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PubMed2000

Clinical utility, factor analysis, and further validation of the memorial delirium assessment scale in patients with advanced cancer: Assessing delirium in advanced cancer.

BACKGROUND: Delirium is a common neuropsychiatric complication in patients with advanced cancer. The Memorial Delirium Assessment Scale (MDAS) is a recently developed 10-item severity rating instrument. The purpose of the current prospective study was to further assess the clinical utility, factor structure, and validity of the MDAS in a relatively homogeneous population of patients with advanced cancer. METHODS: Study entry of 104 patients occurred on their consecutive admission to a tertiary-level, acute palliative care unit in a university-affiliated teaching hospital. Patients underwent regular cognitive screening using the Mini-Mental State Examination, and serial monitoring of delirium using standardized semistructured interviews and MDAS ratings, up to the study endpoints of either patient discharge or death. RESULTS: Seventy-one patients met Diagnostic and Statistical Manual (of Mental Disorders)-IV criteria for a first episode of delirium. In 15 of 71 (21%) patients with a first episode of delirium, the first MDAS ratings were prorated because of dyspnea, fatigue, or profound delirium. In the remaining 56 patients (79%), the first MDAS ratings were rated fully and therefore evaluable. Correlations among the scale items ranged from moderate to low (correlation coefficient [r] = 0.68-0.02). Analysis of the pattern of factor loadings identified two primary correlated factors: global cognitive (Factor I) and neurobehavioral (Factor II) (r = 0.33). Cronbach alpha coefficients for Factors I and II were 0.8 and 0.66, respectively, indicating a relatively high level of correlation for items within each. The Cronbach alpha coefficient for all 10 items was 0.78, suggesting a general underlying factor. In a larger sample of complete MDAS ratings (n = 330) a cutoff total MDAS score of 7 of 30 yielded the highest sensitivity (98%) and specificity (96%) for delirium diagnosis. The MDAS was correlated moderately with the Mini-Mental State Examination (r = 0.55). CONCLUSIONS: The authors concluded that the MDAS structure is representative of the many features of delirium, broadly grouped as global cognitive and neurobehavioral dimensions. Prorating item scores is necessary in approximately 20% of advanced cancer patients with delirium. This poses potential limitations on the applicability of the MDAS in research. Conversely, the ability to prorate item scores confers a clinical advantage to the instrument when assessing delirium in a patient population with advanced cancer.

Aged↗
PubMed1995

A brief method for assessing social development: structure, reliability, stability, and developmental validity of the Interpersonal Competence Scale.

The Interpersonal Competence Scale (ICS-T) is a set of brief rating scales for teachers and parents. It consists of 18 items that assess social and behavioural characteristics of children and youths. The ICS-T yields three primary factors: AGG (argues, trouble at school, fights), POP (popular with boys, popular with girls, lots of friends), and ACA (spelling, math). Subsidiary factors include AFF (smile, friendly), OLY (appearance, sports, wins), and INT (shyness, sad, worry). The psychometric properties of the scale (internal structure, reliability, long-term stability) are presented and evaluated over successive ages. The scale factors have been linked to contemporaneous observations of behavior and social network membership. Developmental validity of the ICS-T includes the significant prediction of later school dropout and teenage parenthood. The ICS-T scale is described, along with instructions for use and scoring.

Adolescent↗
PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗
PubMed2004

Physiologically based pharmacokinetic/pharmacodynamic model for the organophosphorus pesticide diazinon.

Diazinon (DZN) is an organophosphorus pesticide with the possibility for widespread exposures. The toxicological effects of DZN are primarily mediated through the effects of its toxic metabolite, DZN-oxon on acetylcholinesterases, which results in accumulation of acetylcholine at neuronal junctions. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to quantitatively assess the kinetics of DZN and its metabolites in blood and the inhibition of cholinesterases in plasma, RBC, brain, and diaphragm. Focused in vivo pharmacokinetic studies were conducted in male Sprague-Dawley rats and the data were used to refine the model. No overt toxicity was noted following doses up to 100mg/kg. However, cholinesterases in plasma, RBC, brain and diaphragm were substantially inhibited at doses of 50 mg/kg. In plasma, total cholinesterase was inhibited to less than 20% of control by 6 h post dosing with 100 mg/kg. Inhibition of brain acetylcholinesterase (AChE) following 100 mg/kg exposures was approximately 30% of control by 6 h. Diaphragm butyrylcholinesterase (BuChE) inhibition following 100 mg/kg dosing was to less than 20% of control by 6 h. The PBPK/PD model was used to describe the concentrations of DZN and its major, inactive metabolite, 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) in plasma and urinary elimination of IMHP. The fit of the model to plasma, RBC, brain, and diaphragm total cholinesterase and BuChE activity was also assessed and the model was further validated by fitting data from the open literature for intraperitoneal, intravenous, and oral exposures to DZN. The model was shown to quantitatively estimate target tissue dosimetry and cholinesterase inhibition following several routes of exposures. This model further confirms the usefulness of the model structure previously validated for chlorpyrifos and shows the potential utility of the model framework for other related organophosphate pesticides.

