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At least 1,765 records · Page 98Linked to original sources
PubMed2006

Measuring the impact of diabetes through patient report of treatment satisfaction, productivity and symptom experience.

OBJECTIVE: Diabetes is a common, debilitating chronic illness with multiple impacts. The impact on treatment satisfaction, productivity impairment and the symptom experience may be among the most important for patient-reported outcomes. This study developed and validated disease-specific, patient-reported measures for these outcomes that address limitations in currently available measures. METHODS: Data was collected from the literature, experts and patients and a conceptual model of the patient-reported impact of diabetes was created. Item pools, based on the conceptual model, were then generated. The items were administered to 991 diabetes patients via a web-based survey to perform item reduction, identify relevant factor structures and assess reliability and validity following an a-priori analysis plan. RESULTS: All validation criteria and hypotheses were met resulting in three new, valid measures: a 21-item Satisfaction Measure (three sub-scales: burden, efficacy and symptoms), a 30-item Symptom Measure and a 14-item Productivity Measure assessing both life and work productivity impairments. CONCLUSION: This triad of measures captures important components of the multifaceted diabetes patient experience and can be considered as valid, viable options when choosing measures to assess patient-reported outcomes. Addressing these outcomes may assist researchers and clinicians to develop more patient-centered diabetes interventions and care.

Adult↗
PubMed1991

The Aberrant Behavior Checklist with children and adolescents with dual diagnosis.

The Aberrant Behavior Checklist (ABC; Aman, Singh, Stewart, & Field, 1985a, 1985b) is a 58-item third-party informant rating scale originally developed for institutionalized, low-functioning adolescents and adults. The present study investigated the appropriateness of the scale for youngsters with dual diagnosis of mental retardation and psychiatric disturbance. Over a period of 2 1/2 years, 204 patients (199 after data reduction) from a child psychiatry unit were rated twice daily by direct care staff. Data analysis addressed internal consistency, interrater reliability, criterion validity, and robustness of the factor structure. Internal consistency was satisfactory with alpha coefficients ranging from .82 to .94. Interrater reliability varied between subscales but was relatively low (Pearson correlations between .39 to .61). In terms of its criterion validity, the ABC was sensitive to psychiatric diagnoses and age and the original 5-factor structure was robust (congruence coefficients ranged between .80 to .89). Yet, only a relatively small proportion of the variance (31.5%) was explained by factor analysis indicating possible limitations of the ABC for this population. Given the paucity of assessment instruments for this particular population and the difficulty involved in developing new population-specific instruments, the ABC can be recommended for children and adolescents with dual diagnosis.

Adolescent↗
PubMed2003

Calculation of mutational free energy changes in transition states for protein folding.

Recent advances in experimental and computational methods have made it possible to determine with considerable accuracy the structures whose formation is rate limiting for the folding of some small proteins-the transition state ensemble, or TSE. We present a method to analyze and validate all-atom models of such structures. The method is based on the comparison of experimental data with the computation of the change in free energy of the TSE resulting from specific mutations. Each mutation is modeled individually in all members of an ensemble of transition state structures using a method originally developed to predict mutational changes in the stability of native proteins. We first apply this method to six proteins for which we have determined the TSEs with a technique that uses experimental mutational data (Phi-values) as restraints in the structure determination and find a highly significant correlation between the calculated free energy changes and those derived from experimental kinetic data. We then use the procedure to analyze transition state structures determined by molecular dynamics simulations of unfolding, again finding a high correlation. Finally, we use the method to estimate changes in folding rates of several hydrophobic core mutants of Fyn SH3. Taken together, these results show that the procedure developed here is a tool of general validity for analyzing, assessing, and improving the quality of the structures of transition states for protein folding.

Amino Acid Sequence↗
PubMed2006

A brief mental health outcomes measure: translation and validation of the Czech version of the Schwartz Outcomes Scale-10.

