Stillinger-Weber potential for elastic and fracture properties in graphene and carbon nanotubes.

This paper presents a new framework for determining the Stillinger-Weber (SW) potential parameters for modeling fracture in graphene and carbon nanotubes. In addition to fitting the equilibrium material properties, the approach allows fitting the potential to the forcing behavior as well as the mechanical strength of the solid, without requiring ad hoc modification of the nearest-neighbor interactions for avoiding artificial stiffening of the lattice at larger deformation. Consistent with the first-principles results, the potential shows the Young's modulus of graphene to be isotropic under symmetry-preserving and symmetry-breaking deformation conditions. It also shows the Young's modulus of carbon nanotubes to be diameter-dependent under symmetry-breaking loading conditions. The potential addresses the key deficiency of existing empirical potentials in reproducing experimentally observed glass-like brittle fracture in graphene and carbon nanotubes. In simulating the entire deformation process leading to fracture, the SW-potential costs several factors less computational time compared to the state-of-the-art interatomic potentials that enables exploration of the fracture processes in large atomistic systems which are inaccessible otherwise.

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy].

OBJECTIVE: To evaluate efficacy and safety of injectable extended-release naltrexone (XR-NTX, Vivitrol), an opioid receptor antagonist, in the treatment of opioid dependence, we carried out a 1-year open-label extension study. MATERIAL AND METHODS: The study followed the initial 6-month randomized, double-blind, PBO-controlled investigation of XR-NTX, used in dose 380 mg, as a treatment for opioid dependence. The study was conducted at 13 clinical sites in Russia. The main measurements were monthly urine samples (efficacy) and adverse events (safety). RESULTS AND CONCLUSION: The open-label extension included 114 patients (67 continued on XR-NTX and 47 switched from placebo). Overall, 62.3% (95% CI: 52.7%, 71.2%) of patients completed the extension. Urine testing revealed that 50.9% (41.5%, 60.4%) were abstinent from opioids at all assessments during the 1-year open-label phase. Adverse events were reported by 21.1% of patients. Elevations in liver function tests occurred in 16.7% of patients. No severe adverse events were reported. The data obtained demonstrate the long-term safety and efficacy of XR-NTX in opioid dependent patients.

Estimation of Parkinson's disease survival in Israeli men and women, using health maintenance organization pharmacy data in a unique approach.

The aim of this work was to estimate in an incident cohort of pharmacy-based PD patients the survival of men and women accounting for age at treatment initiation and to compare their gender-specific survival with that of the general Israeli population. A population-based cohort of 4,848 incident pharmacy-based PD cases with definite/probable/possible certainty was previously identified using a drug-tracer approach for 1999-2008. Survival analysis was performed for two time scales: survival after treatment initiation (disease duration), and life-time survival (life expectancy). Kaplan-Meier curves and Cox regressions were used to compare survival across gender. Gender-specific SMRs were calculated from national rates and were compared using Poisson regression. During the follow-up from first purchase of any anti-parkinsonian drug (mean 4.0 ± 2.6 years, range 2 months-10 years), 1,266 (26 %) of the cases died. Younger age at first anti-parkinsonian drug purchase and female gender were associated with increased survival after treatment initiation (HR = 1.089, 95 % CI 1.080-1.098 for 1-year age increase; HR = 0.716, 95 % CI 0.640-0.800, females vs. males). Life-time survival increased with older age at first anti-parkinsonian drug purchase and female gender (HR = 0.759, 95 % CI 0.746-0.771 for 1-year age increase; HR = 0.694, 95 % CI 0.621-0.776, females vs. males). Sensitivity analysis on a sub-cohort of definite cases (n = 2501) yielded similar results. In comparison to the general Israeli population, mortality among pharmacy-based PD patients was significantly increased (SMR(men) = 1.69, 95 % CI 1.57-1.81, SMR(women) = 1.49, 95 % CI 1.37-1.62), differently between genders (p < 0.01). Female gender was associated with longer, perhaps more benign disease course, and longer life expectancy. Earlier age at anti-parkinsonian drug initiation increased disease duration, but was associated with shorter life expectancy.

[Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomized trial].

