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PubMed2005

Validation of a histamine H3 receptor model through structure-activity relationships for classical H3 antagonists.

Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists. A putative binding site for classical, imidazole-derived H(3) antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H(3) antagonist (compound 1, pK(i)=8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H(3) antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H(3) antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.

Amino Acid Sequence↗
PubMed1999

Total neutron diffraction: a route to the correct local structure of disordered LaMo2O5 and its application to the model compound Zn2Mo3O8.

Analysis of Bragg diffraction is the normal route to the structure of crystalline materials. Here we demonstrate the use of total neutron diffraction in determining the local structure in the disordered lanthanum molybdate LaMo(2)O(5). An average structure with space-group symmetry P6(3)/mmc accounts for the Bragg scattering and shows that the compound contains the rare Mo(6)O(18) cluster and a unique type of Mo-Mo bonded sheet. However, this gives an incomplete picture of the structure, since it does not reveal how the sites with fractional occupancy are occupied at a local level. Two models describing possible local structures are constructed by removing symmetry elements present in the average structure. Total correlation functions, T(r), calculated from these structures, with space-group symmetry P6(3)mc and P3;m1, are compared with the experimental T(r) to show the validity of these local structures. The close relationship between the T(r)'s of the component structures gives an insight into why disorder occurs in LaMo(2)O(5). The calculated and experimental T(r)'s for a model compound, Zn(2)Mo(3)O(8), are compared to show the agreement expected from an ordered crystalline material. Remaining discrepancies between our model and the experimental T(r) give an insight into the origin of additional disorder in LaMo(2)O(5).

Journal Article↗
PubMed2006

The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue.

OBJECTIVES: To validate a latent class structure derived empirically from a clinical data set obtained from persons with chronic medically unexplained fatigue. METHODS: The strategies utilized in this validation study included: recalculating latent class analysis (LCA) results varying random seeds and the number of initial random starting sets; recalculating LCA results by substituting alternate variables to demonstrate a robust solution; determining the statistical significance of between-class differences on disability, fatigue and demographic measures omitted from the data set used for LCA; cross-classifying class membership using established Centers for Disease Control and Prevention (CDC) research criteria for chronic fatigue syndrome (CFS) to compare the relative proportions of subjects designated CFS, chronic fatigue (not CFS) or healthy controls captured by the latent classes. RESULTS: Recalculation of results and substitution of variables for low-loading variables demonstrated a robust LCA result. Highly significant between-class differences were confirmed between Class 2 (well) and those interpreted as ill/fatigued. Analysis of between-class differences for the fatigue groups revealed significant differences for all disability and fatigue variables, but with equivalent levels of reported activity and reduction in motivation. Cross-classification against established CDC criteria demonstrated that 89% of subjects constituting Class 2 (well) were indeed nonfatigued controls. A general tendency for grouping CFS cases in the multiple symptomatic classes was noted. CONCLUSION: This study established reasonably good validity for an empirically-derived latent class solution reflecting considerable heterogeneity among subjects with medically unexplained chronic fatigue. This work strengthens the growing understanding of CFS as a heterogeneous entity comprised of several conditions with different underlying pathophysiological mechanisms.

Adult↗
PubMed1997

Development and factor analytic validation of the SPANAS among women in Spain: (more) cross-cultural convergence in the structure of mood.

We reported our findings on the development and preliminary validation of a Spanish-language measure of positive and negative affect. Using confirmatory factor analytic techniques on data generated by 708 women in northern Spain, we obtained reasonable construct validity and reliability data for the measure. Consistent with past cross-cultural studies, a two-factor Positive Affect-Negative Affect (PA-NA)structure emerged, with PA and NA as relatively independent entities. The structure in this sample converged with that reported for a culturally separate group of participants. This factor structure has therefore revealed invariance across a number of cultural groups in Asia, Europe, and North America.

Adult↗
PubMed2003

Assessing personality disorders using a systematic clinical interview: evaluation of an alternative to structured interviews.