The Schwartz Outcomes Scale-10 (SOS-10) is a 10-item scale developed to measure the effectiveness of psychiatric treatments. Using standard methodology, we translated the scale into Czech and examined the psychometric properties of the Czech version. 207 in-patients admitted to Prague Psychiatric Center were included in the study. All patients completed the SOS at admission and discharge. The SOS-10 scale was also administered to 170 persons from the general population. Reliability, validity and sensitivity to treatment change of the Czech SOS-10 were analyzed. The Cronbach's alpha coefficient was 0.92. The item-total correlation coefficients varied from 0.56 to 0.82. The SOS-10 correlated well with condition-specific measures including depression (BDI) and anxiety (BAI) and a global self-rated symptom severity scale (CGI). The SOS-10 also had significant correlations with the Health, Basic needs, Relationship, and Leisure time domains of the Czech version of the Subjective Quality of Life Analysis (SQUALA-CZ). The scale discriminated well between patients and controls, with patients scoring significantly lower on all SOS items. The patient sample's admission and discharge scores were significantly different, indicating that the scale is sensitive to treatment changes. We concluded that the Czech SOS-10 is valid with reliability and factor structure similar to the American language version.

Adolescent↗
PubMed1997

A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S: from biostructural pathology to species-specific cofactor activity.

Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its gamma-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS 'faces' involving regions of residues Arg49-Gln52-Lys97 (TSR-EGF-1) and Thr103-Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.

1-Carboxyglutamic Acid↗
PubMed1993

Boltzmann's principle, knowledge-based mean fields and protein folding. An approach to the computational determination of protein structures.

The data base of known protein structures contains a tremendous amount of information on protein-solvent systems. Boltzmann's principle enables the extraction of this information in the form of potentials of mean force. The resulting force field constitutes an energetic model for protein-solvent systems. We outline the basic physical principles of this approach to protein folding and summarize several techniques which are useful in the development of knowledge-based force fields. Among the applications presented are the validation of experimentally determined protein structures, data base searches which aim at the identification of native-like sequence structure pairs, sequence structure alignments and the calculation of protein conformations from amino acid sequences.

Amino Acid Sequence↗
PubMedDate not supplied

Lead hopping using SVM and 3D pharmacophore fingerprints.

The combination of 3D pharmacophore fingerprints and the support vector machine classification algorithm has been used to generate robust models that are able to classify compounds as active or inactive in a number of G-protein-coupled receptor assays. The models have been tested against progressively more challenging validation sets where steps are taken to ensure that compounds in the validation set are chemically and structurally distinct from the training set. In the most challenging example, we simulate a lead-hopping experiment by excluding an entire class of compounds (defined by a core substructure) from the training set. The left-out active compounds comprised approximately 40% of the actives. The model trained on the remaining compounds is able to recall 75% of the actives from the "new" lead series while correctly classifying >99% of the 5000 inactives included in the validation set.

Computer Simulation↗
PubMed2003

Predicting HIV drug resistance with neural networks.

MOTIVATION: Drug resistance is a very important factor influencing the failure of current HIV therapies. The ability to predict the drug resistance of HIV protease mutants may be useful in developing more effective and longer lasting treatment regimens. METHODS: The HIV resistance is predicted to two current protease inhibitors, Indinavir and Saquinavir. The problem was approached from two perspectives. First, a predictor was constructed based on the structural features of the HIV protease-drug inhibitor complex. A particular structure was represented by its list of contacts between the inhibitor and the protease. Next, a classifier was constructed based on the sequence data of various drug resistant mutants. In both cases, self-organizing maps were first used to extract the important features and cluster the patterns in an unsupervised manner. This was followed by subsequent labelling based on the known patterns in the training set. RESULTS: The prediction performance of the classifiers was measured by cross-validation. The classifier using the structure information correctly classified previously unseen mutants with an accuracy of between 60 and 70%. Several architectures were tested on the more abundant sequence data. The best single classifier provided an accuracy of 68% and a coverage of 69%. Multiple networks were then combined into various majority voting schemes. The best combination yielded an average of 85% coverage and 78% accuracy on previously unseen data. This is more than two times better than the 33% accuracy expected from a random classifier.

Algorithms↗
PubMed2006

Theoretical model of restriction endonuclease HpaI in complex with DNA, predicted by fold recognition and validated by site-directed mutagenesis.

