The relationship between CFH and ARMS2 genotypes and neuroretinal function in persons without age-related macular degeneration

Purpose: To determine whether neuroretinal function differs in healthy persons with and without common risk gene variants for age- related macular degeneration (AMD) and no ophthalmoscopic signs of AMD, and to compare those findings in persons with manifest early AMD. Methods and Participants: Neuroretinal function was assessed with the multifocal electroretinogram (mfERG) (VERIS, Redwood City, CA,) in 32 participants (22 healthy persons with no clinical signs of AMD and 10 early AMD patients). The 22 healthy participants with no AMD were risk genotypes for either the CFH (rs380390) and/or ARMS2 (rs10490920). We used a slow flash mfERG paradigm (3 inserted frames) and a 103 hexagon stimulus array. Recordings were made with DTL electrodes; fixation and eye movements were monitored online. Trough N1 to peak P1 (N1P1) response densities and P1-implicit times (IT) were analysed in 5 concentric rings. Results: N1P1 response densities (mean ± SD) for concentric rings 1-3 were on average significantly higher in at-risk genotypes (ring 1: 17.97 nV/deg2 ± 1.9, ring 2: 11.7 nV/deg2 ±1.3, ring 3: 8.7 nV/deg2 ± 0.7) compared to those without risk (ring 1: 13.7 nV/deg2 ± 1.9, ring 2: 9.2 nV/deg2 ±0.8, ring 3: 7.3 nV/deg2 ± 1.1) and compared to persons with early AMD (ring 1: 15.3 nV/deg2 ± 4.8, ring 2: 9.1 nV/deg2 ±2.3, ring 3 nV/deg2: 7.3± 1.3) (p<0.5). The group implicit times, P1-ITs for ring 1 were on average delayed in the early AMD patients (36.4 ms ± 1.0) compared to healthy participants with (35.1 ms ± 1.1) or without risk genotypes (34.8 ms ±1.3), although these differences were not significant. Conclusion: Neuroretinal function in persons with normal fundi can be differentiated into subgroups based on their genetics. Increased neuroretinal activity in persons who carry AMD risk genotypes may be due to genetically determined subclinical inflammatory and/or histological changes in the retina. Assessment of neuroretinal function in healthy persons genetically susceptible to AMD may be a useful early biomarker before there is clinical manifestation of AMD.

Morphometry and abnormalities of the feet of Kaimanawa feral horses in New Zealand

Objective: The present study investigated the foot health of the Kaimanawa feral horse population and tested the hypotheses that horses would have a large range of foot morphology and that the incidence of foot abnormality would be significantly high. Procedures: Abnormality was defined as a variation from what the two veterinarian assessors considered as optimal morphology and which was considered to impact negatively on the structure and/or function of the foot. Fifteen morphometric variables were measured on four calibrated photographic views of all four feet of 20 adult Kaimanawa feral horses. Four morphometric variables were measured from the lateromedial radiographs of the left forefoot of each horse. In addition, the study identified the incidence of gross abnormality observed on the photographs and radiographs of all 80 feet. Results: There was a large variation between horses in the morphometric dimensions, indicating an inconsistent foot type. Mean hoof variables were outside the normal range recommended by veterinarians and hoof care providers; 35% of all feet had a long toe conformation and 15% had a mediolateral imbalance. Abnormalities included lateral (85% of horses) and dorsal (90% of horses) wall flares, presence of laminar rings (80% of horses) and bull-nose tip of the distal phalanx (75% of horses). Both hypotheses were therefore accepted. Conclusions: The Kaimanawa feral horse population demonstrated a broad range of foot abnormalities and we propose that one reason for the questionable foot health and conformation is lack of abrasive wearing by the environment. In comparison with other feral horse populations in Australia and America there may be less pressure on the natural selection of the foot of the Kaimanawa horses by the forgiving environment of the Kaimanawa Ranges. Contrary to popular belief, the feral horse foot type should not be used as an ideal model for the domestic horse foot.