The aim of this study was to assess interrater reliability and provide initial data bearing on the validity of a method of assessing personality disorders (PDs) that does not presume that patients can accurately self-report personality pathology. In a sample of 24 outpatients, two clinician-judges independently applied the Shedler-Westen Assessment Procedure-200 (SWAP-200; Westen & Shedler, 1999a, 2000), a 200-item Q-sort procedure for assessing personality pathology, to data from the Clinical Diagnostic Interview (Westen, 2002), a systematic clinical interview that mirrors and standardizes methods used by experienced clinicians to diagnose personality. In 16 of the 24 cases, the treating clinician also independently described the patient using the SWAP-200 Q-sort, based on longitudinal knowledge of the patient over the course of treatment, blind to the interview data. Interrater reliability was uniformly high, with median correlations between interviewers at r > .80. Interviewer-treating clinician correlations were also high, with median convergent validity coefficients at r > .80. Diagnostic overlap (discriminant validity) was moderate for dimensional DSM-IV diagnoses, reflecting extensive comorbidity among disorders, but minimal for empirically derived diagnoses identified in prior research. Treating clinicians' dimensional PD diagnoses using this method also strongly predicted interviewer-rated measures of adaptive functioning. The findings provide preliminary support for the reliability and validity of an alternative to structured interviews for diagnosing personality pathology, and suggest that the way to improve validity of personality diagnosis may not be to minimize clinical inference but to quantify it using psychometric instruments.

Adult↗
PubMed2004

A structural similarity analysis of double-helical DNA.

A database of the structural properties of all 32,896 unique DNA octamer sequences has been calculated, including information on stability, the minimum energy conformation and flexibility. The contents of the database have been analysed using a variety of Euclidean distance similarity measures. A global comparison of sequence similarity with structural similarity shows that the structural properties of DNA are much less diverse than the sequences, and that DNA sequence space is larger and more diverse than DNA structure space. Thus, there are many very different sequences that have very similar structural properties, and this may be useful for identifying DNA motifs that have similar functional properties that are not apparent from the sequences. On the other hand, there are also small numbers of almost identical sequences that have very different structural properties, and these could give rise to false-positives in methods used to identify function based on sequence alignment. A simple validation test demonstrates that structural similarity can differentiate between promoter and non-promoter DNA. Combining structural and sequence similarity improves promoter recall beyond that possible using either similarity measure alone, demonstrating that there is indeed information available in the structure of double-helical DNA that is not readily apparent from the sequence.

DNA↗
PubMed1999

Conformational properties of native sperm whale apomyoglobin in solution.

Apomyoglobin from sperm whale is often used for studies of ligand binding, protein folding, and protein stability. In an effort to describe its conformational properties in solution, homonuclear and heteronuclear (13C and 15N) NMR methods were applied to the protein in its native state. Assignments were confirmed for nuclear Overhauser effects (NOEs) involving side chain and backbone protons in the folded regions of the structure. These NOEs were used to derive distance restraints. The shifts induced by the hydrophobic dye 8-anilino-1-naphthalenesulfonic acid (ANS) were inspected in the regions remote from its binding site and served as an indicator of conformational flexibility. 3JalphaH-NH values were obtained to assess dihedral angle averaging and to provide additional restraints. A family of structures was calculated with X-PLOR and an ab initio simulated annealing protocol using holomyoglobin as a template. Where the structure appeared well defined by chemical shift, line width, ANS perturbation, and density of NOEs, the low resolution model of apomyoglobin provides a valid approximation for the structure. The new model offers an improved representation of the folded regions of the protein, which encompass the A, B, E, helices as well as parts of the G and H helices. Regions that are less well defined at this stage of calculations include the CD corner and the end of the H-helix. The EF-F-FG segment remains uncharacterized.

Animals↗
PubMed2006

Classical QSAR study on chromene derivatives as lanosterol 14alpha- demethylase inhibitor: a non azole antifungal target.

A lanosterol 14alpha-demethylase inhibitors of chromene series were subjected to classical quantitative structural activity relationship studies. Apart from the indicator variables encoding for different group contribution, there are various physico-chemical descriptors like steric, thermodynamic and electronic parameters, which were applied to explore the structural requirements for inhibition of enzyme. Multiple linear regression analysis shows that substituents on the appended alkylated ether and the carbon chain length, which should not be more than six at R3 and R1 positions in the parent nucleus, are essential to modulate the activity. Electronic parameters such as highest occupied molecular orbital energy and dipole dipole energy have been found to play an important contribution for biological activity. From the orientation or distribution of the total molecular structures in 3D space, it was assessed that Principal Moments of Inertia at X-axis is detrimental for fungal inhibitory activity. Thus validated models bring important structural insights to aid the design of potent lanosterol 14alpha-demethylase inhibitors prior to their synthesis.

