Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.

PurposeWe determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.MethodsA total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.ResultsSeveral distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).ConclusionsThe PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets

Electronic structure and magnetism of equiatomic FeN

In order to investigate the phase stability of equiatomic FeN compounds and the structure-dependent magnetic properties, the electronic structure and total energy of FeN with NaCl, ZnS and CsCl structures and various magnetic configurations are calculated using the first-principles TB-LMTO-ASA method. Among all the FeN phases considered, the antiferromagnetic NaCl structure with q=(00pi) is found to have the lowest energy at the theoretical equilibrium volume. However, the FM NaCl phase lies only 1mRyd higher. The estimated equilibrium lattice constant for nonmagnetic ZnS-type FeN agrees quite well with the experimental value, but for the AFM NaCl phase the estimated value is 6.7% smaller than that observed experimentally. For ZnS-type FeN, metastable magnetic states are found for volumes larger than the equilibrium value. On the basis of an analysis of the atom- and orbital-projected density of states and orbital-projected Crystal Orbital Hamilton Population, the iron-nitrogen interactions in NM ZnS, AFM NaCl and FM CsCl structures are discussed. The leading Fe-N interactions is due to the d-p iron-nitrogen hybridization, while considerable s-p and p-p hybridizations are also observed in all three phases. The iron magnetic moment in FeN is found to be highly sensitive to the nearest-neighboring Fe-N distance. In particular, the magnetic moment shows an abrupt drop from a value of about 2 muB to zero with the reduction of the Fe-N distance for the ZnS and CsCl structures.Comment: 12 pages, 6 figure

Holmium dodeca­iodidoiron-octa­hedro-hexa­holmium, {FeHo6}I12Ho

Single crystals of {FeHo6}I12Ho were obtained during the reaction of HoI3 with metallic holmium and iron in a sealed tantalum container. The crystal structure consists of isolated holmium clusters encapsulating a single Fe atom, {FeHo6} ( symmetry). The rare earth metal atoms are surrounded by 12 edge-capping and six terminal iodide ligands that either connect the clusters to each other directly or via HoI6 octa­hedra ( symmetry)

Superatom Representation of High-TC Superconductivity Revisited

A "super-atom" conceptual interface between chemistry and physics is proposed in order to assist in the search for higher TC superconductors. High-TC superconductivity HTSC is articulated as the entanglement of two disjoint electronic manifolds in the vicinity of a common Fermi energy. The resulting HTSC ground state couples near-degenerate protected local "super-atom" states to virtual magnons in an antiferromagnetic AFM embedding. The composite Cooper pairs emerge as the interaction particles for virtual magnons mediated "self-coherent entanglement" of super-atom states. A H\"uckel type resonating valence bond RVB formalism is employed in order to illustrate the real-space Cooper pairs as well as their delocalization and Bose Einstein condensation BEC on a ring of super-atoms. The chemical potential \mu(BEC) for Cooper pairs joining the condensate is formulated in terms of the super-exchange interaction, and consequently the TC in terms of the Ne\'el temperature. A rationale for the robustness of the HTSC ground state is proposed: achieving local maximum "electron correlation entropy" at the expense of non-local phase rigidity.Comment: 25 pages, 2 figures. arXiv admin note: substantial text overlap with arXiv:1007.411

Risk factors for accommodative esotropia among hypermetropic children

PURPOSE. Identification of risk factors for accommodative esotropia may help to determine which children with hyperopia may benefit from early spectacle correction or preventive therapy. METHODS. Participants in the family history study were 95 consecutive patients, aged 18 to 60 months, with accommodative esotropia. Participants in the binocular sensory function study were a subgroup of 41 children enrolled in the family history study within 1 month of onset, while the esodeviation was still intermittent. Participants in the hypermetropia study were 345 consecutive patients, ages 12 months to 8 years, with refractive error of ϩ2.00 D or greater and no esodeviation before age 12 months. RESULTS. In the family history study, 23% of children with accommodative esotropia had an affected first-degree relative, and 91% had at least one affected relative. In the binocular sensory function study, random-dot stereoacuity was abnormal in 41% of children, whereas an abnormal motion VEP, Worth 4-dot, or positive 4-PD base-out prism responses were present in 4% or less of the children. In the hypermetropia study, patients with a mean spherical equivalent of Ͻ ϩ3.00 D and significant anisometropia had a 7.8-fold increased risk for accommodative esotropia over nonanisometropic patients. CONCLUSIONS. A positive family history, subnormal random-dot stereopsis, and hypermetropic anisometropia each pose a significant risk for the development of accommodative esotropia. Assessment of these risk factors in conjunction with refractive screening should help to identify those children who are most likely to benefit from early spectacle correction or preventive treatment. (Invest Ophthalmol Vis Sci. 2005;46:526 -529

Safety Assessment of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa: The 4-Year DHAX Trial

