Loss of APOLD1: a new vascular bleeding disorder?

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Effect of VPAC1 Blockade on Adipose Tissue Formation and Composition in Mouse Models of Nutritionally Induced Obesity

Background. The pituitary adenylate cyclase activating polypeptide (PACAP) may affect adipogenesis and adipose tissue formation through interaction with its G-protein-coupled receptor VPAC1. Methods. We have used a monoclonal antibody (MAb 23A11) blocking VPAC1 in mouse models of nutritionally induced obesity. Results. Administration of MAb 23A11 (25 mg/kg body weight i.p. twice weekly) to 5-week old male C57Bl/6 mice kept on a high-fat diet for 15 weeks had no significant effect on weight gain, nor on subcutaneous (SC) or gonadal (GON) adipose tissue mass, as compared to the control MAb 1C8. However, adipocyte hypertrophy was observed in SC adipose tissue of MAb 23A11 treated mice. In a second study, 24 weeks old obese mice were treated for 5 weeks with MAb 23A11, without effect on body weight or fat mass, as compared to treatment with MAb 1C8. In addition, MAb 23A11 had no significant effect on glucose tolerance or insulin resistance in lean or obese C57Bl/6 mice. Conclusion. Blocking VPAC1 does not significantly affect adipose tissue formation in mouse models of diet-induced obesity, although it may be associated with mild adipocyte hypertrophy

What’s new in using platelet research? To unravel thrombopathies and other human disorders

This review on platelet research focuses on defects of adhesion, cytoskeletal organisation, signal transduction and secretion. Platelet defects can be studied by different laboratory platelet functional assays and morphological studies. Easy bruising or a suspected platelet-based bleeding disorder is of course the most obvious reason to test the platelet function in a patient. However, nowadays platelet research also contributes to our understanding of human pathology in other disciplines such as neurology, nephrology, endocrinology and metabolic diseases. Apart from a discussion on classical thrombopathies, this review will also deal with the less commonly known relation between platelet research and disorders with a broader clinical phenotype. Classical thrombopathies involve disorders of platelet adhesion such as Glanzmann thrombastenia and Bernard-Soulier syndrome, defective G protein signalling diseases with impaired phospholipase C activation, and abnormal platelet granule secretion disorders such as gray platelet disorder and delta-storage pool disease. Other clinical symptoms besides a bleeding tendency have been described in MYH9-related disorders and Duchenne muscular dystrophy due to adhesion defects, and also in disorders of impaired Gs signalling, in Hermansky Pudlack disease and Chediak Higashi disease with abnormal secretion. Finally, platelet research can also be used to unravel novel mechanisms involved in many neurological disorders such as depression and autism with only a subclinical platelet defect

Reading projects

"By reading only six hours a day", says Marianne Dashwood, outlining her plan of future application to her sister Elinor in Sense and Sensibility, "I shall gain in the course of a twelve-month a great deal of instruction which I now feel myself to want." She adds: "Our own library is too well known to me, to be resorted to for any thing beyond mere amusement. But there are many works well worth reading at the Park; and there are others of more modern production which I know I can borrow of Colonel Brandon" (301). We know, to some extent, what was in the Dashwoods' own library – volumes of Cowper, Scott and Thomson are mentioned. But what might Marianne have borrowed at Barton Park and Delaford? Which publications would Colonel Brandon have considered most appropriate for her project of self-improvement? Elinor considers Marianne's plan excessive, but what would have been a more realistic amount of time for her to spend reading each day, and where might she have done it

Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction

Pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of hormones that activate Gsalpha, encoded by the imprinted GNAS gene. PHP-Ib patients have isolated Parathormone (PTH) resistance and GNAS epigenetic defects while PHP-Ia cases present with hormone resistance and characteristic features jointly termed as Albright's Hereditary Osteodystrophy (AHO) due to maternally inherited GNAS mutations or similar epigenetic defects as found for PHP-Ib. Pseudopseudohypoparathyroidism (PPHP) patients with an AHO phenotype and no hormone resistance and progressive osseous heteroplasia (POH) cases have inactivating paternally inherited GNAS mutations.We here describe 17 subjects with an AHO-like phenotype that could be compatible with having PPHP but none of them carried Gsalpha mutations. Functional platelet studies however showed an obvious Gs hypofunction in the 13 patients that were available for testing. Methylation for the three differentially methylated GNAS regions was quantified via the Sequenom EpiTYPER. Patients showed significant hypermethylation of the XL amplicon compared to controls (36 ± 3 vs. 29 ± 3%; p<0.001); a pattern that is reversed to XL hypomethylation found in PHPIb. Interestingly, XL hypermethylation was associated with reduced XLalphaS protein levels in the patients' platelets. Methylation for NESP and ExonA/B was significantly different for some but not all patients, though most patients have site-specific CpG methylation abnormalities in these amplicons. Since some AHO features are present in other imprinting disorders, the methylation of IGF2, H19, SNURF and GRB10 was quantified. Surprisingly, significant IGF2 hypermethylation (20 ± 10 vs. 14 ± 7%; p<0.05) and SNURF hypomethylation (23 ± 6 vs. 32 6%; p<0.001) was found in patients vs. controls, while H19 and GRB10 methylation was normal.In conclusion, this is the first report of methylation defects including GNAS in patients with an AHO-like phenotype without endocrinological abnormalities. Additional studies are still needed to correlate the methylation defect with the clinical phenotype