Animals↗
PubMed2006

The onion-ring structure for Pd-Pt bimetallic clusters.

The onion-ring structure is validated in the Pd-Pt bimetallic clusters of total atom numbers 147 and 309 through the Monte Carlo method by using the second-moment approximation of the tight-binding (TB-SMA) potentials, which is conceived in predicting the possible structures of the bimetallic clusters by He et al. [J. Am. Chem. Soc. 2003, 125, 11034] and Hwang et al. [J. Am. Chem. Soc. 2005, 127, 11140]. In the onion-ring structure, Pd atoms and Pt atoms occupy alternate layers of the clusters. The formation of the onion-ring structure can be associated with the fact that the single Pt impurity is favorable to stay in the subsurface layer and the central part of bimetallic clusters.

Letter↗
PubMed1997

A novel method for structure-based prediction of ion channel conductance properties.

A rapid and easy-to-use method of predicting the conductance of an ion channel from its three-dimensional structure is presented. The method combines the pore dimensions of the channel as measured in the HOLE program with an Ohmic model of conductance. An empirically based correction factor is then applied. The method yielded good results for six experimental channel structures (none of which were included in the training set) with predictions accurate to within an average factor of 1.62 to the true values. The predictive r2 was equal to 0.90, which is indicative of a good predictive ability. The procedure is used to validate model structures of alamethicin and phospholamban. Two genuine predictions for the conductance of channels with known structure but without reported conductances are given. A modification of the procedure that calculates the expected results for the effect of the addition of nonelectrolyte polymers on conductance is set out. Results for a cholera toxin B-subunit crystal structure agree well with the measured values. The difficulty in interpreting such studies is discussed, with the conclusion that measurements on channels of known structure are required.

Adenosine Triphosphatases↗
PubMed2003

Gene3D: structural assignments for the biologist and bioinformaticist alike.

The Gene3D database (http://www.biochem.ucl.ac.uk/bsm/cath_new/Gene3D/) provides structural assignments for genes within complete genomes. These are available via the internet from either the World Wide Web or FTP. Assignments are made using PSI-BLAST and subsequently processed using the DRange protocol. The DRange protocol is an empirically benchmarked method for assessing the validity of structural assignments made using sequence searching methods where appropriate assignment statistics are collected and made available. Gene3D links assignments to their appropriate entries in relevent structural and classification resources (PDBsum, CATH database and the Dictionary of Homologous Superfamilies). Release 2.0 of Gene3D includes 62 genomes, 2 eukaryotes, 10 archaea and 40 bacteria. Currently, structural assignments can be made for between 30 and 40 percent of any given genome. In any genome, around half of those genes assigned a structural domain are assigned a single domain and the other half of the genes are assigned multiple structural domains. Gene3D is linked to the CATH database and is updated with each new update of CATH.

Animals↗
PubMed2003

[German version of the Strength and Difficulties Questionnaire (SDQ-German)--overview and evaluation of initial validation and normative results].

The Strengths and Difficulties Questionnaire (SDQ) is a short behavioural screening questionnaire which can be completed in about five minutes by parents and teachers of 4- to 16-year-olds or as self-report by 11- to 16-year-olds. The English original has already been fully evaluated and is widely used in research and clinical practice. The instrument was translated into German in 1997, and several evaluative studies have since been completed. The present paper gives an overview of this novel instrument and summarizes the normative and validation studies to date. A normative study on a field sample of 930 children demonstrated that the distributions of raw scores in the German parent SDQ closely resemble those found in the English version, while a factor analysis of the German data yielded a pattern of loadings which convincingly replicated the original scale structure. Initial validation studies showed that the parent-, teacher-, and self-completed SDQ-Deu correlates well with the considerably longer German versions of the Child Behavior Checklist (CBCL) and respective teacher and self-report derivatives (TRF, YSR). Both parent-rated instruments are equally able to distinguish between a community and a clinic sample, and between subgroups with and without specified categories of disorders within a clinic sample. After discussing possible uses of the SDQ-Deu as well as similarities and differences to other scales, we conclude that the German SDQ is just as useful and valid an instrument for many clinical and research purposes as the English original.

