Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS)

Platelet reactivity, an important factor in hemostasis and chronic disease, has widespread inter-individual variability with a substantial genetic contribution. Previously, our group performed a genome-wide association study of platelet reactivity identifying single nucleotide polymorphisms (SNPs) associated with ADP- and epinephrine- induced aggregation, including SNPs in MRVI1, PIK3CG, JMJD1C, and PEAR1, among others. Here, we assessed the association of these previously identified SNPs with ADP-, thrombin-, and shear- induced platelet aggregation. Additionally, we sought to expand the association of these SNPs with blood cell counts and hemostatic factors. To accomplish this, we examined the association of 12 SNPs with seven platelet reactivity and various hematological measures in 1300 middle-aged men in the Caerphilly Prospective Study. Nine of the examined SNPs showed at least suggestive association with platelet reactivity. The strongest associations were with rs12566888 in PEAR1 to ADP-induced (p = 1.51 × 10^?7) and thrombin-induced (p = 1.91 × 10^?6) reactivity in platelet rich plasma. Our results indicate PEAR1 functions in a relatively agonist independent manner, possibly through subsequent intracellular propagation of platelet activation. rs10761741 in JMJD1C showed suggestive association with ADP-induced reactivity (p = 1.35 × 10^?3), but its strongest associations were with platelet-related cell counts (p = 1.30 × 10^?9). These associations indicate variation in JMJD1C influences pathways that modulate platelet development as well as those that affect reactivity. Associations with other blood cell counts and hemostatic factors were generally weaker among the tested SNPs, indicating a specificity of these SNPs’ function to platelets. Future genome-wide analyses will further assess association of these genes and identify new genes important to platelet biology.     

Crohn''s Colitis Complicated by Superimposed Invasive Amebic Colitis

The clinical characteristics and endoscopic appearance of inflammatory bowel disease (IBD) may be very similar to those of amebic colitis. Physicians, especially in areas in which amebiasis is endemic, are familiar with this difficulty. Moreover, in individual cases, it may even be impossible to distinguish between the two conditions, since stool specimens, bowel biopsies, and serological studies may be negative for Entamoeba histolytica, even in the presence of invasive amebic colitis. Invasive amebiasis may rarely be superimposed on IBD, which further complicates the issue. We report here a young patient with a 7-yr history of Crohn's colitis proven histologically who developed invasive amebic colitis during steroid and 6-mercaptopurine treatment for active disease. Stool specimens, mucosal biopsies, and serological studies were negative for E. histolytica, and the diagnosis was established on pathological examination of a surgically resected bowel. Anti-amebic therapy should be considered in endemic areas in cases of persistent IBD.     

EGF receptor family: twisting targets for improved cancer therapies

Abstract

The epidermal growth factor receptor (EGFR) undergoes a conformational change in response to ligand binding. The ligand-induced changes in cell surface aggregation and mobility have a profound effect on the function of all the family members. Ligand also activates the EGFR intracellular kinase, stimulating proliferation and cell survival. The EGFR family are often activated, overexpressed or mutated in cancer cells and therapeutic drugs (including antibodies) can slow the progress of some cancers. This article provides a brief, annotated summary of the presentations and discussion which occurred at the Epidermal Growth Factor Receptor – Future Directions Conference held in Jerusalem in November 2013.     

Regulatory element copy number differences shape primate expression profiles

Gene expression differences are shaped by selective pressures and contribute to phenotypic differences between species. We identified 964 copy number differences (CNDs) of conserved sequences across three primate species and examined their potential effects on gene expression profiles. Samples with copy number different genes had significantly different expression than samples with neutral copy number. Genes encoding regulatory molecules differed in copy number and were associated with significant expression differences. Additionally, we identified 127 CNDs that were processed pseudogenes and some of which were expressed. Furthermore, there were copy number-different regulatory regions such as ultraconserved elements and long intergenic noncoding RNAs with the potential to affect expression. We postulate that CNDs of these conserved sequences fine-tune developmental pathways by altering the levels of RNA.     

Acute-Onset Cerebellar Symptoms in Lhermitte–Duclos Disease: Case Report

Adult-onset Lhermitte–Duclos disease (LD), or dysplastic cerebellar gangliocytoma, is a hamartoma considered pathognomonic for Cowden disease. Classically, LD has a progressive and insidious onset of symptoms. In this case report, we present a patient having rapid neurological deterioration from acute-onset LD. There are only three reported cases of acute LD presentation. A 22-year-old female presented to the emergency department with diplopia, dysarthria, dysphagia, and gait instability which developed within 6 h. A non-contrast CT scan revealed diffuse attenuation in the left cerebellum and mild ventricular dilatation. LP revealed no organisms. Magnetic resonance imaging revealed salient “tiger stripe” appearance of the left cerebellar cortex and effacement of the fourth ventricle. The patient subsequently underwent suboccipital craniotomy and gross total resection of the lesion. The tumor histology showed distortion of normal cerebellar architecture with dysplastic ganglion cells, loss of Purkinje cells, atrophy of the white matter, and expansion of cerebellar folia. Findings were consistent with adult-onset Lhermitte–Duclos disease.     

Biofilm Formation within the Interface of Bovine Root Dentin Treated with Conjugated Chitosan and Sealer Containing Chitosan Nanoparticles

IntroductionThe purpose of this study was to assess biofilm formation within sealer-dentin interfaces of root segments filled with gutta-percha and sealer incorporated with chitosan (CS) nanoparticles with and without canal surface treatment with different formulations of CS.MethodsStandardized canals of 4-mm bovine root segments (N = 35) were filled with gutta-percha and pulp canal sealer incorporated with CS nanoparticles without surface treatment (group CS) or after surface treatment with phosphorylated CS (group PHCS), CS-conjugated rose bengal and photodynamic irradiation (group CSRB), or a combination of both PHCS and CSRB (group RBPH). The control group was filled with gutta-percha and an unmodified sealer. After 7 days of setting, specimens were aged in buffered solution at 37°C for 1 or 4 weeks. Monospecies biofilms of Enterococcus faecalis were grown on specimens for 7 days in a chemostat-based biofilm fermentor. Biofilm formation within the sealer-dentin interface was assessed with confocal laser scanning microscopy.ResultsIn the 4-week–aged specimens only, the mean biofilm areas were significantly smaller than in the control for the CS (P = .008), PHCS (P = .012), and RBPH (P = .034) groups. The percentage of the biofilm-covered interface also was significantly lower than in the control for the CS (P = .024) and PHCS (P = .003) groups. The CS, PHCS, and RBPH groups did not differ significantly.ConclusionsIncorporating CS nanoparticles into the zinc oxide–eugenol sealer inhibited biofilm formation within the sealer-dentin interface. This effect was maintained when canals were treated with phosphorylated CS, and it was moderated by canal treatment with CS-conjugated rose bengal and irradiation.