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PubMed2002

Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, noncompetitive antagonist of the metabotropic glutamate 1 receptor.

A model of the rmGlu1 seven-transmembrane domain complexed with a negative allosteric modulator, 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)- 1,6-dihydro-pyrimidine-5-carbonitrile (EM-TBPC) was constructed. Although the mGlu receptors belong to the family 3 G-protein-coupled receptors with a low primary sequence similarity to rhodopsin-like receptors, the high resolution crystal structure of rhodopsin was successfully applied as a template in this model and used to select residues for site-directed mutagenesis. Three mutations, F801(6.51)A, Y805(6.55)A, and T815(7.39)M caused complete loss of the [(3)H]EM-TBPC binding and blocked the EM-TBPC-mediated inhibition of glutamate-evoked G-protein-coupled inwardly rectifying K(+) channel current and [Ca(2+)](i) response. The mutation W798(6.48)F increased the binding affinity of antagonist by 10-fold and also resulted in a marked decrease in the IC(50) value (4 versus 128 nm) compared with wild type. The V757(5.47)L mutation led to a dramatic reduction in binding affinity by 13-fold and a large increase in the IC(50) value (1160 versus 128 nm). Two mutations, N7474(5.51)A and N7504(5.54)A, increased the efficacy of the EM-TBPC block of the glutamate-evoked [Ca(2+)](i) response. We observed a striking conservation in the position of critical residues. The residues Val-757(5.47), Trp-798(6.48), Phe-801(6.51), Tyr-805(6.55), and Thr-815(7.39) are critical determinants of the EM-TBPC-binding pocket of the mGlu1 receptor, validating the rhodopsin crystal structure as a template for the family 3 G-protein-coupled receptors. In our model, the aromatic ring of EM-TBPC might interact with the cluster of aromatic residues formed from Trp-798(6.48), Phe-801(6.51), and Tyr-805(6.55), thereby blocking the movement of the TM6 helix, which is crucial for receptor activation.

Allosteric Site↗

PubMed2005

Assessing strategies for improved superfamily recognition.

There are more than 200 completed genomes and over 1 million nonredundant sequences in public repositories. Although the structural data are more sparse (approximately 13,000 nonredundant structures solved to date), several powerful sequence-based methodologies now allow these structures to be mapped onto related regions in a significant proportion of genome sequences. We review a number of publicly available strategies for providing structural annotations for genome sequences, and we describe the protocol adopted to provide CATH structural annotations for completed genomes. In particular, we assess the performance of several sequence-based protocols employing Hidden Markov model (HMM) technologies for superfamily recognition, including a new approach (SAMOSA [sequence augmented models of structure alignments]) that exploits multiple structural alignments from the CATH domain structure database when building the models. Using a data set of remote homologs detected by structure comparison and manually validated in CATH, a single-seed HMM library was able to recognize 76% of the data set. Including the SAMOSA models in the HMM library showed little gain in homolog recognition, although a slight improvement in alignment quality was observed for very remote homologs. However, using an expanded 1D-HMM library, CATH-ISL increased the coverage to 86%. The single-seed HMM library has been used to annotate the protein sequences of 120 genomes from all three major kingdoms, allowing up to 70% of the genes or partial genes to be assigned to CATH superfamilies. It has also been used to recruit sequences from Swiss-Prot and TrEMBL into CATH domain superfamilies, expanding the CATH database eightfold.

Databases, Protein↗

PubMed2005

[The situation of patients with dementia may be rectified by Ginkgo biloba. Results of a health services research study concerning the ability of patients with dementia, quality of life of the nursing family members and total treatment costs].

UNLABELLED: BACKGROUND AND ISSSUES: Ginkgo biloba-extracts are often used in therapy of patients with dementia. In this study, benefit and structure of Ginkgo biloba-extract EGb 761 in treatment of patients with dementia was examined. PATIENTS AND METHODS: For the assessment of quality of life of care-taking relatives and patients as well as treatment costs were documented. The study was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years. Society's perspective was taken. Barthel-Index and MMST were also documented. Because of significant differences at inclusion of both cohorts, a matched-pairs-analysis and multiple regression analysis conducted. RESULTS: According to PLC a significant improvement in quality-of-life of care-taking relatives (p < 0.001) and patients (positive mood p = 0.018, negative mood p < 0.001) was only observed in the Ginkgo-cohort. Also Barthel-Index indicated an improvement in the Ginkgo-cohort (p < or = 0,001). MMST-scores increased significantly only in the Ginkgo-cohort (p < 0.001). Average total cost per patient amounted to 3.614,75 euro in the standard-cohort, whereas these costs per patient in the Ginkgo-cohort amounted to 3.031,78 euro (p = 0.067). Results were confirmed by matched-pairs-analysis. RESULTS: Ginkgo treatment has a valid place in caretaking structure of health services. Gingko attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.

