Ca2+-Mg2+-dependent ATP-ase activity in hemodialyzed children. Effect of a hemodialysis session

In the course of chronic kidney disease (CKD) the intracellular erythrocyte calcium (Cai2+) level increases along with the progression of the disease. The decreased activity of Ca2+-Mg2+-dependent ATP-ase (PMCA) and its endogenous modulators calmodulin (CALM), calpain (CANP), and calpastatin (CAST) are all responsible for disturbed calcium metabolism. The aim of the study was to analyze the activity of PMCA, CALM, and the CANP-CAST system in the red blood cells (RBCs) of hemodialyzed (HD) children and to estimate the impact of a single HD session on the aforementioned disturbances. Eighteen patients on maintenance HD and 30 healthy subjects were included in the study. CALM, Cai2+ levels and basal PMCA (bPMCA), PMCA, CANP, and CAST activities were determined in RBCs before HD, after HD, and before the next HD session. Prior to the HD session, the level of Cai2+ and the CAST activity were significantly higher, whereas bPMCA, PMCA, and CANP activities and the CALM level were significantly lower than in controls. After the HD session, the Cai2+ concentration and the CAST activity significantly decreased compared with the basal values, whereas the other parameters significantly increased, although they did not reach the levels of healthy children. The values observed prior to both HD sessions were similar. Cai2+ homeostasis is severely disturbed in HD children, which may be caused by the reduction in the PMCA activity, CALM deficiency, and CANP-CAST system disturbances. A single HD session improved these disturbances but the effect is transient

Gluten sensitivity enteropathy in patients with recurrent aphthous stomatitis

<p>Abstract</p> <p>Background</p> <p>Gluten sensitive enteropathy (GSE) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in susceptible individuals. Recurrent aphthous stomatitis (RAS) may be the sole manifestation of GSE. The aim of this study was to determine the prevalence of gluten sensitivity enteropathy (GSE) in a large group of patients with RAS and assess the efficacy of gluten free diet (GFD) on the improvement of aphthous lesions in those who were diagnosed with GSE.</p> <p>Methods</p> <p>Two hundred and forty seven patients with RAS were included. The patients had at least three aphthous attacks per year. Patients were screened by IgA anti-endomysial antibody (EMA), IgA anti tissue transglutaminase (TTG) and serum IgA level. Those with a positive serology underwent endoscopic biopsies of the duodenal mucosa and patients with negative serology were excluded. The diagnosis of GSE was based on a positive serological test and abnormal duodenal histology. For patients with GSE, gluten free diet was recommended.</p> <p>Results</p> <p>Six out of 247 RAS patients had positive TTG test alone, and one had positive EMA and TTG. All 7 patients with positive serologic tests underwent duodenal biopsies. Histological findings were compatible with GSE in all of them (Marsh I in four patients, Marsh II in two patients and Marsh IIIB in one another.). The mean age of GSE patients was 27.42 ± 10.56 (range, 13 to 40) years old. They were suffering from RAS for an average duration of 4.5 years. All of the 7 GSE patients had not responded to the routine anti-aphthae medications, including topical corticosteroids, tetracycline and colchicine. Four patients who adhered to a strict gluten-free diet showed noticeable improvement in their aphthous lesions over a period of 6 months.</p> <p>Conclusion</p> <p>A significant minority (e.g. 2.83%) of RAS patients have GSE. This could be compared with the 0.9% prevalence of GSE in the general population of Iran. This study suggests that evaluation for celiac disease is appropriate in patients with RAS. Additionally, the unresponsiveness to conventional anti-aphthae treatment could be an additional risk indicator.</p

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis

Brain activity underlying negative self- and other-perception in adolescents: The role of attachment-derived self-representations