Adolescent↗
PubMed2000

Selecting protein targets for structural genomics of Pyrobaculum aerophilum: validating automated fold assignment methods by using binary hypothesis testing.

Three-dimensional protein folds were assigned to all ORFs of the recently sequenced genome of the hyperthermophilic archaeon Pyrobaculum aerophilum. Binary hypothesis testing was used to estimate a confidence level for each assignment. A separate test was conducted to assign a probability for whether each sequence has a novel fold-i.e., one that is not yet represented in the experimental database of known structures. Of the 2,130 predicted nontransmembrane proteins in this organism, 916 matched a fold at a cumulative 90% confidence level, and 245 could be assigned at a 99% confidence level. Likewise, 286 proteins were predicted to have a previously unobserved fold with a 90% confidence level, and 14 at a 99% confidence level. These statistically based tools are combined with homology searches against the Online Mendelian Inheritance in Man (OMIM) human genetics database and other protein databases for the selection of attractive targets for crystallographic or NMR structure determination. Results of these studies have been collated and placed at http://www.doe-mbi.ucla.edu/people/parag/P A_HOME/, the University of California, Los Angeles-Department of Energy Pyrobaculum aerophilum web site.

Algorithms↗
PubMed2004

Fishing for allosteric sites on GABA(A) receptors.

GABA(A) receptors have structural and functional homology with a super-family of cys-loop ligand-gated ion channel receptors including the nicotinic acetylcholine receptors. Amino acid residues involved in ligand-binding pockets are homologous among super-family members, leading to the multiple-loop model of binding sites situated at subunit interfaces, validated by structural studies on the nicotinic acetylcholine receptor and water-soluble snail acetylcholine binding protein. This article will briefly review the literature on the agonist binding sites on the receptor super-family, and then describe the current situation for attempts to identify sites for allosteric modulators on the GABA(A) receptors. A combination of mutagenesis and photoaffinity labeling with anesthetic ligands has given some leads in this endeavor. Current work by others and ourselves focuses on three putative sites for modulators: (1) within the ion channel domain TM2, near the extracellular end; (2) the agonist binding sites and homologous pockets at other subunit interfaces of the pentameric receptor; and (3) on the linker region stretching from the agonist site loop C to the top of the TM1 region. It is likely that concrete structural information will be forthcoming soon.

Allosteric Site↗
PubMed2006

Three-dimensional structure of a type III glutamine synthetase by single-particle reconstruction.

GlnN, the type III glutamine synthetase (GSIII) from the medically important, anaerobic, opportunistic pathogen Bacteroides fragilis, has 82.8 kDa subunits that share only 9% sequence identity with the type I glutamine synthetases (GSI), the only family for which a structure is known. Active GlnN was found predominantly in a single peak that eluted from a calibrated gel-filtration chromatography column at a position equaivalent to 0.86(+/-0.08) MDa. Negative-stain electron microscopy enabled the identification of double-ringed particles and single hexameric rings ("pinwheels") resulting from partial staining. A 2D average of these pinwheels showed marked similarity to the corresponding structures found in preparations of GSI, except that the arms of the subunits were 40% longer. Reconstructions from particles embedded in vitreous ice showed that GlnN has a double-ringed, dodecameric structure with a 6-fold dihedral space group (D6) symmetry and dimensions of 17.0 nm parallel with the 6-fold axis and 18.3 nm parallel with the 2-fold axes. The structures, combined with a sequence alignment based on structural principles, showed how many aspects of the structure of GSI, and most notably the alpha/beta barrel fold active site were preserved. There was evidence for the presence of this structure in the reconstructed volume, thus, identifying the indentations between the pinwheel spokes as putative active sites and suggesting conservation of the overall molecular geometry found in GSI despite their low level of global homology. Furthermore, docking of GSI into the reconstruction left sufficient plausibly located unoccupied density to account for the additional residues in GSIII, thus validating the structure.

Amino Acid Sequence↗
PubMed2000

[Obtaining samples of the human diaphragm during upper laparotomy. A structural analysis].

