Factor VIII-hydrolyzing IgG in acquired and congenital hemophilia

Anti-factor VIII (FVIII) inhibitory IgG may arise as alloantibodies to therapeutic FVIII in patients with congenital hemophilia A, or as autoantibodies to endogenous FVIII in individuals with acquired hemophilia. We have described FVIII-hydrolyzing IgG both in hemophilia A patients with anti-FVIII IgG and in acquired hemophilia patients. Here, we compared the properties of proteolytic auto- and allo-antibodies. Rates of FVIII hydrolysis differed significantly between the two groups of antibodies. Proline-phenylalanine-arginine-methylcoumarinamide was a surrogate substrate for FVIII-hydrolyzing autoantibodies. Our data suggest that populations of proteolytic anti-FVIII IgG in acquired hemophilia patients are different from that of inhibitor-positive hemophilia A patients.

Drosophila indirect flight muscle specific Act88F actin mutants as a model system for studying congenital myopathies of the human ACTA1 skeletal muscle actin gene

Most human ACTA1 skeletal actin gene mutations cause dominant, congenital myopathies often with severely reduced muscle function and neonatal mortality. High sequence conservation of actin means many mutated ACTA1 residues are identical to those in the Drosophila Act88F, an indirect flight muscle specific sarcomeric actin. Four known Act88F mutations occur at the same actin residues mutated in ten ACTA1 nemaline mutations, A138D/P, R256H/L, G268C/D/R/S and R372C/S. These Act88F mutants were examined for similar muscle phenotypes. Mutant homozygotes show phenotypes ranging from a lack of myofibrils to almost normal sarcomeres at eclosion. Aberrant Z-disc-like structures and serial Z-disc arrays, ‘zebra bodies’, are observed in homozygotes and heterozygotes of all four Act88F mutants. These electron-dense structures show homologies to human nemaline bodies/rods, but are much smaller than those typically found in the human myopathy. We conclude that the Drosophila indirect flight muscles provide a good model system for studying ACTA1 mutations.

Effect of calcium deficiency on the mechanical properties of hydroxyapatite crystals

The deterioration of the mechanical properties of bone with age is related to several factors including the structure, organization and chemistry of the constituent phases; however, the relative contribution of each of these factors is not well understood. In this study, we have investigated the effect of chemistry (calcium deficiency) on the mechanical properties of single crystals of hydroxyapatite. Single crystals of stoichiometric crystals grown by the flux method and calcium-deficient platelet crystals grown using wet chemical methods were used as model systems. Using nanoindentation, we show that calcium deficiency leads to an 80% reduction in the hardness and elastic modulus and at least a 75% reduction in toughness in plate-shaped hydroxyapatite crystals. Measurement of local mechanical properties using nanoindentation and nanoscale chemistry through elemental mapping in a transmission electron microscope points to a direct correlation between the observed spatial variation in composition and the large scatter in the measured hardness and modulus values. (C) 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

H I deficiency in cluster spiral galaxies - Dependence on galaxy size

From the available H I data on spiral galaxies in three rich Abell clusters and the Virgo Cluster, it is shown that galaxies with medium to large optical sizes tend to be more severely deficient in atomic hydrogen than the small galaxies. This is so both in terms of the fractional number of galaxies that are deficient and the amount of gas lost by a galaxy. The fraction of H I-deficient galaxies increases with size over most of the size range, saturating or dropping only for the largest galaxies. A comparative study is made of various currently accepted gas removal mechanisms, namely those which are a result of galaxy-intracluster medium interactions, e.g., ram pressure stripping, as well as those due to galaxy-galaxy interactions, i.e., collisions and tidal interactions. It is shown that, with the exception of tidal interactions, all of these mechanisms would produce a size dependence in H I deficiency that is the opposite of that observed. That is, the gas in the largest galaxies would be the least affected by these mechanisms. However, if there is significant mass segregation, these processes may give the trends observed in the size dependence of H I deficiency.

An unusual distribution of glucose-6-phosphate dehydrogenase deficiency of south Indian newborn population.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is seen at a higher frequency in many national and ethnic groups in areas of current or former malaria endemicity. A screening programme undertaken to evaluate the gene frequencies for this deficiency in the highly inbred South Indian population of Karnataka revealed that of the 5140 neonates screened, 7.8% were G6PD deficient with no correlation between the reported level of inbreeding and enzyme deficiency. An interesting finding was the equal number of male (198) and female (207) individuals, with G6PD activity of less than 3 IU. The possible implications of this finding with regard to the expression of G6PD gene is discussed.

Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels

``The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre + post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups.'' (C) 2013 Elsevier Inc. All rights reserved.

Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature

Purpose: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. Methods: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. Results: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. Conclusions: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here.

Modification of Extended Open Frameworks with Fluorescent Tags for Sensing Explosives: Competition between Size Selectivity and Electron Deficiency

Three new electron-rich metal-organic frameworks (MOF-1-MOF-3) have been synthesized by employing ligands bearing aromatic tags. The key role of the chosen aromatic tags is to enhance the -electron density of the luminescent MOFs. Single-crystal X-ray structures have revealed that these MOFs form three-dimensional porous networks with the aromatic tags projecting inwardly into the pores. These highly luminescent electron-rich MOFs have been successfully utilized for the detection of explosive nitroaromatic compounds (NACs) on the basis of fluorescence quenching. Although all of the prepared MOFs can serve as sensors for NACs, MOF-1 and MOF-2 exhibit superior sensitivity towards 4-nitrotoluene (4-NT) and 2,4-dinitrotoluene (DNT) compared to 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitrobenzene (TNB). MOF-3, on the other hand, shows an order of sensitivity in accordance with the electron deficiencies of the substrates. To understand such anomalous behavior, we have thoroughly analyzed both the steady-state and time-resolved fluorescence quenching associated with these interactions. Determination of static Stern-Volmer constants (K-S) as well as collisional constants (K-C) has revealed that MOF-1 and MOF-2 have higher K-S values with 4-NT than with TNT, whereas for MOF-3 the reverse order is observed. This apparently anomalous phenomenon was well corroborated by theoretical calculations. Moreover, recyclability and sensitivity studies have revealed that these MOFs can be reused several times and that their sensitivities towards TNT solution are at the parts per billion (ppb) level.

A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1) observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.