Type II restriction enzymes are commercially important deoxyribonucleases and very attractive targets for protein engineering of new specificities. At the same time they are a very challenging test bed for protein structure prediction methods. Typically, enzymes that recognize different sequences show little or no amino acid sequence similarity to each other and to other proteins. Based on crystallographic analyses that revealed the same PD-(D/E)XK fold for more than a dozen case studies, they were nevertheless considered to be related until the combination of bioinformatics and mutational analyses has demonstrated that some of these proteins belong to other, unrelated folds PLD, HNH, and GIY-YIG. As a part of a large-scale project aiming at identification of a three-dimensional fold for all type II REases with known sequences (currently approximately 1000 proteins), we carried out preliminary structure prediction and selected candidates for experimental validation. Here, we present the analysis of HpaI REase, an ORFan with no detectable homologs, for which we detected a structural template by protein fold recognition, constructed a model using the FRankenstein monster approach and identified a number of residues important for the DNA binding and catalysis. These predictions were confirmed by site-directed mutagenesis and in vitro analysis of the mutant proteins. The experimentally validated model of HpaI will serve as a low-resolution structural platform for evolutionary considerations in the subgroup of blunt-cutting REases with different specificities. The research protocol developed in the course of this work represents a streamlined version of the previously used techniques and can be used in a high-throughput fashion to build and validate models for other enzymes, especially ORFans that exhibit no sequence similarity to any other protein in the database.

Amino Acid Sequence↗
PubMed2005

Design of monolimb using finite element modelling and statistics-based Taguchi method.

BACKGROUND: Monolimb is a transtibial prosthesis having the socket and shank molded into one piece of thermoplastic material. If properly designed, the shank of a monolimb can have a controlled deflection during walking which simulates the ankle joint motions to some extent. However, there is no clear guidance for the design of monolimb considering the dilemma between shank flexibility and structural integrity. METHODS: Finite element analysis was used to simulate structural tests based on ISO10328 on monolimbs of different configurations. Statistics-based Taguchi method was employed to identify the significance of each design factor in controlling the deformation and stress within monolimbs. The design factors considered were the thickness of the thermoplastics, anteroposterior and medialateral dimensions of the elliptical shank, and depth of the posterior seam line. By progressively fine-tuning the design factors, the monolimb configuration was optimized giving offering appropriate flexibilities of the shank and would not structurally fail in normal uses. Experimental structural test was used to validate the finite element model. FINDINGS: Anteroposterior dimension of the shank was shown to be the most important design factor determining the peak von Mises stress values, deformation and dorsiflexion angles of monolimbs. Depth of seam line appears much less important than the other three factors. A monolimb fulfilling the design requirements was suggested. Experimental test results reasonably matched with the finite element results. INTERPRETATION: Finite element analysis and Taguchi method was shown to be an effective method in optimizing the structural design of prostheses. Further prosthetic design can be facilitated based on the degree of importance of the design factors on the structural behavior of the prosthesis. Gait analysis of amputees using the suggested monolimb design is needed in the future.

Algorithms↗
PubMed2004

Molecular dynamics (MD) simulations and large-angle X-ray scattering (LAXS) studies of the solid-state structure and assembly of isotactic (R)-poly(2,2'-dioxy-1,1'-binaphthyl-)phosphazene in the bulk state and in the cast film.

The intrachain conformation, molecular structure and interchain assembly of isotactic (R)-poly(2,2'-dioxy-1,1'-binaphthyl)phosphazene (P-DBNP) both in the bulk state (I) and in the cast film (II) were studied by molecular dynamics (MD) simulations of models, as implemented by a bias potential for the analysis of the radial distribution function (RDF) obtained from large-angle X-ray scattering (LAXS) data. The microscopic structure and order extension of the polymer changed from I to II, as qualitatively shown in the shapes of their experimentally measured RDF curves. With the use of a bias potential, the MD simulations provided a much more accurate analysis of the models, as seen in the reproduction of the RDFs. The chiral P-DBNP chain was found to be consistent with helix conformations in both the I and the II samples. The predominant interchain clustering motif was best reproduced with a seven-chain model. In the case of I, the maximum chain length was 18 monomeric -R(2)NP- units, while in the case of the cast film II the chain was more elongated, up to distances of approximately 100 A, equivalent to over 48 monomeric -R(2)NP- units. The seven-chain assembly was accounted for in terms of nonbonded interactions favouring the minimum voids area between the seven tubular structures of the material. The results validate our earlier finding that MD analysis with implementation of a biasing potential for the RDFs can provide quantitative information on the structural and conformational features of amorphous solids. The combined theoretical and experimental approach was found to be a useful tool to detect, locate and evaluate the intra- and intermolecular modifications of materials subsequent to their phase transformation and, as in the present case, changes in their microscopic structures or preparation methods.