UNLABELLED: The diaphragm seems to undergo adaptive structural change in chronic obstructive pulmonary disease. The possibility of obtaining muscle specimens is limited, however, particularly when respiratory function is severely affected. OBJECTIVE: To assess the viability of a new technique for obtaining diaphragm muscle samples appropriate for structural assessment even from patients with severe functional change, and to study the size of fibers in relation to severity of disease. METHODS: Fifteen muscle specimens were obtained from patients (aged 57 +/- 15 years) by abdominal laparotomy. All had undergone full lung function testing. Muscle samples were taken during surgery using a new technique involving formation of a tobacco pouch with dome biopsy. The method had been previously validated in animal models. Later, the biopsies were processed to evaluate fiber proportions and sizes (ATPase dyes at different levels of pH). RESULTS: The 15 patients had a wide range of lung function results (FEV1 22-120% ref); 4 were severely affected (FEV1 < or = 50% ref). Nutritional status was normal in all cases; FEV1/FVC was 67 +/- 13%, RV was 134 +/- 55% ref, maximal mouth pressure (PImmax) was -75 +/- 27 cmH2O, transdiaphragmatic pressure (PIdimax) was 96 +/- 26 cmH2O, DLCO was 87 +/- 26% ref and PaO2 was 89 +/- 14 mmHg. We were able to obtain specimens valid for structural analysis from all patients with no complications. Light type I fibers predominated (54 +/- 9%) and size was normal overall (57 +/- 9 microns minimum diameter [Dm] atrophy index 195 +/- 243, and hypertrophy index 66 +/- 78), with no differences between the two fiber subtypes (Dm 58 +/- 8 microns for type I and 61 +/- 8 microns for type II). Overall size correlated inversely with static volumes (e.g. Dm with RV, r = -0.729, p < 0.01). CONCLUSIONS: The laparoscopic technique described is simple and safe for use in humans to obtain diaphragm muscle specimens that are valid for morphometric analysis, allowing us to enlarge the range of subjects that can be enrolled for this type of study. The fiber muscles studied are smaller when functional involvement is greater in chronic obstructive pulmonary disease.

Adult↗
PubMed2003

A nonempirical anisotropic atom-atom model potential for chlorobenzene crystals.

A nearly nonempirical, transferable model potential is developed for the chlorobenzene molecules (C6ClnH6-n, n = 1 to 6) with anisotropy in the atom-atom form of both electrostatic and repulsion interactions. The potential is largely derived from the charge densities of the molecules, using a distributed multipole electrostatic model and a transferable dispersion model derived from the molecular polarizabilities. A nonempirical transferable repulsion model is obtained by analyzing the overlap of the charge densities in dimers as a function of orientation and separation and then calibrating this anisotropic atom-atom model against a limited number of intermolecular perturbation theory calculations of the short-range energies. The resulting model potential is a significant improvement over empirical model potentials in reproducing the twelve chlorobenzene crystal structures. Further validation calculations of the lattice energies and rigid-body k = 0 phonon frequencies provide satisfactory agreement with experiment, with the discrepancies being primarily due to approximations in the theoretical methods rather than the model intermolecular potential. The potential is able to give a good account of the three polymorphs of p-dichlorobenzene in a detailed crystal structure prediction study. Thus, by introducing repulsion anisotropy into a transferable potential scheme, it is possible to produce a set of potentials for the chlorobenzenes that can account for their crystal properties in an unprecedentedly realistic fashion.

Journal Article↗
PubMed1991

Reassessing the validity and reliability of the MMPI Alexithymia Scale.

In the past decade, alexithymia has emerged as a heuristically useful personality construct used to explain the pathogenesis of a variety of physical illnesses, including classical psychosomatic diseases, somatization disorders, hypochondriasis, and somatoform pain disorders. Unfortunately, research evaluating the alexithymia construct has been conducted with little attention to assessing the psychometric properties of various scales used to measure it. In two separate studies, we examined various scale and item properties as well as the factor structure and validity of the Minnesota Multiphasic Personality Inventory Alexithymia Scale (MMPI-A), one of the most commonly used scales to assess alexithymia. In Study 1, the 22 items that comprise the MMPI-A were extracted from a computerized MMPI data bank which included separate samples of psychiatric inpatients and outpatients. Poor item-to-scale characteristics and only moderate levels of internal reliability were found for both samples. Factor analysis produced factors that were poorly related to the theoretical domains of the alexithymia construct. In Study 2, we found little support for validity of the scale as those patients identified as alexithymic and nonalexithymic by the MMPI-A did not differ on several theoretically relevant scales. These results question seriously the value of the MMPI-A in investigating the alexithymia construct.

Adult↗
PubMed2002

Validation of the dimensional factor structure of the personality psychopathology five in clinical and nonclinical samples.

