Chinese family with diffuse oesophageal leiomyomatosis: A new COL4A5/COL4A6 deletion and a case of gonosomal mosaicism

© 2015 Liu et al. Background: Diffuse oesophageal leiomyomatosis (DOL) is a rare disorder characterized by tumorous overgrowth of the muscular wall of the oesophagus. DOL is present in 5 % of Alport syndrome (AS) patients. AS is a rare hereditary disease that involves varying degrees of hearing impairment, ocular changes and progressive glomerulonephritis leading to renal failure. In DOL-AS patients, the genetic defect consists of a deletion involving the COL4A5 and COL4A6 genes on the X chromosome. Case presentation: We report a two-generation family (4 individuals; parents and two children, one male and one female) with two members (mother and son) affected with oesophageal leiomyomatosis. Signs of potential renal failure, which characterizes AS, were only apparent in the index patient (son) 2 years and three months after the initial diagnosis of DOL. Blood DNA from the four family members were submitted to exome sequencing and array genotyping to perform a genome wide screening for disease causal single nucleotide (SN) and copy number (CN) variations. Analyses revealed a new 40kb deletion encompassing from intron 2 of COL4A5 to intron 1 of COL4A6 at Xq22.3. The breakpoints were also identified. Possible confounding pathogenic exonic variants in genes known to be involved in other extracellular matrices disorders were also shared by the two affected individuals. Meticulous analysis of the maternal DNA revealed a case of gonosomal mosaicism. Conclusions: This is the first report of gonadosomal mosaicism associated to DOL-AS.published_or_final_versio

Identification of 5,6-trans-epoxyeicosatrienoic acid in the phospholipids of red blood cells.

A novel eicosanoid, 5,6-trans-epoxy-8Z,11Z,14Z-eicosatrienoic acid (5,6-trans-EET), was identified in rat red blood cells. Characterization of 5,6-trans-EET in the sn-2 position of the phospholipids was accomplished by hydrolysis with phospholipase A(2) followed by gas chromatography/mass spectrometry as well as electrospray ionization-tandem mass spectrometry analyses. The electron ionization spectrum of 5,6-erythro-dihydroxyeicosatrienoic acid (5,6-erythro-DHET), converted from 5,6-trans-EET in the samples, matches that of the authentic standard. Hydrogenation of the extracted 5,6-erythro-DHET with platinum(IV) oxide/hydrogen resulted in an increase of the molecular mass by 6 daltons and the same retention time shift as an authentic standard in gas chromatography, suggesting the existence of three olefins as well as the 5,6-erythro-dihydroxyl structure in the metabolite. Match of retention times by chromatography indicated identity of the stereochemistry of the red blood cell 5,6-erythro-DHET vis à vis the synthetic standard. High pressure liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of the phospholipase A(2)-hydrolyzed lipid extracts from red blood cells revealed match of the mass spectrum and retention time of the compound with the authentic 5,6-trans-EET standard, providing direct evidence of the existence of 5,6-trans-EET in red blood cells. The presence of other trans-EETs was also demonstrated. The ability of both 5,6-trans-EET and its product 5,6-erythro-DHET to relax preconstricted renal interlobar arteries was significantly greater than that of 5,6-cis-EET. In contrast, 5,6-cis-EET and 5,6-trans-EET were equipotent in their capacity to inhibit collagen-induced rat platelet aggregation, whereas 5,6-erythro-DHET was without effect. We propose that the red blood cells serve as a reservoir for epoxides which on release may act in a vasoregulatory capacity

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Background: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. Methods: We aim to identify genetic risk factors by a “trio-based” exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Results: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Conclusions: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD

Characterization of mouse orofacial pain and the effects of lesioning TRPV1-expressing neurons on operant behavior