UNLABELLED: We aimed to assess the efficacy and safety of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. Two hundreds and fifty patients with opioid dependence were enrolled into the double-blind, placebo-controlled, randomized, 24-week trial. Patients aged 18 years or over who had inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX (n=124) or placebo (n=126). Participants also received 12 biweekly counseling sessions. The primary endpoint was the response profile for confirmed abstinence during weeks 5-24 assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid- free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. IN CONCLUSION: XR-NTX represents a new treatment option. XR-NTX in conjunction with psychosocial treatment was more effective for treatment of opioid dependence compare to psychosocial support and placebo.

Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist.

The entity described by Gunnar Stickler, which included hereditary arthro-ophthalmopathy associated with retinal detachment, has recently been recognised to consist of a number of subgroups, which might now more correctly be referred to as the Stickler syndromes. They are the most common clinical manifestation of the type II/XI collagenopathies and are the most common cause of inherited rhegmatogenous retinal detachment. This review article is intended to provide the ophthalmologist with an update on current research, subgroups, and their diagnosis together with a brief overview of allied conditions to be considered in the clinical differential diagnosis. We highlight the recently identified subgroups with a high risk of retinal detachment but with minimal or absent systemic involvement--a particularly important group for the ophthalmologist to identify.

Using molecular principal axes for structural comparison: determining the tertiary changes of a FAB antibody domain induced by antigenic binding.

BACKGROUND: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared. RESULTS: A new approach is applied to determine the structural changes that an antibody protein domain experiences upon its interaction with an antigenic target. These changes are determined with the use of two different, however comparable, sets of principal axes that are obtained by diagonalizing the second-order tensors that yield the moments-of-geometry as well as an ellipsoidal characterization of domain shape, prior to and after interaction. Determination of these sets of axes for structural comparison requires no internal symmetry features of the domains, depending solely upon their representation in three-dimensional space. This representation may involve atomic, Calpha, or residue centroid coordinates. The present analysis utilizes residue centroids. When the structural changes are minimal, the principal axes of the domains, prior to and after interaction, are essentially comparable and consequently may be used for structural comparison. When the differences of the axes cannot be neglected, but are nevertheless slight, a smaller relatively invariant substructure of the domains may be utilized for comparison. The procedure yields two distance metrics for structural comparison. First, the displacements of the residue centroids due to antigenic binding, referenced to the ellipsoidal principal axes, are noted. Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain. CONCLUSION: With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

Hydrophobic and acidic moments of a nucleoplasmin NP-core chaperone.

A recent crystal structure, at atomic resolution, of the NO38-core chaperone has revealed a decamer comprised of a dimer of pentamers, with each pentamer consisting of closely coupled eight-stranded beta-barrel monomers. This N-terminal core domain of the chaperone shares the Nucleoplasmin family fold and is presumed to assist the binding of the core histones in their assembly into nucleosomes during DNA replication and repair. The present work provides a measure of the hydrophobic residue burial about the different interfaces and centers of the NO38-core multimeric structure. While the hydrophobic "pentameric ring," comprised of the hydrophobic cores of the monomers and prevalence of non-polar residues at their interfaces is observed, a hydrophobic bias with respect to the center of the pentamer is also found, and consequently also expected to contribute to the thermostability of the multimer. Structural and chromatographic analysis had shown the NO38-core chaperone to bind (H3-H4)2 histone tetramers as well as H2A-H2B dimers. The acidic dipole, which reflects the spatial disposition of the acidic residues of the core monomer points to the lateral region of the monomers comprising the oligomers, and thereby, shows it to be the region of charge that would optimally complement the basic charge of the histones in their electrostatic binding to the chaperone. It is also pointed out that the prevalence of basic residues on the short helices of the histone cores also provides regions of charge that would complement histone binding to the chaperone.

Efficacy and safety of preprandial human insulin inhalation powder versus injectable insulin in patients with type 1 diabetes.

