Genetic polymorphisms of the N-acetyltransferase genes and risk of Parkinson's disease.

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals).

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Crystal engineering in the gem-alkynol family: the key role of water in the structure of 2,3,5,6-tetrabromo-trans-1,4-diethynyl-cyclohexa-2,5-diene-1,4-diol dihydrate determined by X-ray and neutron diffraction at 150 K.

The structure of the title compound has been determined using low-temperature (150 K) single-crystal X-ray and neutron diffraction data. Crystals adopt the uncommon space group P4(2)/ncm and display a complex set of intermolecular interactions in which the water molecules play the crucial role: the water O-atom [O2(w)] accepts two hydrogen bonds and both water H atoms act as bifurcated donors. A set of O--H...O hydrogen bonds is formed around the 4(2) axis comprising (a) a cyclic tetrameric synthon involving four donor-H from two water molecules and two O(hydroxy) acceptors from two parent molecules, and (b) short discrete O(hydroxy)--H...O2(w) hydrogen bonds which link these tetramers along the c axis. Four Br...Br interactions [3.708 (1) A] form cyclic Br(4) tetramers around the 4 axis and are linked to the O--H...O system via O2(w)--H...Br bonds with H...Br = 2.995 (2) A. Finally, the O--H...O system is further linked to the parent molecules via C identical with C...H...O2(w) bonds of 2.354 (3) A. The supramolecular structure of the title hydrate is compared with that of the non-hydrated parent molecule, which also forms cyclic O--H...O bonded tetrameric synthons, and with its (non-hydrated) tetrachloro analogue, which forms cyclic tetrameric Cl(4) synthons [Madhavi, Desiraju et al. (2000b). Acta Cryst. B56, 1063--1070].

General method for the description, visualization and comparison of metal coordination spheres: geometrical preferences, deformations and interconversion pathways.

The coordination sphere geometry of metal atoms (M) in their complexes with organic and inorganic ligands (L) is often compared with the geometry of archetypal forms for the appropriate coordination number, n in ML(n) species, by use of the k = n( n- 1)/2 L-M-L valence angles subtended at the metal centre. Here, a Euclidean dissimilarity metric, R(c)(x), is introduced as a one-dimensional comparator of these k-dimensional valence-angle spaces. The computational procedure for R(c)(x), where x is an appropriate archetypal form (e.g. an octahedron in ML(6) species), takes account of the atomic permutational symmetry inherent in ML(n) systems when no distinction is made between the individual ligand atoms. It is this permutational symmetry, of order n!, that precludes the routine application of multivariate analytical techniques, such as principal component analysis (PCA), to valence angle data for all but the lowest metal coordination numbers. It is shown that histograms of R(c)(x) values and, particularly, scatterplots of R(c)(x) values computed with respect to two or more different appropriate archetypal forms (e.g. tetrahedral and square-planar four-coordinations), provide information-rich visualizations of the observed geometrical preferences of metal coordination spheres retrieved from, e.g. the Cambridge Structural Database. These mappings reveal the highly populated clusters of similar geometries, together with the pathways that map their geometrical interconversions. Application of R(c)(x) analysis to the geometry of four- and seven-coordination spheres provides information that is at least comparable to, and in some cases is more complete than, that obtained by PCA.

4-Ethynyl-4-hydroxycyclohexan-1-one and 4-ethynyl-4-hydroxy-2,3,5, 6-tetramethylcyclohexa-2,5-dien-1-one.

The title compounds, C(8)H(10)O(2), (I), and C(12)H(14)O(2), (II), occurred as by-products in the controlled synthesis of a series of bis(gem-alkynols), prepared as part of an extensive study of synthon formation in simple gem-alkynol derivatives. The two 4-(gem-alkynol)-1-ones crystallize in space group P2(1)/c, (I) with Z' = 1 and (II) with Z' = 2. Both structures are dominated by O-H. O=C hydrogen bonds, which form simple chains in the cyclohexane derivative, (I), and centrosymmetric dimers, of both symmetry-independent molecules, in the cyclohexa-2,5-diene, (II). These strong synthons are further stabilized by C[triple-bond]C-H. O=C, C(methylene)-H.O(H) and C(methyl)-H.O(H) interactions. The direct intermolecular interactions between donors and acceptors in the gem-alkynol group, which characterize the bis(gem-alkynol) analogues of (I) and (II), are not present in the ketone derivatives studied here.

Racemic 1,2-diphenylbut-3-yn-2-ol.