Journal Article↗
PubMed2004

The metal bonding domain of the antitumor drug Fe(II)-bleomycin: a DFT investigation.

The geometric and electronic structure of ferrous complexes of bleomycin (Fe(II)BLM) has been investigated by means of density functional theory (DFT) calculations. The active site of this antitumor drug is a highly distorted octahedral complex, with the coordination sphere completed by the five known endogenous ligands, including pyrimidine, imidazole, deprotonated amide, and secondary and primary amines. We have addressed the controversial issue of the nature of the sixth axial ligand, which we have identified as the oxygen of the carbamoyl group. Our conclusions are further validated by a comparison with structural data derived from NMR experiments. Moreover, because of the high sensitivity of structural data on the pH of the environment, we have investigated the effect of a different protonation state of the histidine amide on the geometric structure of the Fe(II)BLM complex. The extensive model of the active site of bleomycin considered in this work allows us to check the limitations of previous investigations based on simplified models.

Antineoplastic Agents↗
PubMed2001

[Quality assurance of data collection and data processing in epidemiologic study data].

Quality assurance of the data generating processes in epidemiologic studies is a prerequisite for the internal validity of study results. This paper presents practical aspects of such a quality assurance system pertaining to the planning, data gathering, data entry and data processing phase of a study. It is concerned with data obtained in the framework of a project rather than with data accumulating continuously in private practices, research institutes or veterinary faculties. During the planning phase of a project, standard operating protocols should be developed that assure a reliable performance of observation, coding and data entry. The data base structure, consisting of tables, input validation rules and queries, should be predefined and well documented. A data safety concept will provide the necessary integrity, physical safety and availability of the data. The paper presents technical solutions to common data processing problems with emphasis on re-coding and relational data base facilities (Microsoft-ACCESS) using a hypothetical study on risk factors for mastitis.

Animals↗
PubMed1999

Validation of the single-stranded channel conformation of gramicidin A by solid-state NMR.

The monovalent cation selective channel formed by a dimer of the polypeptide gramicidin A has a single-stranded, right-handed helical motif with 6.5 residues per turn forming a 4-A diameter pore. The structure has been refined to high resolution against 120 orientational constraints obtained from samples in a liquid-crystalline phase lipid bilayer. These structural constraints from solid-state NMR reflect the orientation of spin interaction tensors with respect to a unique molecular axis. Because these tensors are fixed in the molecular frame and because the samples are uniformly aligned with respect to the magnetic field of the NMR spectrometer, each constraint restricts the orientation of internuclear vectors with respect to the laboratory frame of reference. The structural motif of this channel has been validated, and the high-resolution structure has led to precise models for cation binding, cation selectivity, and cation conductance efficiency. The structure is consistent with the electrophysiological data and numerous biophysical studies. Contrary to a recent claim [Burkhart, B. M., Li, N., Langs, D. A., Pangborn, W. A. & Duax, W. L. (1998) Proc. Natl. Acad. Sci. USA 95, 12950-12955], the solid-state NMR constraints for gramicidin A in a lipid bilayer are not consistent with an x-ray crystallographic structure for gramicidin having a double-stranded, right-handed helix with 7.2 residues per turn.

Gramicidin↗
PubMed2004

Mechanistic insights from a refined three-dimensional model of integrin alphaIIbbeta3.