Proton-transfer compounds with 4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (sulfamethazine): the structures and hydrogen-bonding in the salts with 5-nitrosalicylic acid and picric acid

The structures of the anhydrous proton-transfer compounds of the sulfa drug sulfamethazine with 5-nitrosalicylic acid and picric acid, namely 2-(4-aminobenzenesulfonamido)-4,6-dimethylpyrimidinium 2-hydroxy-5-nitrobenzoate, C12H15N4O2S(+)·C7H4NO4(-), (I), and 2-(4-aminobenzenesulfonamido)-4,6-dimethylpyrimidinium 2,4,6-trinitrophenolate, C12H15N4O2S(+)·C6H2N3O7(-), (II), respectively, have been determined. In the asymmetric unit of (I), there are two independent but conformationally similar cation-anion heterodimer pairs which are formed through duplex intermolecular N(+)-H...Ocarboxylate and N-H...Ocarboxylate hydrogen-bond pairs, giving a cyclic motif [graph set R2(2)(8)]. These heterodimers form separate and different non-associated substructures through aniline N-H...O hydrogen bonds, one one-dimensional, involving carboxylate O-atom acceptors, the other two-dimensional, involving both carboxylate and hydroxy O-atom acceptors. The overall two-dimensional structure is stabilized by π-π interactions between the pyrimidinium ring and the 5-nitrosalicylate ring in both heterodimers [minimum ring-centroid separation = 3.4580 (8) Å]. For picrate (II), the cation-anion interaction involves a slightly asymmetric chelating N-H...O R2(1)(6) hydrogen-bonding association with the phenolate O atom, together with peripheral conjoint R1(2)(6) interactions between the same N-H groups and O atoms of the ortho-related nitro groups. An inter-unit amine N-H...Osulfone hydrogen bond gives one-dimensional chains which extend along a and inter-associate through π-π interactions between the pyrimidinium rings [centroid-centroid separation = 3.4752 (9) Å]. The two structures reported here now bring to a total of four the crystallographically characterized examples of proton-transfer salts of sulfamethazine with strong organic acids.

Thermal analysis and vibrational spectroscopic characterization of the boro silicate mineral datolite – CaBSiO4(OH)

The objective of this work is to determine the thermal stability and vibrational spectra of datolite CaBSiO4(OH) and relate these properties to the structure of the mineral. The thermal analysis of datolite shows a mass loss of 5.83% over a 700–775 °C temperature range. This mass loss corresponds to 1 water (H2O) molecules pfu. A quantitative chemical analysis using electron probe was undertaken. The Raman spectrum of datolite is characterized by bands at 917 and 1077 cm−1 assigned to the symmetric stretching modes of BO and SiO tetrahedra. A very intense Raman band is observed at 3498 cm−1 assigned to the stretching vibration of the OH units in the structure of datolite. BOH out-of-plane vibrations are characterized by the infrared band at 782 cm−1. The vibrational spectra are based upon the structure of datolite based on sheets of four- and eight-membered rings of alternating SiO4 and BO3(OH) tetrahedra with the sheets bonded together by calcium atoms.

Molecular cocrystals of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine: hydrogen bonding in the structures of the 1:1 adduct with 2-(naphthalen-2-yloxy)acetic acid and the salt with 3,5-dinitrobenzoic acid

The structures of the anhydrous products from the interaction of 2-amino-5-(4-bromophenyl)-1,3,4-thiadiazole with (2-naphthoxy)acetic acid, the 1:1 adduct C8H6BrN3S . C12H10O3 (I) and 3,5-dinitrobenzoic acid, the salt C8H7BrN3S+ C7H3N2O6- (II) have been determined. In the adduct (I), a heterodimer is formed through a cyclic hydrogen-bonding motif [graph set R2/2(8)], involving carboxylic acid O-H...N(hetero)and amine N-H...O(carboxyl) interactions. The heterodimers are essentially planar with a thiadiazole to naphthyl ring dihedral angle of 15.9(2)deg. and the intramolecular thiadiazole to phenyl ring angle of 4.7(2)deg. An amine N-H...N(hetero) hydrogen bond between the heterodimers generates a one-dimensional chain structure extending down [001]. Also present are weak benzene-benzene and naphthalene-naphthalene pi-pi stacking interactions down the b axis [minimum ring centroid separation, 3.936(3) Ang.]. With the salt (II), the cation-anion association is also through a cyclic R2/2(8) motif but involving duplex N-H...O(carboxyl) hydrogen bonds, giving a heterodimer which is close to planar [dihedral angles between the thiadiazole ring and the two benzene rings, 5.00(16)deg. (intra) and 7.23(15)deg. (inter)]. A secondary centrosymmetric cyclic N-H...O(carboxyl) hydrogen-bonding association involving the second amino H-atom generates a heterotetramer. Also present in the crystal are weak pi-pi i-\p interactions between thiadiazolium rings [minimum ring centroid separation, 3.936(3)Ang.], as well as a short Br...O(nitro) interaction [3.314(4)Ang.]. The two structures reported here now provide a total of three crystallographically characterized examples of co-crystalline products from the interaction of 2-amino-5-(4-bromophenyl)-1,3,4-thiadiazole with carboxylic acids, of which only one involves proton-transfer.