Molecules of the title compound, C(16)H(14)O, are chiral and crystallize in space group P-4 with Z' = 2, and with one R and one S molecule in the asymmetric unit. The conformations of the phenyl rings in the two independent molecules differ slightly. Supramolecular organization in the crystal is via tetrameric O-H. H(O) hydrogen-bonded synthons formed separately by each conformer. These tetrameric synthons stack along the c axis via C[triple-bond]C-H.O(H) hydrogen bonds. The only link between the conformer stacks is provided by weaker C(methylene)-H and C(phenyl)-H interactions with pi(arene) density.

Intramolecular hydrogen bonds: common motifs, probabilities of formation and implications for supramolecular organization.

A systematic survey of the Cambridge Structural Database (CSD) has identified all intramolecular hydrogen-bonded ring motifs comprising less than 20 atoms with N and O donors and acceptors. The probabilities of formation P(m) of the 50 most common motifs, which chiefly comprise five- and six-membered rings, have been derived by considering the number of intramolecular motifs which could possibly form. The most probable motifs (P(m) > 85%) are planar conjugated six-membered rings with a propensity for resonance-assisted hydrogen bonding and these form the shortest contacts, whilst saturated six-membered rings typically have P(m) < 10%. The influence of intramolecular-motif formation on intermolecular hydrogen-bond formation has been assessed for a planar conjugated model substructure, showing that a donor-H is considerably less likely to form an intermolecular bond if it forms an intramolecular one. On the other hand, the involvement of a carbonyl acceptor in an intramolecular bond does not significantly affect its ability to act as an intermolecular acceptor and thus carbonyl acceptors display a substantially higher inclination for bifurcation if one hydrogen bond is intramolecular.

Graph-set and packing analysis of hydrogen-bonded networks in polyamide structures in the Cambridge Structural Database.

The hydrogen-bond networks and crystal packing of 81 unique secondary di- and polyamides in the Cambridge Structural Database are investigated. Graph-set analysis, as implemented in the RPluto program, is used to classify network motifs. These have been rationalized in terms of the relative dispositions of the amide groups. Peptide and retropeptides exhibit significant conformational flexibility, which permits alternative hydrogen-bonding patterns. In peptides, dihedral angles of -psi approximately varphi approximately 105 degrees allow an antiparallel ladder arrangement, containing rings of either the same or alternating sizes. For retropeptides, and diamides with an odd number of CH(2) spacers, this conformation leads to a parallel ladder with rings of equal size. If varphi approaches -60 degrees and psi 180 degrees, ladders adopt a helical twist, and if the conformation is distorted further, a three-dimensional network is usually adopted. Diamides with aromatic or an even number of CH(2) spacers generally form either antiparallel ladders or sheets, although some exhibit both polymorphs. Symmetry relationships within and between hydrogen-bonded chains, ladders and sheets in the crystal packing have also been analysed. Polyamides form considerably more complex networks, although many of the structural motifs present in the diamides occur as components of these networks.

Physical growth, sexual maturation, body image and sickle cell disease.

PURPOSE: This study assessed delays in physical growth and sexual maturation, self-esteem and body image in youth with homozygous sickle hemoglobin disease (HgbSS). METHOD: A consecutive sample of 30 subjects age 8 through 19 with homozygous sickle cell disease (hemoglobin SS) and a similar number of control subjects matched for age, race, gender and socioeconomic status and free of chronic illness were examined for height, weight and Tanner staging of sexual development. Subjects also completed the Body Cathexis Scale and Piers-Harris Self-Concept Scale. Assessments were with paired samples t-tests. RESULTS: The subjects with sickle cell disease had significantly lower weights and were shorter than matched control subjects. Sexual development (physical) was also delayed in the sickle cell subjects. The study failed to find significant differences for either body image or self-esteem. CONCLUSIONS: The latency age and adolescent subjects with sickle cell disease had significant delays in physical (height, weight, secondary sexual characteristics) maturation. The study failed to find significant differences in either self-esteem or body image between the two groups. Theoretical constructs from the literature were presented which questioned the belief that these expected delays in physical growth and sexual maturation have an adverse effect upon self-esteem and body image.

Carbonyl-carbonyl interactions stabilize the partially allowed Ramachandran conformations of asparagine and aspartic acid.

Asparagine and aspartate are known to adopt conformations in the left-handed alpha-helical region and other partially allowed regions of the Ramachandran plot more readily than any other non-glycyl amino acids. The reason for this preference has not been established. An examination of the local environments of asparagine and aspartic acid in protein structures with a resolution better than 1.5 A revealed that their side-chain carbonyls are frequently within 4 A of their own backbone carbonyl or the backbone carbonyl of the previous residue. Calculations using protein structures with a resolution better than 1.8 A reveal that this close contact occurs in more than 80% of cases. This carbonyl-carbonyl interaction offers an energetic sabilization for the partially allowed conformations of asparagine and aspartic acid with respect to all other non-glycyl amino acids. The non-covalent attractive interactions between the dipoles of two carbonyls has recently been calculated to have an energy comparable to that of a hydrogen bond. The preponderance of asparagine in the left-handed alpha-helical region, and in general of aspartic acid and asparagine in the partially allowed regions of the Ramachandran plot, may be a consequence of this carbonyl-carbonyl stacking interaction.