One of teenagers' key developmental tasks is to engage in new and meaningful relationships with peers and adults outside the family context. Attachment-derived expectations about the self and others in terms of internal attachment working models have the potential to shape such social reorientation processes critically and thereby influence adolescents' social-emotional development and social integration. Because the neural underpinnings of this developmental task remain largely unknown, we sought to investigate them by functional magnetic resonance imaging. We asked n = 44 adolescents (ages 12.01-18.84 years) to evaluate positive and negative adjectives regarding either themselves or a close other during an adapted version of the well-established self-other trait-evaluation task. As measures of attachment, we obtained scores reflecting participants' positive versus negative attachment-derived self- and other-models by means of the Relationship Questionnaire. We controlled for possible confounding factors by also obtaining scores reflecting internalizing/externalizing problems, schizotypy, and borderline symptomatology. Our results revealed that participants with a more negative attachment-derived self-model showed increased brain activity during positive and negative adjective evaluation regarding the self, but decreased brain activity during negative adjective evaluation regarding a close other, in bilateral amygdala/parahippocampus, bilateral anterior temporal pole/anterior superior temporal gyrus, and left dorsolateral prefrontal cortex. These findings suggest that a low positivity of the self-concept characteristic for the attachment anxiety dimension may influence neural information processing, but in opposite directions when it comes to self- versus (close) other-representations. We discuss our results in the framework of attachment theory and regarding their implications especially for adolescent social-emotional development and social integration

Friedreich's Ataxia (GAA)n•(TTC)n Repeats Strongly Stimulate Mitotic Crossovers in Saccharomyces cerevisae

Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)n•(TTC)n tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)n•(TTC)n tracts can be a potent source of loss of heterozygosity in yeast

A comparative study between mixed-type tumours from human salivary and canine mammary glands

<p>Abstract</p> <p>Background</p> <p>In comparative pathology, canine mammary tumours have special interest because of their similarities with human breast cancer. Mixed tumours are uncommon lesions in the human breast, but they are found most frequently in the mammary gland of the female dogs and in the human salivary glands. The aim of the study was to compare clinical, morphological and immunohistochemical features of human salivary and canine mammary gland mixed tumours, in order to evaluate the latter as an experimental model for salivary gland tumours.</p> <p>Methods</p> <p>Ten examples of each mixed tumour type (human pleomorphic adenoma and carcinomas ex-pleomorphic adenomas and canine mixed tumour and metaplastic carcinoma) were evaluated. First, clinical and morphologic aspects of benign and malignant variants were compared between the species. Then, streptavidin-biotin-peroxidase immunohistochemistry was performed to detect the expression of cytokeratins, vimentin, p63 protein, estrogen receptor, β-catenin, and E-cadherin.</p> <p>Results</p> <p>After standardization, similar age and site distributions were observed in human and canine tumours. Histological similarities were identified in the comparison of the benign lesions as well. Metaplastic carcinomas also resembled general aspects of carcinomas ex-pleomorphic adenomas in morphological evaluation. Additionally, immunohistochemical staining further presented similar antigenic expression between lesions.</p> <p>Conclusion</p> <p>There are many similar features between human salivary and canine mammary gland mixed tumours. This observation is of great relevance for those interested in the study and management of salivary gland tumours, since canine lesions may constitute useful comparative models for their investigations.</p

The P2X1 receptor and platelet function

Extracellular nucleotides are ubiquitous signalling molecules, acting via the P2 class of surface receptors. Platelets express three P2 receptor subtypes, ADP-dependent P2Y1 and P2Y12 G-protein-coupled receptors and the ATP-gated P2X1 non-selective cation channel. Platelet P2X1 receptors can generate significant increases in intracellular Ca2+, leading to shape change, movement of secretory granules and low levels of αIIbβ3 integrin activation. P2X1 can also synergise with several other receptors to amplify signalling and functional events in the platelet. In particular, activation of P2X1 receptors by ATP released from dense granules amplifies the aggregation responses to low levels of the major agonists, collagen and thrombin. In vivo studies using transgenic murine models show that P2X1 receptors amplify localised thrombosis following damage of small arteries and arterioles and also contribute to thromboembolism induced by intravenous co-injection of collagen and adrenaline. In vitro, under flow conditions, P2X1 receptors contribute more to aggregate formation on collagen-coated surfaces as the shear rate is increased, which may explain their greater contribution to localised thrombosis in arterioles compared to venules within in vivo models. Since shear increases substantially near sites of stenosis, anti-P2X1 therapy represents a potential means of reducing thrombotic events at atherosclerotic plaques

Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma

Background: The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma.Methods: PXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.Results: PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).Conclusions: PXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease