarcinoma in Barrett’s esophagus, pancreatic malignancies), detection of lesions (e.g., polyp identification and classification, small-bowel bleeding lesion on capsule endoscopy, pancreatic cystic lesions), development of objective scoring systems for risk stratification, predicting disease prognosis or treatment response [e.g., determining survival in patients post-resection of hepatocellular carcinoma), determining which patients with inflammatory bowel disease (IBD) will benefit from biologic therapy], or evaluation of metrics such as bowel preparation score or quality of endoscopic examination. The objective of this comprehensive review is to analyze the available AI-related studies pertaining to the entirety of the gastrointestinal tract, including the upper, middle and lower tracts; IBD; the hepatobiliary system; and the pancreas, discussing the findings and clinical applications, as well as outlining the current limitations and future directions in this field.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.     

Pancreatic cancer surgery and nutrition management: a review of the current literature

Surgery remains the only curative treatment for pancreaticobiliary tumors. These patients typically present in a malnourished state. Various screening tools have been employed to help with preoperative risk stratification. Examples include the subjective global assessment (SGA), malnutrition universal screening tool (MUST), and nutritional risk index (NRI). Adequate studies have not been performed to determine if perioperative interventions, based on nutrition risk assessment, result in less morbidity and mortality. The routine use of gastric decompression with nasogastric sump tubes may be unnecessary following elective pancreatic resections. Instead, placement should be selective and employed on a case-by-case basis. A wide variety of feeding modalities are available, oral nutrition being the most effective. Artificial nutrition may be provided by temporary nasal tube (nasogastric, nasojejunal, or combined nasogastrojejunal tube) or surgically placed tube [gastrostomy (GT), jejunostomy (JT), gastrojejunostomy tubes (GJT)], and intravenously (parenteral nutrition, PN). The optimal tube for enteral feeding cannot be determined based on current data. Each is associated with a specific set of complications. Dual lumen tubes may be useful in the presence of delayed gastric emptying (DGE) as the stomach may be decompressed while feeds are delivered to the jejunum. However, all feeding tubes placed in the small intestine, except direct jejunostomies, commonly dislodge and retroflex into the stomach. Jejunostomies are associated with less frequent, but more serious complications. These include intestinal torsion and bowel necrosis. PN is associated with septic, metabolic, and access-related complications and should be the feeding strategy of last-resort. Enteral feeds are clearly preferred over parental nutrition. A sound understanding of perioperative nutrition may improve patient outcomes. Patients undergoing pancreatic cancer surgery should undergo multidisciplinary nutrition screening and intervention, and the surgical/oncological team should include nutrition professionals in managing these patients in the perioperative period.