Antifungal Agents↗
PubMedDate not supplied

Development and initial validation of an instrument to measure physician-pharmacist collaboration from the physician perspective.

OBJECTIVE: Using a conceptual model of collaborative working relationships between pharmacists and physicians, a measure for physician-pharmacist collaboration from the physician perspective was developed. The measure was analyzed for its factor structure, internal consistency, construct validity, and other psychometric properties. METHODS: An initial 27-item Physician-Pharmacist Collaboration Instrument (PPCI) was developed to assess seven themes about professional relationships using Likert scales. The PPCI was mailed to a random sample of 1000 primary care physicians. Principal component analysis was used to assess the structure and uncover underlying dimensions of the initial instrument. Items were evaluated for inclusion or exclusion into a refined instrument. Internal consistency was assessed by calculating Alpha coefficients for each identified factor. Convergent validity was assessed using Spearman correlations between the identified factors and a previous measure of collaborative care. After measure refinement, confirmatory factor analysis was used to evaluate the fit of both versions of the instrument. RESULTS: Three hundred forty usable surveys were returned for a response rate of 34%. Almost 70% of the respondents were male with a mean age of 45.8. A majority were family practice physicians (72.1%) in private practice (67.3%). Three unique factors were identified during principal component analysis and utilized in a confirmatory factor analysis. Both a full and a 14-item reduced model were constructed and tested. Cronbach's alpha for the three factors of the full model ranged from 0.91 to 0.97, while the reliability for the reduced model ranged from 0.86 to 0.96. Comparative fit indexes of 0.97 and 0.98 were obtained, indicating good fit for the models. CONCLUSIONS: The results indicate good reliability and validity of the refined (14-item) PPCI. This instrument can be useful as a research tool for assessment of the physicians' perspective about a physician-pharmacist relationship. Further research is warranted to examine if the extent of relationship development, as measured with the PPCI, can affect patient care outcomes.

Attitude of Health Personnel↗
PubMed2005

General and targeted statistical potentials for protein-ligand interactions.

We present a novel atom-atom potential derived from a database of protein-ligand complexes. First, we clarify the similarities and differences between two statistical potentials described in the literature, PMF and Drugscore. We highlight shortcomings caused by an important factor unaccounted for in their reference states, and describe a new potential, which we name the Astex Statistical Potential (ASP). ASP's reference state considers the difference in exposure of protein atom types towards ligand binding sites. We show that this new potential predicts binding affinities with an accuracy similar to that of Goldscore and Chemscore. We investigate the influence of the choice of reference state by constructing two additional statistical potentials that differ from ASP only in this respect. The reference states in these two potentials are defined along the lines of Drugscore and PMF. In docking experiments, the potential using the new reference state proposed for ASP gives better success rates than when these literature reference states were used; a success rate similar to the established scoring functions Goldscore and Chemscore is achieved with ASP. This is the case both for a large, general validation set of protein-ligand structures and for small test sets of actives against four pharmaceutically relevant targets. Virtual screening experiments for these targets show less discrimination between the different reference states in terms of enrichment. In addition, we describe how statistical potentials can be used in the construction of targeted scoring functions. Examples are given for cdk2, using four different targeted scoring functions, biased towards increasingly large target-specific databases. Using these targeted scoring functions, docking success rates as well as enrichments are significantly better than for the general ASP scoring function. Results improve with the number of structures used in the construction of the target scoring functions, thus illustrating that these targeted ASP potentials can be continuously improved as new structural data become available.

Binding Sites↗
PubMed1999

MEARA sequence repeat of human CstF-64 polyadenylation factor is helical in solution. A spectroscopic and calorimetric study.