<p>Abstract</p> <p>Background</p> <p>Rodent models of orofacial pain typically use methods adapted from manipulations to hind paw; however, limitations of these models include animal restraint and subjective assessments of behavior by the experimenter. In contrast to these methods, assessment of operant responses to painful stimuli has been shown to overcome these limitations and expand the breadth of interpretation of the behavioral responses. In the current study, we used an operant model based on a reward-conflict paradigm to assess nociceptive responses in three strains of mice (SKH1-Hr^hr, C57BL/6J, TRPV1 knockout). We previously validated this operant model in rats and hypothesized in this study that wild-type mice would demonstrate a similar thermal stimulus-dependent response and similar operant pain behaviors. Additionally, we evaluated the effects on operant behaviors of mice manipulated genetically (e.g., TRPV1 k.o.) or pharmacologically with resiniferatoxin (RTX), a lesioning agent for TRPV1-expressing neurons. During the reward-conflict task, mice accessed a sweetened milk reward solution by voluntarily position their face against a neutral or heated thermode (37–55°C).</p> <p>Results</p> <p>As the temperature of the thermal stimulus became noxiously hot, reward licking events in SKH1-Hr^hrand C57BL/6J mice declined while licking events in TRPV1 k.o. mice were insensitive to noxious heat within the activation range of TRPV1 (37–52°C). All three strains displayed nocifensive behaviors at 55°C, as indicated by a significant decrease in reward licking events. Induction of neurogenic inflammation by topical application of capsaicin reduced licking events in SKH1-Hr^hrmice, and morphine rescued this response. Again, these results parallel what we previously documented using rats in this operant system. Following intracisternal treatment with RTX, C57BL/6J mice demonstrated a block of noxious heat at both 48 and 55°C. RTX-treated TRPV1 k.o. mice and all vehicle-treated mice displayed similar reward licking events as compared to the pre-treatment baseline levels. Both TRPV1 k.o. and RTX-treated C57BL/6J had complete abolishment of eye-wipe responses following corneal application of capsaicin.</p> <p>Conclusion</p> <p>Taken together, these results indicate the benefits of using the operant test system to investigate pain sensitivity in mice. This ability provides an essential step in the development of new treatments for patients suffering from orofacial pain disorders.</p

Element release and reaction-induced porosity alteration during shale-hydraulic fracturing fluid interactions

The use of hydraulic fracturing techniques to extract oil and gas from low permeability shale reservoirs has increased significantly in recent years. During hydraulic fracturing, large volumes of water, often acidic and oxic, are injected into shale formations. This drives fluid-rock interaction that can release metal contaminants (e.g., U, Pb) and alter the permeability of the rock, impacting the transport and recovery of water, hydrocarbons, and contaminants. To identify the key geochemical processes that occur upon exposure of shales to hydraulic fracturing fluid, we investigated the chemical interaction of hydraulic fracturing fluids with a variety of shales of different mineralogical texture and composition. Batch reactor experiments revealed that the dissolution of both pyrite and carbonate minerals occurred rapidly, releasing metal contaminants and generating porosity. Oxidation of pyrite and aqueous Fe drove precipitation of Fe(III)-(oxy)hydroxides that attenuated the release of these contaminants via co-precipitation and/or adsorption. The precipitation of these (oxy)hydroxides appeared to limit the extent of pyrite reaction. Enhanced removal of metals and contaminants in reactors with higher fluid pH was inferred to reflect increased Fe-(oxy)hydroxide precipitation associated with more rapid aqueous Fe(II) oxidation. The precipitation of both Al- and Fe-bearing phases revealed the potential for the occlusion of pores and fracture apertures, whereas the selective dissolution of calcite generated porosity. These pore-scale alterations of shale texture and the cycling of contaminants indicate that chemical interactions between shales and hydraulic fracturing fluids may exert an important control on the efficiency of hydraulic fracturing operations and the quality of water recovered at the surface