AIMS/HYPOTHESIS: The efficacy and safety of human insulin inhalation powder (HIIP) plus insulin glargine were compared to subcutaneously injected insulin (SC insulin) plus insulin glargine in patients with type 1 diabetes. METHODS: This was a randomised, open-label crossover study in which one group of patients received preprandial HIIP plus insulin glargine for 12 weeks, followed by the same duration with preprandial SC insulin (lispro or regular) plus insulin glargine. Another group of patients received the reverse treatment sequence. The trial was designed as a non-inferiority comparison of the two treatments for effect on HbA(1c); blood glucose levels were also monitored. Safety assessments included adverse event reporting and hypoglycaemic events. RESULTS: HbA(1c) at endpoint was 7.95+/-0.12% for the HIIP treatment and 8.06+/-0.12% for the SC insulin treatment; mean changes from baseline to endpoint were -0.08 and 0.00%, respectively, (p=NS). The upper limit of the 95% CI of mean difference in HbA(1c) between the two treatments was 0.02%, indicating that HIIP was not inferior relative to SC insulin, as measured against the pre-defined margin of 0.3%. Fasting blood glucose was significantly lower for HIIP treatment (8.09+/-0.33 mmol/l; n=117) than for SC insulin treatment (9.05+/-0.33 mmol/l; n=111) (p=0.01). Safety profiles were comparable between the two treatments. The rate of any hypoglycaemia (least-squares mean adjusted for 30 days+/-SE) was 8.9+/-0.7 and 8.2+/-0.8 for HIIP and SC insulin treatments, respectively, (p=0.29). The rate of nocturnal hypoglycaemia was greater for HIIP (4.2+/-0.4) than for SC insulin (2.7+/-0.4; p<0.001). CONCLUSIONS/INTERPRETATION: HIIP was similar in efficacy to SC insulin for glycaemic control in type 1 diabetes mellitus. The two treatments had comparable safety profiles.

Asymmetry in the burial of hydrophobic residues along the histone chains of eukarya, archaea and a transcription factor.

BACKGROUND: The histone fold is a common structural motif of proteins involved in the chromatin packaging of DNA and in transcription regulation. This single chain fold is stabilized by either homo- or hetero-dimer formation in archaea and eukarya. X-ray structures at atomic resolution have shown the eukaryotic nucleosome core particle to consist of a central tetramer of two bound H3-H4 dimers flanked by two H2A-H2B dimers. The c-terminal region of the H3 histone fold involved in coupling the two eukaryotic dimers of the tetramer, through a four-fold helical bundle, had previously been shown to be a region of reduced burial of hydrophobic residues within the dimers, and thereby provide a rationale for the observed reduced stability of the H3-H4 dimer compared with that of the H2A-H2B dimer. Furthermore, comparison between eukaryal and archaeal histones had suggested that this asymmetry in the distribution of hydrophobic residues along the H3 histone chains could be due to selective evolution that enhanced the coupling between the eukaryotic dimers of the tetramer. RESULTS AND DISCUSSION: The present work describes calculations utilizing the X-ray structures at atomic resolution of a hyperthermophile from Methanopyrus kandleri (HMk) and a eukaryotic transcription factor from Drosophila melanogaster (DRm), that are structurally homologous to the eukaryotic (H3-H4)2 tetramer. The results for several other related structures are also described. Reduced burial of hydrophobic residues, at the homologous H3 c-terminal regions of these structures, is found to parallel the burial at the c-terminal regions of the H3 histones and is, thereby, expected to affect dimer stability and the processes involving histone structural rearrangement. Significantly different sequence homology between the two histones of the HMk doublet with other archaeal sequences is observed, and how this might have occurred during selection to enhance tetramer stability is described.

The hydrophobicity of the H3 histone fold differs from the hydrophobicity of the other three folds.

The eukaryotic histone dimers, H3-H4 and H2A-H2B, are formed in the cytosol prior to being transported into the nucleus and assembled into the nucleosome. Residue side-chain distances from the interior of the histone dimers are obtained with an ellipsoidal spatial metric and structural information provided by X-ray analyses at atomic resolution of the nucleosome core particles. While the spatial hydrophobic moment profiles of the dimers are comparable with profiles obtained previously that characterize the hydrophobic core of single-chain, single-domain globular soluble proteins, correlation coefficients between the side-chain hydrophobicities and distances from the interior of the H3-H4 dimer and H2A-H2B dimer differ significantly. This difference is traced to the H3 histone fold, which segregates fewer hydrophobic residues within the protein interior than the three other folds. Examination of the correlation coefficient between residue hydrophobicity and side-chain distance from the dimer interior over local regions of the fold sequence shows that the region of reduced correlation is associated mainly with the residues at the carboxyl end of the H3 histone fold, the helical region of the fold involved in the H3-H3' binding of the (H3-H4)(2) tetramer of the nucleosome. Hydrophobic interactions apparently contribute to the binding of this fourfold helical bundle and this evolutionary requirement may trade off against the requirement for H3-H4 dimer stability. The present results provide a different view than previously proposed, albeit of similar origin, to account for the reduced stability of the H3-H4 dimer compared with the H2A-H2B dimer.