Citation: Hughbanks-Wheaton DK, Birch DG, Fish GE, et al. Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial. Invest Ophthalmol Vis Sci. 2014;55:4958-4966. DOI: 10.1167/iovs.14-14437 PURPOSE. Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks. METHODS. Males (n ¼ 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA ¼ 33; placebo ¼ 27) adhered to the protocol ‡ 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment-emergent adverse events including blood chemistry metabolites were recorded. RESULTS. By year 4, supplementation elevated plasma and red blood cell-DHA 4.4-and 3.6-fold, respectively, compared with the placebo group (P < 0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P > 0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort. CONCLUSIONS. Long-term, high-dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances. (ClinicalTrials.gov number, NCT00100230.) Keywords: biosafety, fatty acids, adverse events R etinitis pigmentosa (RP) is a retinal degenerative disease characterized by night blindness and visual field constriction 1 with four underlying inheritance patterns. The X-linked form of RP (XLRP) is among the most severe with night blindness often detectable by age 5 years 2-4 and legal blindness by the second or third decade. Gene defects are known to cause retinal degeneration, yet factors such as environment, diet, stress, and/or metabolism may modify disease severity. Many patients with RP have lower plasma and red blood cell (RBC) levels of the n3 polyunsaturated fatty acid docosahexaenoic acid (DHA; 22:6n3) than normally-sighted controls. 5 Blood DHA was significantly correlated with age-adjusted ERG responses in XLRP such that patients with lower RBC-DHA tended to have lower ERG amplitudes. 6 These findings were similarly documented in approximately 70% of female XLRP carriers (Hoffman DR, et al. IOVS 1998;39:ARVO Abstract 725). A reduction in DHA biosynthesis was demonstrated in XLRP using stable isotopes to assess in vivo metabolism 7 suggesting that downregulation of hepatic D 5 desaturase may contribute to subnormal blood DHA levels. Thus, daily supplementation with DHA may bypass any decrease in DHA biosynthesis. Docosahexaenoic acid comprises 1% to 5% of membrane fatty acids in most human tissues; however, it is the most abundant fatty acid in the retina. 8 This n3 fatty acid can increase membrane fluidity and modify the mobility of vital proteins and activities of retinal enzymes, 9,10 promote photoreceptor differentiation, 11 and antiapoptotic activity. 12 The highly unsaturated nature of DHA makes it a potential target for free radical oxidative damage. Increased polyunsaturated fatty acid (PUFA) intake, particularly long-chain PUFAs (LCPUFAs; >18 carbons), may lead to elevated oxidative stress and subsequent membrane damage. 15 Numerous n3-supplementation studies report elevations in low-and highdensity lipoprotein (LDL and HDL)-cholesterol

Genomic rearrangements of the PRPF31 gene account for

PURPOSE. To determine whether genomic rearrangements in the PRPF31 (RP11) gene are a frequent cause of autosomal dominant retinitis pigmentosa (adRP) in a cohort of patients with adRP. METHODS. In a cohort of 200 families with adRP, disease-causing mutations have previously been identified in 107 families. To determine the cause of disease in the remaining families, linkage testing was performed with markers for 13 known adRP loci. In a large American family, evidence was found of linkage to the PRPF31 gene, although DNA sequencing revealed no mutations. SNP testing throughout the genomic region was used to determine whether any part of the gene was deleted. Aberrant segregation of a SNP near exon 1 was observed, leading to the testing of additional SNPs in the region. After identifying an insertion-deletion mutation, the remaining 92 families were screened for genomic rearrangements in PRPF31 with multiplex ligation-dependent probe amplification (MLPA). RESULTS. Five unique rearrangements were identified in the 93 families tested. In the large family used for linkage exclusion testing, an insertion-deletion was found that disrupts exon 1. The other four mutations identified in the cohort were deletions, ranging from 5 kb to greater than 45 kb. Two of the large deletions encompass all PRPF31 as well as several adjacent genes. The two smaller deletions involve either 5 or 10 completely deleted exons. CONCLUSIONS. In an earlier long-term study of 200 families with adRP, disease-causing mutations were identified in 53% of the families. Mutation-testing by sequencing missed large-scale genomic rearrangements such as insertions or deletions. MLPA was used to identify genomic rearrangements in PRPF31 in five families, suggesting a frequency of approximately 2.5%. Mutations in PRPF31 now account for 8% of this adRP cohort

A germanate transparent conductive oxide

Wide bandgap conductors such as In2O3 and ZnO are used as transparent conducting oxides (TCOs). To date, TCOs are realized using post transition metal cations with largely spread s-orbitals such as In3+, Sn4+, Zn2+ and Cd2+. On the other hand, no good electronic conductor has been realized in oxides of Al, Si and Ge. Here we report the conversion of an oxide of Ge into a good electronic conductor by employing the concept of superdegeneracy. We find that cubic SrGeO3, synthesized under high pressure, displays a direct bandgap of 3.5 eV, a carrier mobility of 12 cm2(Vs)−1, and conductivities of 3 Scm−1 (DC) and 400 Scm−1 (optical conductivity). This is the first Ge-based electronic conductive oxide, and expands the family of TCOs from ionic oxides to covalent oxides