Confirmatory factor analysis (CFA) was used to determine whether the latent structure underlying the items composing the MMPI-2 Personality Psychopathology Five scales (PSY-5; Harkness, McNulty, & Ben-Porath, 1995) is representative of the theoretical model that informed their construction. Results from the CFA revealed a good fit between the hypothesized five-factor model and the obtained latent factor structure in both clinical (n = 284) and nonclinical (n = 351) samples. Moreover, the PSY-5 model proved to be a better fit than a random five-factor model and a one-factor model. Correlations between the PSY-5 scales and a set of MMPI-2 (DSM-IV) personality disorder scales provided additional evidence of convergent and discriminant validity.

Adult↗
PubMed2006

Validation of the Taiwanese version of the Brief Fatigue Inventory.

We validated the Taiwanese version of the Brief Fatigue Inventory (BFI-T) in a sample of 439 Taiwanese patients with multiple cancer diagnoses. Internal consistency was indicated by Cronbach alphas of 0.96 for fatigue-related severity and 0.95 for interference. Test-retest reliability was 0.89 for fatigue severity and 0.91 for interference. Factor analysis revealed a one-factor structure. Convergent validity was examined by correlating the BFI-T worst fatigue and fatigue severity composite scores with POMS vigor and fatigue subscales scores. Known-group validity was established by comparing BFI-T worst fatigue and severity composite scores between patients with low functional status and high functional status and between inpatients and outpatients. The BFI-T's sensitivity was examined by comparing BFI-T severity and interference composite scores before, during, and after chemotherapy treatment in a subsample of 20 breast cancer patients. The BFI-T is reliable, valid, and sensitive for measuring cancer-related fatigue severity and interference among Taiwanese cancer patients.

Adult↗
PubMed2004

Validation of a fluid-structure interaction model of a heart valve using the dynamic mesh method in fluent.

Simulations of coupled problems such as fluid-structure interaction (FSI) are becoming more and more important for engineering purposes. This is particularly true when modeling the aortic valve, where the FSI between the blood and the valve determines the valve movement and the valvular hemodynamics. Nevertheless only a few studies are focusing on the opening and closing behavior during the ejection phase (systole). In this paper, we present the validation of a FSI model using the dynamic mesh method of Fluent for the two-dimensional (2D) simulation of mechanical heart valves during the ejection phase of the cardiac cycle. The FSI model is successfully validated by comparing simulation results to experimental data obtained from in vitro studies using a CCD camera.

Algorithms↗
PubMed2003

Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design.

The aurora kinases are a novel oncogenic family of mitotic serine/threonine kinases (S/T kinases) that are overexpressed in a number of solid tumors, including pancreas and colorectal cancer. A PSI-BLAST search [National Center for Biotechnology Information (NCBI)] with the sequence of the S/T kinase domain of human aurora1 kinase [also known as AUR1, ARK2, AIk2, AIM-1, and STK12] and human aurora2 kinase (also known as AUR2, ARK1, AIK, BTAK, and STK15) showed a high sequence similarity to the three-dimensional structures of bovine cAMP-dependent kinase [Brookhaven Protein Data Bank code 1CDK], murine cAMP-dependent kinase (1APM), and Caenorhabditis elegans twitchin kinase (1KOA). When the aurora1 or aurora2 sequence was input into the tertiary structure prediction programs THREADER and 3D-PSSM (three-dimensional position-sensitive scoring matrix), the top structural matches were 1CDK, 1APM, and 1KOA, confirming that these domains are structurally conserved. The structural models of aurora1 and aurora2 were built using 1CDK as the template structure. Molecular dynamics and docking simulations, targeting the ATP binding site of aurora2 with adenylyl imidodiphosphate (AMP-PNP), staurosporine, and six small molecular S/T kinase inhibitors, identified active-site residues that interact with these inhibitors differentially. The docked structures of the aurora2-AMP-PNP and aurora2-staurosporine complexes indicated that the adenine ring of AMP-PNP and the indolocarbazole moiety of staurosporine have similar positions and orientations and provided the basis for the docking of the other S/T kinase inhibitors. Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2 in which H-89 and 6,7-dimethoxyquinazoline compounds exhibited high binding energies compared with that of staurosporine. The calculated binding energies for the docked small-molecule inhibitors were qualitatively consistent with the IC(50) values generated using an in vitro kinase assay. The aurora2 structural model provides a rational basis for site-directed mutagenesis of the active site; design of novel H-89, staurosporine, and quinazoline analogues; and the screening of the available chemical database for the identification of other novel, small-molecular entities.

Amino Acid Sequence↗