Underlying hydrophobic sequence periodicity of protein tertiary structure.

Hydropathy plots or window averages over local stretches of the sequence of residue hydrophobicity have revealed patterns related to various protein tertiary structural features. This has enabled identification of regions of the sequence that are at the surface or within the interior of globular soluble proteins, regions located within the lipid bilayer of transmembrane proteins, portions of the sequence that characterize repeating motifs, as well as motifs that usefully characterize different protein structural families. This, therefore, provides one example of the generally expressed maxim that "sequence determines structure". On the other hand, a number of previous investigations have shown the rapidly varying values of residue hydrophobicity along the sequence to be distributed approximately randomly. So one might question just how much of the sequence actually determines structure. It is, therefore, of interest to extract that part of this rapidly varying distribution of residue hydrophobicity that is responsible for the longer wavelength variations that correlate with protein tertiary structural features and to determine their prevalence within the entire distribution. This is accomplished by a finite Fourier analysis of the sequence of residue hydrophobicity and of a new measure of residue distance from the protein interior. Calculations are performed on a number of globins, immunoglobulins, cuprodoxins, and papain-like structures. The spectral power of the Fourier amplitudes of the frequencies extracted, whose inverse transforms underlie the windowed values of residue hydrophobicity is shown to be a small fraction of the total power of the hydrophobicity distribution and thereby consistent with a distribution that might appear to be predominantly random. The wide range of sequence identity between proteins having the same fold, all exhibiting similar small fractions of power amplitude that correlate with the longer wavelength inside-to-outside excursions of the amino acid residues, supports the general contention that close sequence identity is an expression of a close evolutionary relationship rather than an expression of structural similarity. Practical implications of the present analysis for protein structure prediction and engineering are also described.

Soy formula complicates management of congenital hypothyroidism.

AIMS: To test the hypothesis that feeding soy formula to infants with congenital hypothyroidism (CH) leads to prolonged increase of thyroid stimulating hormone (TSH). METHODS: The study was a review of 78 patients seen during their first year of life between 1990 and 1998. Data regarding clinical diagnosis, date of treatment initiation, TSH, levothyroxine dose, weight, length, and diet information from each visit were collected from the charts. RESULTS: There were eight patients in the soy diet group and 70 in the non-soy diet group. There was no significant difference between the two groups in the starting dose of levothyroxine or the change in this dose over one year. There was a significant difference between the two groups in the following areas: time to TSH normalisation, first TSH on treatment, percentage with increased TSH at 4 months of age, percentage with increased TSH throughout the first year of life, and in the overall trend of TSH at each visit. CONCLUSIONS: Infants fed soy formula had prolonged increase of TSH when compared to infants fed non-soy formula. These infants need close monitoring of free thyroxine and TSH measurements, and they may need increased levothyroxine doses to achieve normal thyroid function tests.

Degenerative spondylolisthesis at the L4-L5 in a 32-year-old female with previous fusion for idiopathic scoliosis: a case report.

We report a case of degenerative L4-L5 spondylolisthesis in a 32-year-old female who had undergone thoracic (lower level T12) fusion as a teenager. All other levels in the lumbar spine were normal on magnetic resonance imaging. Subsequent fusion of L4-L5 led to improvement in function and alleviation of pain for more than 4 years. The possible relationship between the previous fusion and degenerative spondylolisthesis is discussed.

Hydrophobic moments of tertiary protein structures.

The helical hydrophobic moment is a measure of the amphiphilicity of a segment of protein secondary structure. Such measure yields information of potential relevance for issues relating to cell surface binding and secondary structure function. The present article describes a global analog of the helical hydrophobic moment. The global moment provides a concise measure of the degree and direction of the amphiphilicity or hydrophobic imbalance across the entire protein tertiary structure. Therefore, this measure is a succinct representation of the spatial organization of residue hydrophobicity for each protein. With this measure, a simple comparison of the hydrophobic imbalance or segregation of different protein structures can be made. For example, two structures having the same fold and close in root-mean-square deviation may exhibit very different overall hydrophobic organization. Such difference is classified simply by the global moment. Furthermore, the direction of the global moment may point to regions of functional interest. Certain formal issues in the development of such moment are described, and a number of applications to particular protein structures are discussed.