Cone Ratios in Myopia and Emmetropia: A Pilot Study

Purpose There is a suggestion that the long wavelength-sensitive (LWS)-to-middle wavelength-sensitive (MWS) cone ratio in the retina is associated with myopia. The aim was to measure the LWS/MWS amplitude modulation ratio, an estimate of the LWS/MWS cone ratio, in young adult emmetropes and myopes. Methods Multifocal visual evoked potentials were measured when the LWS and MWS cone systems were excited separately using the method of silent substitution. The 30 young adult participants (22 to 33 years) included 10 emmetropes (mean [±SD] refraction, +0.3 [±0.4] diopters [D]) and 20 myopes (mean [±SD] refraction, -3.4 [±1.7] D). Results The LWS/MWS amplitude modulation ratios ranged from 0.56 to 1.80 in the central 3- to 13-degree diameter ring and from 0.94 to 1.91 in the peripheral 13- to 30-degree diameter ring. Within the central ring, the mean (±SD) ratios were 1.20 (±0.26) and 1.20 (±0.33) for the emmetropic and the myopic groups, respectively. For the peripheral ring, the mean (±SD) ratios were 1.48 (±0.27) and 1.30 (±0.27), respectively. There were no significant differences in the ratios between the emmetropic and myopic groups for either the central (p = 0.99) or peripheral (p = 0.08) rings. For the latter, more myopic refractive error was associated with lower LWS/MWS amplitude modulation ratio; the refraction explained 16% (p = 0.02) of variation in ratio. Conclusions The relationship between the LWS/MWS amplitude modulation ratios and refraction at 13 to 30 degrees indicates that a large longitudinal study of changes in refraction in persons with known cone ratio is required to determine if a low LWS/MWS cone ratio is associated with myopia development.

Crystal structures of the co-crystalline adduct 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine--4-nitrobenzoic acid (1/1) and the salt 2-amino-5-(4-bromophenyl)-1,3,4-thiadiazol-3-ium 2-carboxy-4,6-dinitrophenolate

The structures of the 1:1 co-crystalline adduct C8H6BrN3S . C7H5NO4 (I) and the salt C8H7BrN3S+ C7H3N2O7- (II) from the interaction of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine with 4-nitrobenzoic acid and 3,5-dinitrosalicylic acid, respectively, have been determined. The primary inter-species association in both (I) and (II) is through duplex R2/2(8) (N-H...O/O-H...O) or (N-H...O/N-H...O) hydrogen bonds, respectively, giving heterodimers. In (II), these are close to planar [dihedral angles between the thiadiazole ring and the two phenyl rings are 2.1(3)deg. (intra) and 9.8(2)deg. (inter)], while in (I) these angles are 22.11(15) and 26.08(18)deg., respectively. In the crystal of (I), the heterodimers are extended into a one-dimensional chain along b through an amine N-...N(thiadiazole) hydrogen bond but in (II), a centrosymmetric cyclic heterotetramer structure is generated through N-H...O hydrogen bonds to phenol and nitro O-atom acceptors and features, together with the primary R2/2(8) interaction, conjoined R4/6(12), R2/1(6) and S(6) ring motifs. Also present in (I) are pi--pi interactions between thiadiazole rings [minimum ring centroid separation, 3.4624(16)deg.] as well as short Br...O(nitro) interactions in both (I) and (II) [3.296(3)A and 3.104(3)A, respectively].

Crystal structures and hydrogen bonding in the proton transfer salts of nicotine with 3,5-dinitrosalicylic acid and 5-sulfosalicylic acid

The structures of the 1:1 anhydrous salts of nicotine (NIC) with 3,5-dinitrosalicylic acid (DNSA) and 5-sulfosalicylic acid (5-SSA), namely (1R,2S)-1-methyl-2-(3-pyridyl)-1H-pyrrolidin-1-ium 2-carboxy-4,6-dinitrophenolate, C10H15N2+ C7H3N2O7-, (I) and (1R,2S)-1-methyl-2-(3-pyridyl)-1H-pyrrolidin-1-ium 3-carboxy-4-hydroxybenzenesulfonate, C10H15N2+ C7H5O6S-, (II) are reported. The asymmetric units of both (I) and (II) comprise two independent nicotinium cations (C and D) and either two DNSA or two 5-SSA anions (A and B), respectively. One of the DNSA anions shows a 25% rotational disorder in the benzene ring system. In the crystal of (I), inter-unit pyrrolidinium N-H...N(pyridine) hydrogen bonds generate zigzag NIC cation chains which extend along a while the DNSA anions are not involved in any formal inter-species hydrogen bonding but instead form pi--pi associated stacks which parallel the NIC chains along a [ring centroid separation, 3.857(2)A]. Weak C-H...O interactions between chain substructures give an overall three-dimensional structure. With (II), A and B anions form independent zigzag chains with C and D cations, respectively, through carboxylic acid O-H...N(pyridine) hydrogen bonds. These chains, which extend along b are pseudo-centrosymmetrically related and give pi--pi interactions between the benzene rings of anions A and B and the pyridine rings of the NIC cations C and D, respectively [ring centroid separations, 3.6422(19) and 3.7117(19)A]. Present also are weak intermolecular C-H...O hydrogen-bonding interactions between the chains, giving an overall three-dimensional structure.