Deep vein thrombi associated with the use of plastic ankle-foot orthoses.

Deep vein thrombosis (DVT) is a well-known complication of neurologic disorders that result in immobility, such as stroke and spinal cord injury. There is little information available, however, regarding the association of DVT with orthotic devices commonly used in this patient population. We report an unusual case in which lesser saphenous vein DVTs were associated with the use of plastic ankle-foot orthoses (PAFOs) in a patient with chronic inflammatory demyelinating polyradiculoneuropathy treated with plasmaphoresis and intravenous Ig. The possible role of PAFOs in the development of the DVTs, as well as other contributing factors such as plasmaphoresis, is discussed. The need for posthospitalization DVT prophylaxis in patients with paralysis is reviewed.

Comparison of conformer distributions in the crystalline state with conformational energies calculated by ab initio techniques.

The conformational preferences of 12 molecular substructures in the crystalline state have been determined and compared with those predicted for relevant model compounds by ab initio molecular orbital calculations. Least-squares regression shows that there is a statistically significant correlation between the crystal-structure conformer distributions and the calculated potential-energy differences, even though the calculations relate to a gas-phase environment. Torsion angles associated with high strain energy (> 1 kcal mol-1) appear to be very unusual in crystal structures and, in general, high-energy conformers are underrepresented in crystal structures compared with a gas-phase, room-temperature Boltzmann distribution. It is concluded that crystal packing effects rarely have a strong systematic effect on molecular conformations. Therefore, the conformational distribution of a molecular substructure in a series of related crystal structures is likely to be a good guide to the corresponding gas-phase potential energy surface.

Emergency treatment of status epilepticus.

Status epilepticus occurs in more than 50,000 people in the United States each year and should be considered a neurologic emergency. A variety of drugs are used to treat status epilepticus, including i.v. benzodiazepines, phenytoin, and barbiturates. They are all short of being ideal, primarily because of difficulties with administration or associated toxicity. Fosphenytoin, a prodrug and phosphate ester of phenytoin, was developed to overcome the drawbacks associated with i.v. phenytoin. With its efficacy, safety, and ease of administration, fosphenytoin is a valuable option for the treatment of status epilepticus.

Shape information from a critical point analysis of calculated electron density maps: application to DNA-drug systems.

A computational method is described for mapping the volume within the DNA double helix accessible to the groove-binding antibiotic netropsin. Topological critical point analysis is used to locate maxima in electron density maps reconstructed from crystallographically determined atomic coordinates. The peaks obtained in this way are represented as ellipsoids with axes related to local curvature of the electron density function. Combining the ellipsoids produces a single electron density function which can be probed to estimate effective volumes of the interacting species. Close complementarity between host and ligand in this example shows the method to give a good representation of the electron density function at various resolutions. At the atomic level, the ellipsoid method gives results which are in close agreement with those from the conventional spherical van der Waals approach.

Molecular scene analysis: application of a topological approach to the automated interpretation of protein electron-density maps.

Methods to assist in the spatial and visual analysis of electron-density maps have been investigated as part of a project in molecular scene analysis [Fortier, Castleden, Glasgow, Conklin, Walmsley, Leherte & Allen (1993). Acta Cryst. D49, 168-178]. In particular, the usefulness of the topological approach for the segmentation of medium-resolution (3 A) maps of proteins and their interpretation in terms of structural motifs has been assessed. The approach followed is that proposed by Johnson [Johnson (1977). ORCRIT. The Oak Ridge Critical Point Network Program. Chemistry Division, Oak Ridge National Laboratory, USA] which provides a global representation of the electron-density distribution through the location, identification and linkage of its critical points. In the first part of the study, the topological approach was applied to calculated maps of three proteins of small to medium size so as to develop a methodology that could then be used for analyzing maps of medium resolution. The methodology was then applied to both calculated and experimental maps of penicillopepsin at 3 A resolution. The study shows that the networks of critical points can provide a useful segmentation of the maps, tracing the protein main chains and capturing their conformation. In addition, these networks can be parsed in terms of secondary-structure motifs, through a geometrical analysis of the critical points. The procedure adopted for secondary-structure recognition, which was phrased in terms of geometry-based rules, provides a basis for a further automated implementation of a more complete set of recognition operations through the use of artificial-intelligence techniques.