Spatial profiling of protein hydrophobicity: native vs. decoy structures.

A recent study of 30 soluble globular protein structures revealed a quasi-invariant called the hydrophobic ratio. This invariant, which is the ratio of the distance at which the second order hydrophobic moment vanished to the distance at which the zero order moment vanished, was found to be 0.75 +/- 0.05 for 30 protein structures. This report first describes the results of the hydrophobic profiling of 5,387 non-redundant globular protein domains of the Protein Data Bank, which yields a hydrophobic ratio of 0.71 +/- 0.08. Then, a new hydrophobic score is defined based on the hydrophobic profiling to discriminate native-like proteins from decoy structures. This is tested on three widely used decoy sets, namely the Holm and Sander decoys, Park and Levitt decoys, and Baker decoys. Since the hydrophobic moment profiling characterizes a global feature and requires reasonably good statistics, this imposes a constraint upon the size of the protein structures in order to yield relatively smooth moment profiles. We show that even subject to the limitations of protein size (both Park & Levitt and Baker sets are small protein decoys), the hydrophobic moment profiling and hydrophobic score can provide useful information that should be complementary to the information provided by force field calculations.

Hydrophobicity of transmembrane proteins: spatially profiling the distribution.

A hallmark of soluble globular protein tertiary structure is a hydrophobic core and a protein exterior populated predominantly by hydrophilic residues. Recent hydrophobic moment profiling of the spatial distribution of 30 globular proteins of diverse size and structure had revealed features of this distribution that were comparable. Analogous profiling of the hydrophobicity distribution of the alpha-helical buried bundles of several transmembrane proteins, as the lipid/protein interface is approached from within the bilayer, reveals spatial hydrophobicity profiles that contrast with those obtained for the soluble proteins. The calculations, which enable relative changes of hydrophobicity to be simply identified over the entire spatial extent of the multimer within the lipid bilayer, show the accumulated zero-order moments of the bundles to be mainly inverted with respect to that found for the soluble proteins. This indicates a statistical increase in the average residue hydrophobic content as the lipid bilayer is approached. This result differs from that of a relatively recent calculation and qualitatively agrees with earlier calculations involving lipid exposed and buried residues of the alpha-helices of transmembrane proteins. Spatial profiling, over the entire spatial extent of the multimer with scaled values of residue hydrophobicity, provides information that is not available from calculations using lipid exposure alone.

A two-component nucleation model of protein hydrophobicity.

A fundamental characteristic of soluble globular protein structure is a hydrophobic core and protein exterior comprised predominantly of hydrophilic residues. This distribution of amino acid residue hydrophobicity, from protein interior to exterior, has recently been profiled with the use of hydrophobic moments. The calculations enable comparison of the radial hydrophobicity distribution of different proteins and had revealed two features common to 30 proteins of diverse size and structure. One, a global feature, is the overall shape of the second-order ellipsoidal hydrophobic moment. The second, a specific feature, is a quasi-invariant hydrophobic-ratio of distances. Both features are dependent upon the rates of increase, from protein interior to exterior, of the accumulated numbers of hydrophobic and hydrophilic amino acid residues. These rates can be simulated simply with a two-component nucleation model of protein hydrophobicity. The model provides insight into the origin of the shape of the observed hydrophobic moment profiles and of the observed range of hydrophobic ratios. Consistent with observation, it is shown that a relatively wide range of hydrophobic and hydrophilic rates of increase yield a relatively narrow range of hydrophobic ratios. Furthermore, the model identifies one factor, the decrease in residue density with increasing distance from the protein interior, that is critical in providing the range of values that is comparable with the observed range.

Detecting native protein folds among large decoy sets with hydrophobic moment profiling.

A new hydrophobic score will be presented in this paper for detecting native-like folds from a large set of decoy structures. A recent paper (B. D. Silverman, PNAS 98, 4996, 2001) had revealed that for globular proteins there exists a relatively universal constant of 0.74 for a hydrophobic ratio, which is defined as the ratio of radii from the protein centroid at which the second order hydrophobic moment and the zero order moment vanishes. This paper further defines a new hydrophobic score which will be used to examine protein decoys, in particular, the Holm & Sander, Park & Levitt and Baker decoy sets. It will be shown that the hydrophobic score and profile shapes can provide useful information that should be complementary to the information provided by other procedures, such as free energy calculations.

A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency.

Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.