The integrin alpha(IIb)beta(3) plays an important role in platelet function, and abnormalities of this protein result in a serious bleeding disorder, known as Glanzmann thrombasthenia. Although crystallographic data exist for the related integrin alpha(V)beta(3), to date, there are no high resolution structures of integrin alpha(IIb)beta(3) available in the literature. Therefore, it is still unclear how specific elements of the alpha(IIb) subunit contribute to integrin alpha(IIb)beta(3) function. Here we describe a refined model of the alpha(IIb) N-terminal portion of integrin alpha(IIb)beta(3) obtained by using the alpha(V)beta(3) template combined with a new method for predicting the conformations of the unique alpha(IIb) loop regions comprising residues 71-85, 114-125, and 148-164. The refined model was probed based on a structural prediction that differentiates it from standard homology models: specifically, that Lys-118 of alpha(IIb) contacts Glu-171 of beta(3). To test this hypothesis experimentally, the mutant integrin chains alpha(IIb) K118C and beta(3) E171C were cotransfected into HEK 293 cells. We show that the cells expressed the mutants alpha(IIb)beta(3) on their surface as a disulfide-linked dimer, supporting the close proximity between alpha(IIb) Lys-118 and beta(3) Glu-171 predicted from the refined model. This validated model provides a specific structural context for the analysis and interpretation of structure-function relations of integrin alpha(IIb)beta(3). In addition, it suggests mechanistic hypotheses pertaining to both naturally occurring mutations responsible for Glanzmann thrombasthenia and to point mutations that affect ligand binding.

Alanine↗
PubMed1998

Health beliefs and folk models of diabetes in British Bangladeshis: a qualitative study.

OBJECTIVE: To explore the experience of diabetes in British Bangladeshis, since successful management of diabetes requires attention not just to observable behaviour but to the underlying attitudes and belief systems which drive that behaviour. DESIGN: Qualitative study of subjects' experience of diabetes using narratives, semi-structured interviews, focus groups, and pile sorting exercises. A new qualitative method, the structured vignette, was developed for validating researchers' understanding of primary level culture. SUBJECTS: 40 British Bangladeshi patients with diabetes, and 10 non-Bangladeshi controls, recruited from primary care. RESULT: Several constructs were detected in relation to body image, cause and nature of diabetes, food classification, and knowledge of complications. In some areas, the similarities between Bangladeshi and non-Bangladeshi subjects were as striking as their differences. There was little evidence of a fatalistic or deterministic attitude to prognosis, and most informants seemed highly motivated to alter their diet and comply with treatment. Structural and material barriers to behaviour change were at least as important as "cultural" ones. CONCLUSION: Bangladeshi culture is neither seamless nor static, but some widely held beliefs and behaviours have been identified. Some of these have a potentially beneficial effect on health and should be used as the starting point for culturally sensitive diabetes education.

Adult↗
PubMed2002

Assessment of psychosis proneness in African-American college students.

The present study employed the psychometric high-risk method to investigate psychosis proneness in African-American and Caucasian college students recruited from three sites. The goals of the study were to develop norms for African-American students on the Perceptual Aberration (Chapman, Chapman, & Raulin, 1978), Magical Ideation (Eckblad & Chapman, 1983), Revised Social Anhedonia (Eckblad, Chapman, Chapman, & Mishlove, 1982), and Physical Anhedonia Scales (Chapman, Chapman, & Raulin, 1976), as well as to assess the validity of this research method with African-American students. Structured diagnostic interviews were conducted to assess the concurrent validity of these scales for identifying psychosis proneness. The results supported the use of separate norms for male and female African-American students and provided support for the concurrent validity of this research method with African-American and Caucasian college students.

Adolescent↗
PubMed2005

Searching for a reliable orientation of ligands in their binding site: comparison between a structure-based (Glide) and a ligand-based (FIGO) approach in the case study of PDE4 inhibitors.

Two 3D QSAR Grid/Golpe models, differing in the alignment criterion of the studied phosphodiesterase 4 (PDE4) inhibitors, were compared. The docking-guided alignment, obtained by exploiting the known 3D structure of the PDE4, was used to test and validate the field-fit alignment solution proposed by FIGO procedure. The analysis of the direct (docking) and indirect (FIGO) superposition methodologies occurs through the comparison of the respective PLS coefficient maps. The inclusion in the FIGO algorithm of factors related to the hydrophobicity and shape of the molecules leads to promising results, making the new FIGO algorithm a valid alternative in the molecule overlay, particularly when the 3D structure of the target is unknown.

3',5'-Cyclic-AMP Phosphodiesterases↗