The primary structure of the human CstF-64 polyadenylation factor contains 12 nearly identical repeats of a consensus motif of five amino acid residues with the sequence MEAR(A/G). No known function has yet been ascribed to this motif; however, according to secondary structure prediction algorithms, it should form a helical structure in solution. To validate this theoretical prediction, we synthesized a 31 amino acid residue peptide (MEARA(6)) containing six repeats of the MEARA sequence and characterized its structure and stability by circular dichroism (CD) spectroscopy and differential scanning calorimetry (DSC). No effects of concentration on the CD or DSC properties of MEARA(6) were observed, indicating that the peptide is monomeric in solution at concentrations up to 2 mM. The far UV-CD spectra of MEARA(6) indicates that at a low temperature (1 degrees C) the MEARA(6) peptide has a relatively high helical content (76% at pH 2.0 and 65% at pH 7.0). The effects of pH and ionic strength on the CD spectrum of MEARA(6) suggest that a number of electrostatic interactions (e.g., i, i + 3 Arg/Glu ion pair, charge-dipole interactions) contribute to the stability of the helical structure in this peptide. DSC profiles show that the melting of MEARA(6) helix is accompanied by positive change in the enthalpy. To determine thermodynamic parameters of helix-coil transition from DSC profiles for this peptide, we developed a new, semiempirical procedure based on the calculated function for the heat capacity of the coiled state for a broad temperature range. The application of this approach to the partial molar heat capacity function for MEARA(6) provides the enthalpy change for helix formation calculated per amino acid residue as 3.5 kJ/mol.

Amino Acid Sequence↗
PubMed1987

General method validation guidelines for pharmaceutical samples.

Method validation guidelines, which provide an organizational structure for the design and evaluation of a validation procedure, are presented for a wide range of pharmaceutical applications. The validation guidelines are based on the analyte concentration/sample matrix combination to which the method will be applied. These guidelines include the selection of appropriate validation parameters, design considerations for evaluation, and a discussion of acceptance guidelines for the determination of acceptable method performance. A set of tables is included which illustrates the selection and testing procedure and tailors the entire validation process to the specific characteristics of the determination to be made.

Chemistry, Pharmaceutical↗
PubMed2006

Development and testing of a Clinical Learning Environment Diagnostic Inventory for baccalaureate nursing students.

Aim. This paper reports the development and testing of the psychometric properties of the Clinical Learning Environment Diagnostic Inventory for baccalaureate nursing students. Background. The quality of the clinical learning environment is an essential factor in determining the quality of nursing students' clinical experience. It is also well-recognized that the clinical setting can be a source of stress and anxiety for students. To design an optimal clinical learning environment for students, instruments based on the cognitive and socio-emotional aspects of the learning process are necessary. Method. The hypothetical construct of the clinical learning environment was derived from a comprehensive review of the literature, including experiential learning theory and the epistemology of practice. Developing the instrument involved the collection of items through semi-structured interviews, assessing content validity and determining the scaling. After a pilot study, the instrument was tested with 312 undergraduate students and 157 preceptors between September and December 2004. The factor structure was determined by exploratory factor analysis. Results. Exploratory factor analysis produced a five-factor solution that was similar to the hypothetical model. Cronbach's alpha internal consistency reliability coefficients ranged from 0.65 to 0.77 across the five factors. Three-week test-retest reliability coefficients ranged from 0.59 to 0.74. Criterion-related validity and construct validity were estimated by the correlation between the Clinical Learning Environment Diagnostic Inventory and appropriate other instruments and a set of comparison data obtained from the students and preceptors. Conclusion. The findings yielded acceptable estimates of reliability and validity of the Clinical Learning Environment Diagnostic Inventory. Therefore, this instrument is considered useful for assessing learning environments in clinical settings.

Adult↗
PubMed1995

Local and global structural properties of the HIV-MN V3 loop.

Studies of the feasibility of a subunit vaccine to protect against human immunodeficiency virus (HIV) infection have principally focused on the third variable (V3) loop. The principal neutralizing determinant (PND) of HIV-1 is located inside the V3 loop of the surface envelope glycoprotein, gp120. However, progress toward a PND-based vaccine has been impeded by the amino acid sequence variability in the V3 loops of different HIV isolates. Theoretical studies revealed that the variability in sequence and structure of the V3 loop is confined to the N- and C-terminal sides of the conserved GPG crest. This leaves three regions of the V3 loop conserved both in sequence and secondary structure. We present the results of NMR studies that test the validity of our theoretical predictions. Structural studies are reported for the HIV-V3 loop (HIV-MN) in the linear and cyclic (S-S-bridged) forms. For the V3 loop sequence of the HIV-MN isolate, the three conserved secondary structural elements are as underlined below: turns turn helix CTRPNYNKRKRIHIGPGRAFYTTKNIIGTIROAHC Finally, the conformational requirement of the PND in the V3 loop-antibody interaction is tested by monitoring the monoclonal antibody binding to the HIV-MN V3 loop in the linear and cyclic forms by enzyme-linked immunosorbent assay. The binding data reveal that the cyclic V3 loop is a better ligand for the monoclonal antibodies than the linear form although the latter has the same sequence. This means that the monoclonal antibodies recognize the PNDs as conformational epitopes.

