Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation

© 2016 Taylor & Francis. Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses

Manganese oxide catalysts for secondary zinc air batteries: from

An efficient, durable and low cost air cathode with low polarization between the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is essential for a high performance and durable secondary zinc-air battery. Different valence states and morphologies of MnxOy catalysts were synthetized via thermal treatment of EMD (generating Mn2O3 and Mn3O4) and acid digestion of synthetized Mn2O3 (producing a-MnO2) in order to develop an efficient Bifunctional Air Electrode (BAE). Change in the ratio H+ to Mn2O3 during the acid digestion affects the sample microporosity, the crystallographic plane distribution, as well as the physical and chemical adsorbed water which was related to defects, i.e. cation vacancies (Mn4+) and Mn3+. These characteristics were discussed and linked to the electrocatalytic activity. The best ORR performing catalyst was that with the higher surface water content (associated to material BET surface area) and a (310) surface as the 2nd more contributing plane (after 211). On the other hand, the catalyst with the higher structural water and with (110) and (200) crystallographic planes being the most intensity contributors (after 211) was the most OER active material. In this work, it was able to find a relationship between catalyst structure and air-efficiency through a volcano-like relationship between air-efficiency and surface water content. Air-efficiency (also take as round-efficiency discharge/charge in battery context) can be taken as a good descriptor of potentially good materials for Zn-Air secondary batteries technology. In this term, we were able to prepare a Bifunctional Air Electrode based on the selected a-MnO2 sample which demonstrated a roundefficiency of 53%, a DV around 1 V and a neglected loss of the charge potential (about 2.1 V) over the entire lifecycle test (more 200 cycles over 30 hours) with a capacity retention superior to 95%.European Commission H2020: Proyecto ZAS “Zinc Air Secondary innovative nanotech based batteries for efficient energy storage” (Grant Agreement 646186

Myocardial blood flow in man: effects of coronary collateral circulation and coronary artery bypass surgery

A B S T R A C T The effects of coronary artery bypass graft (CAB) and coronary collaterals (CC) even with CAB occluded. Vessels with greater than 80% stenosis or total occlusion by angiography had significant pressure gradients with marked reduction of postobstructive MBF. No significant difference in postobstructive MBF was found when vessels with CC (21±4 ml/min per 100 g) were compared to those without CC (17+4 ml/min per 100 g) (P > 0.4). These studies demonstrate that (a) mean MBF increased 268% after CAB, (b) heterogeneous MBF persisted after CAB, (c) CC were not associated with significant increases in MUBF, and (d) vessels with less than 80% stenosis had less than 20 mm Hg gradient with minimal effect on resting MBF

Host phenotype characteristics and MC1R in relation to early-onset basal cell carcinoma.

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under the age of 40 years. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype-genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under the age of 40 years were identified through Yale's Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for 1 hour (severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08-36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90-20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37-5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC case status (37% of cases) than a single BCC case status. MC1R, number of moles, skin reaction to first summer sun for 1 hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer

Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization

Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK

Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an similar to5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. the mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.Harvard Sch Dent Med, Forsyth Inst, Harvard Forsyth Dept Oral Biol, Boston, MA 02115 USAHarvard Univ, Sch Med, Childrens Hosp, Dept Cell Biol, Boston, MA USAHarvard Univ, Sch Med, Childrens Hosp, Dept Genet, Boston, MA USAHarvard Univ, Sch Med, Childrens Hosp, Div Plast Surg, Boston, MA USAUniversidade Federal de São Paulo, EPM, Campinas, SP, BrazilInst Cirurg Plast Craniofacial SOBRAPAR, Campinas, SP, BrazilShowa Univ, Sch Med, Dept Plast & Reconstruct Surg, Tokyo 142, JapanVirginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USASt Louis Univ, Sch Med, Cardinal Glennon Childrens Hosp, Div Med Genet, St Louis, MO 63104 USAUniv Cape Town, Sch Med, Dept Human Genet, ZA-7925 Cape Town, South AfricaOhio State Univ, Coll Dent, Dept Orthodont, Columbus, OH 43210 USAChildrens Hosp, Dept Genet, Columbus, OH 43205 USAUniv Minnesota, Sch Dent, Dept Oral Biol & Genet, Minneapolis, MN 55455 USAUniversidade Federal de São Paulo, EPM, Campinas, SP, BrazilWeb of Scienc

Validation of the severity index by cardiac catheterization and Doppler echocardiography in patients with aortic sclerosis and stenosis

The severity index is a new echocardiographic measure that is thought to be an accurate indicator of aortic leaflet pathology in patients with AS. However, it has not been validated against cardiac catheterization or Doppler echocardiographic measures of AS severity nor has it been applied to patients with aortic sclerosis. The purposes of this study were to compare the severity index to invasive hemodynamics and Doppler echocardiography across the spectrum of calcific aortic valve disease, including aortic sclerosis and AS. 48 patients with aortic sclerosis and AS undergoing echocardiography and cardiac catheterization comprised the study population. The aortic valve leaflets were assessed for mobility (scale 1 to 6) and calcification (scale 1 to 4) and the severity index was calculated as the sum of the mobility and calcification scores according to the methods of Bahler et al. The severity index increased with increasing severity of aortic valve disease; the severity indices for patients with aortic sclerosis, mild to moderate AS and severe AS were 3.38 ± 1.06, 6.45 ± 2.16 and 8.38 ± 1.41, respectively. The aortic jet velocity by echocardiography and the square root of the maximum aortic valve gradient by cardiac catheterization correlated well with the severity index (r = 0.84, p < 0.0001; r = 0.84, p < 0.0001, respectively). These results confirm that the severity index correlates with hemodynamic severity of aortic valve disease and may prove to be a useful measure in patients with aortic sclerosis and AS