Two-dimensional hydrogen-bonded polymers in the crystal structures of the ammonium salts of phenoxyacetic acid, (4-fluorophenoxy)acetic acid and (4-chloro-2-methylphenoxy)acetic acid

The structures of the ammonium salts of phenoxyacetic acid, NH4+ C8H6O3- (I), (4-fluorophenoxy)acetic acid NH4+ C8H5FO3- (II) and the herbicidally active (4-chloro-2-methylphenoxy)acetic acid (MCPA), NH4+ C9H8ClO3-. 0.5(H2O) (III) have been determined. All have two-dimensional layered structures based on inter-species ammonium N-H...O hydrogen-bonding associations which give core substructures consisting primarily of conjoined cyclic motifs. Crystals of (I) and (II) are isomorphous with the core comprising R2/1(5), R2/1(4) and centrosymmetric R2/4(8) ring motifs, giving two-dimensional layers lying parallel to (100). In (III), the water molecule of solvation lies on a crystallographic twofold rotation axis and bridges two carboxyl O-atoms in an R4/4(12) hydrogen-bonded motif, creating two R3/4(10) rings which together with a conjoined centrosymmetric R2/4(8) ring incorporating both ammonium cations, generate two-dimensional layers lying parallel to (100). No pi-pi ring associations are present in any of the structures.

Multimodal imaging of the collagen and elastic fibre networks in the bovine intervertebral disc

INTRODUCTION. The intervertebral disc is the largest avascular structure in the human body, withstanding transient loads of up to nine times body weight during rigorous physical activity. The key structural elements of the disc are a gel-like nucleus pulposus surrounded by concentric lamellar rings containing criss-crossed collagen fibres. The disc also contains an elastic fiber network which has been suggested to play a structural role, but to date the relationship between the collagen and elastic fiber networks is unclear. CONCLUSION. The multimodal transmitted and reflected polarized light microscopy technique developed here allows clear differentiation between the collagen and elastic fiber networks of the intervertebral disc. The ability to image unstained specimens avoids concerns with uneven stain penetration or specificity of staining. In bovine tail discs, the elastic fiber network is intimately associated with the collagen network.

Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides

The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, −OCl) generated by the myeloperoxidase (MPO)–H2O2–Cl− system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79–86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89–99% decreased rate of reduction) and activated human neutrophils (62–75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.

Study on tracheal collapsibility, compliance, and stress by considering nonlinear mechanical property of cartilage

Tracheal cartilage has been widely regarded as a linear elastic material either in experimental studies or in analytic and numerical models. However, it has been recently demonstrated that, like other fiber-oriented biological tissues, tracheal cartilage is a nonlinear material, which displays higher strength in compression than in extension. Considering the nonlinearity requires a more complex theoretical frame work and costs more to simulate. This study aims to quantify the deviation due to the simplified treatment of the tracheal cartilage as a linear material. It also evaluates the improved accuracy gained by considering the nonlinearity. Pig tracheal rings were used to exam the mechanical properties of cartilage and muscular membrane. By taking into account the asymmetric shape of tracheal cartilage, the collapse behavior of complete rings was simulated, and the compliance of airway and stress in the muscular membrane were discussed. The results obtained were compared with those assuming linear mechanical properties. The following results were found: (1) Models based on both types of material properties give a small difference in representing collapse behavior; (2) regarding compliance, the relative difference is big, ranging from 10 to 40% under negative pressure conditions; and (3) the difference in determining stress in the muscular membrane is small too: <5%. In conclusion, treating tracheal cartilage as a linear material will not cause big deviations in representing the collapse behavior, and mechanical stress in the muscular part, but it will induce a big deviation in predicting the compliance, particularly when the transmural pressure is lower than -0.5 kPa. The results obtained in this study may be useful in both understanding the collapse behavior of trachea and in evaluating the error induced by the simplification of treating the tracheal cartilage as a linear elastic material.