Amino Acid Sequence↗
PubMed1996

Defense mechanisms in adolescents as a function of age, sex, and mental health status.

OBJECTIVE: To modify an existing instrument to provide a valid assessment of defense mechanisms in adolescents and to examine defense structure and usage as a function of age, sex, and mental health status. METHOD: Six hundred ninety-three subjects (187 nonclinic adolescents, 229 internalizing females, 99 incarcerated male delinquents, and 178 nonclinic adults) completed the modified Defense Style Questionnaire (DSQ), which yielded 19 defense scores. RESULTS: Factor analyses of the 19 defense scores on the adolescent sample yielded three factors: Immature, Mature, and Prosocial Defenses. These were similar to those from studies of adults. Additional factor analyses were conducted on defense scores of subjects grouped by age, sex, and mental health status. The Immature and Mature Factors were relatively consistent across groups, but the Prosocial Factor varied by group. Multivariate analyses of variance and analyses of variance on individual and composite defense scores revealed differences by age, sex, and mental health status. CONCLUSIONS: Although the modified DSQ needs further work to improve its psychometric properties, it is clearly fruitful to assess adolescent defense mechanisms. Results from extant studies of adults and males on the structure of defenses cannot be validly extrapolated to other age groups and to females.

Adaptation, Psychological↗
PubMed1995

Psychiatric morbidity in primary public health care: a Nordic multicentre investigation. Part I: method and prevalence of psychiatric morbidity.

The prevalence of mental illness in five different Scandinavian primary care populations was investigated in this study. Patients consecutively consulting their general practitioner a particular week-day were included in the study. Initially the SCL-25 was applied and next the high scores and a sample of the low scores were interviewed by the PSE. In the analysis the screening procedure was first validated. The internal validity of the SCL was tested by means of Rasch latent structure analysis and the external validity tested by ROC/QROC analysis. Based on this, a short 8-item version of the SCL was developed. The prevalence of mental illness in all centres was 0.26 with a minimum of 0.14 in Nacka and a maximum of 0.34 in Turku.

Adolescent↗
PubMed1998

[GSG (Structured Health Regulation)-conforming documentation of surgical interventions in a university clinic--3 years clinical experiences 1994-1996].

The cost increase in the public health sector is steadily mounting and hence politicians are forced to redefine the economic conditions for regulations. As a new quality in the area of inpatient hospital care the new German law of structural health care (GSG), valid as of January 1, 1993 replaces the principle of covering full costs. The GSG law required in our hospital an adjustment of existing EDP structures with integrated automatic remuneration estimate and the installation of a medical structure of the organisation for complete and correct documentation. Weakpoints of the prescribed obligatory ICPM codes and inadequate legal regulations result in a lack of separation or wrong integration of the lump sum payment in individual cases (FP) and special compensation (SE). The summary analysis of the compensation system with a subsequent medical control system showed a primarily inaccurate classification by 12%. There is as yet no proof for the usefulness of a lump sum payment system resulting in a selection of risks.

Cost Control↗
PubMed2004

Consensus alignment server for reliable comparative modeling with distant templates.

Consensus is a server developed to produce high-quality alignments for comparative modeling, and to identify the alignment regions reliable for copying from a given template. This is accomplished even when target-template sequence identity is as low as 5%. Combining the output from five different alignment methods, the server produces a consensus alignment, with a reliability measure indicated for each position and a prediction of the regions suitable for modeling. Models built using the server predictions are typically within 3 A rms deviations from the crystal structure. Users can upload a target protein sequence and specify a template (PDB code); if no template is given, the server will search for one. The method has been validated on a large set of homologous protein structure pairs. The Consensus server should prove useful for modelers for whom the structural reliability of the model is critical in their applications. It is currently available at http://structure.bu.edu/cgi-bin/consensus/consensus.cgi.

Algorithms↗