Heat kernel of integrable billiards in a magnetic field

We present analytical methods to calculate the magnetic response of non-interacting electrons constrained to a domain with boundaries and submitted to a uniform magnetic field. Two different methods of calculation are considered - one involving the large energy asymptotic expansion of the resolvent (Stewartson-Waechter method) is applicable to the case of separable systems, and another based on the small time asymptotic behaviour of the heat kernel (Balian-Bloch method). Both methods are in agreement with each other but differ from the result obtained previously by Robnik. Finally, the Balian-Bloch multiple scattering expansion is studied and the extension of our results to other geometries is discussed.Comment: 13 pages, Revte

Correlations in a confined magnetized free-electron gas

Equilibrium quantum statistical methods are used to study the pair correlation function for a magnetized free-electron gas in the presence of a hard wall that is parallel to the field. With the help of a path-integral technique and a Green function representation the modifications in the correlation function caused by the wall are determined both for a non-degenerate and for a completely degenerate gas. In the latter case the asymptotic behaviour of the correlation function for large position differences in the direction parallel to the wall and perpendicular to the field, is found to change from Gaussian in the bulk to algebraic near the wall.Comment: 24 pages, 10 figures, submitted to J. Phys. A: Math. Ge

Screening for malnutrition in patients with gastro-entero-pancreatic neuroendocrine tumours : a cross-sectional study

Objectives To investigate whether screening for malnutrition using the validated malnutrition universal screening tool (MUST) identifies specific characteristics of patients at risk, in patients with gastro-entero-pancreatic neuroendocrine tumours (GEP-NET). Design Cross-sectional study. Setting University Hospitals Coventry & Warwickshire NHS Trust; European Neuroendocrine Tumour Society Centre of Excellence. Participants Patients with confirmed GEP-NET (n=161) of varying primary tumour sites, functioning status, grading, staging and treatment modalities. Main outcome measure To identify disease and treatment-related characteristics of patients with GEP-NET who score using MUST, and should be directed to detailed nutritional assessment. Results MUST score was positive (≥1) in 14% of outpatients with GEP-NET. MUST-positive patients had lower faecal elastase concentrations compared to MUST-negative patients (244±37 vs 383±20 µg/g stool; p=0.018), and were more likely to be on treatment with long-acting somatostatin analogues (65 vs 38%, p=0.021). MUST-positive patients were also more likely to have rectal or unknown primary NET, whereas, frequencies of other GEP-NET including pancreatic NET were comparable between MUST-positive and MUST-negative patients. Conclusions Given the frequency of patients identified at malnutrition risk using MUST in our relatively large and diverse GEP-NET cohort and the clinical implications of detecting malnutrition early, we recommend routine use of malnutrition screening in all patients with GEP-NET, and particularly in patients who are treated with long-acting somatostatin analogues

Collapse arrest and soliton stabilization in nonlocal nonlinear media

We investigate the properties of localized waves in systems governed by nonlocal nonlinear Schrodinger type equations. We prove rigorously by bounding the Hamiltonian that nonlocality of the nonlinearity prevents collapse in, e.g., Bose-Einstein condensates and optical Kerr media in all physical dimensions. The nonlocal nonlinear response must be symmetric, but can be of completely arbitrary shape. We use variational techniques to find the soliton solutions and illustrate the stabilizing effect of nonlocality.Comment: 4 pages with 3 figure

NMR investigations of the interaction between the azo-dye sunset yellow and Fluorophenol

The interaction of small molecules with larger noncovalent assemblies is important across a wide range of disciplines. Here, we apply two complementary NMR spectroscopic methods to investigate the interaction of various fluorophenol isomers with sunset yellow. This latter molecule is known to form noncovalent aggregates in isotropic solution, and form liquid crystals at high concentrations. We utilize the unique fluorine-19 nucleus of the fluorophenol as a reporter of the interactions via changes in both the observed chemical shift and diffusion coefficients. The data are interpreted in terms of the indefinite self-association model and simple modifications for the incorporation of a second species into an assembly. A change in association mode is tentatively assigned whereby the fluorophenol binds end-on with the sunset yellow aggregates at low concentration and inserts into the stacks at higher concentrations