Consensus recommendations on flow cytometry for the assessment of inherited and acquired disorders of platelet number and function : communication from the ISTH SSC Subcommittee on Platelet Physiology

Flow cytometry is increasingly used in the study of platelets in inherited and acquired disorders of platelet number and function. However, wide variation exists in specific reagents, methods, and equipment used, making interpretation and comparison of results difficult. The goal of the present study was to provide expert consensus guidance on the use of flow cytometry for the evaluation of platelet disorders. A modified RAND/UCLA survey method was used to obtain a consensus among 11 experts from 10 countries across four continents, on the appropriateness of statements relating to clinical utility, pre-analytical variables, instrument and reagent standardization, methods, reporting, and quality control for platelet flow cytometry. Feedback from the initial survey revealed that uncertainty was sometimes due to lack of expertise with a particular test condition rather than unavailable or ambiguous data. To address this, the RAND method was modified to allow experts to self-identify statements for which they could not provide expert input. There was uniform agreement among experts in the areas of instrument and reagent standardization, methods, reporting, and quality control and this agreement is used to suggest best practices in these areas. However, 25.9% and 50% of statements related to pre-analytical variables and clinical utility, respectively, were rated as uncertain. Thus, while citrate is the preferred anticoagulant for many flow cytometric platelet tests, expert opinions differed on the acceptability of other anticoagulants, particularly heparin. Lack of expert consensus on the clinical utility of many flow cytometric platelet tests indicates the need for rigorous multicenter clinical outcome studies

Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects

Background: Pseudohypoparathyroidism (PHP) is caused by (epi) genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis. Methods: The Human Methylation 450K BeadChip was used to analyze genome-wide methylation in 24 PHP patients with parathyroid hormone resistance and 20 age- and gender-matched controls. Patients were previously diagnosed with GNAS-specific differentially methylated regions (DMRs) and include 6 patients with known STX16 deletion (PHP Delta stx16) and 18 without deletion (PHPneg). Results: The array demonstrated that PHP patients do not show DNA methylation differences at the whole-genome level. Unsupervised clustering of GNAS-specific DMRs divides PHP Delta stx16 versus PHPneg patients. Interestingly, in contrast to the notion that all PHP patients share methylation defects in the A/B DMR while only PHP Delta stx16 patients have normal NESP, GNAS-AS1 and XL methylation, we found a novel DMR (named GNAS-AS2) in the GNAS-AS1 region that is significantly different in both PHP Delta stx16 and PHPneg, as validated by Sequenom EpiTYPER in a larger PHP cohort. The analysis of 58 DMRs revealed that 8/18 PHPneg and 1/6 PHP Delta stx16 patients have multi-locus methylation defects. Validation was performed for FANCC and SVOPL DMRs. Conclusions: This is the first genome-wide methylation study for PHP patients that confirmed that GNAS is the most significant DMR, and the presence of STX16 deletion divides PHP patients in two groups. Moreover, a novel GNAS-AS2 DMR affects all PHP patients, and PHP patients seem sensitive to multi-locus methylation defects

Exploring the role of OXTR gene methylation in attachment development: A longitudinal study

he current study explored longitudinally whether oxytocin receptor gene methyla-tion (OXTRm) changes moderated the association between parental sensitivity changesand children’s attachment changes over three waves. Six hundred six Flemish children(10–12 years, 42.8%–44.8% boys) completed attachment measures and provided sali-vary OXTRm data on seven CpG sites. Their parents reported their sensitive parenting.Results suggest that OXTRm changes hardly link to attachment (in)security changesafter the age of 10. Some support was found for interaction effects between parentalsensitivity changes and OXTRm changes on attachment changes over time. Effects sug-gest that for children with increased OXTRm in the promotor region and decreasedmethylation in the inhibitor region over time, increased parental sensitivity was asso-ciated with increased secure attachment and decreased insecure attachment overtime.info:eu-repo/semantics/acceptedVersio