Activities of Daily Living↗

PubMed1993

Relationship between molecular connectivity and carcinogenic activity: a confirmation with a new software program based on graph theory.

For a database of 826 chemicals tested for carcinogenicity, we fragmented the structural formula of the chemicals into all possible contiguous-atom fragments with size between two and eight (nonhydrogen) atoms. The fragmentation was obtained using a new software program based on graph theory. We used 80% of the chemicals as a training set and 20% as a test set. The two sets were obtained by random sorting. From the training sets, an average (8 computer runs with independently sorted chemicals) of 315 different fragments were significantly (p < 0.125) associated with carcinogenicity or lack thereof. Even using this relatively low level of statistical significance, 23% of the molecules of the test sets lacked significant fragments. For 77% of the molecules of the test sets, we used the presence of significant fragments to predict carcinogenicity. The average level of accuracy of the predictions in the test sets was 67.5%. Chemicals containing only positive fragments were predicted with an accuracy of 78.7%. The level of accuracy was around 60% for chemicals characterized by contradictory fragments or only negative fragments. In a parallel manner, we performed eight paired runs in which carcinogenicity was attributed randomly to the molecules of the training sets. The fragments generated by these pseudo-training sets were devoid of any predictivity in the corresponding test sets. Using an independent software program, we confirmed (for the complex biological endpoint of carcinogenicity) the validity of a structure-activity relationship approach of the type proposed by Klopman and Rosenkranz with their CASE program.

Carcinogens↗

PubMed2006

Structure and function in glaucoma: The relationship between a functional visual field map and an anatomic retinal map.

PURPOSE: To examine the relationship between an anatomic map relating the retinal nerve fiber layer (RNFL) distribution to the optic nerve head and a functional map derived from the interpoint correlation of raw sensitivities in visual field (VF) testing. METHODS: Previously, interpoint correlations were generated for all possible pairs of VF test points in a dataset of 98,821 Humphrey VF test results taken from the Moorfields Eye Hospital archive. The relationship between these correlations and the physical distance between the VF test point pairs was evaluated by Pearson's correlation coefficient and multiple regression analysis. The distance between the pairs of VF test points was calculated in two ways. First, the anatomic map was used to estimate the angular distance at the optic nerve head (ONH), between the RNFL bundles corresponding to the VF test points in each pair (ONHd). Second, the retinal distance between pairs of test points was calculated from the Humphrey VF template (RETd). A best-fit model for predicting functional correlation (FC) from ONHd and RETd was constructed and used to formulate a filter incorporating the anatomic-functional correlation data. RESULTS: All scatterplots showed a negative association between interpoint retinal sensitivity correlation values and distance between points: ONHd (R2 = 0.60) and RETd (R2 = 0.33). The raw sensitivity correlation values could be predicted from a multiple regression model using ONHd, RETd, and a combined interaction of ONHd and RETd (R2 = 0.75, P < 0.00001). The construction of a new filter was based on the equation FC = 0.9325 - (0.0029 . ONHd) - (0.0077 . RETd) + (0.0001 . ONHd . RETd). CONCLUSIONS: A good level of association was observed between the strength of correlation between points in the VF and the relative location of those test points in the peripheral retina and in corresponding RNFL bundles at the ONH. These results help to validate the relationship between structure and function and may be of use in the further refinement of physiologically derived VF filters to reduce measurement noise.

Glaucoma, Open-Angle↗

PubMed1996

Content validity of the Quebec licensing examination (OSCE). Assessed by practising physicians.

OBJECTIVE: To assess content validity of the objective structured clinical examination (OSCE), which uses multiple encounters with standardized patients and which is included in the Quebec licensing examination (QLEx). DESIGN: Descriptive study using written questionnaires based on Likert-type scales. SETTING: Examination centres of the QLEx. PARTICIPANTS: Thirteen practising family physicians with 3 to 6 years' practice experience who passed the QLEx OSCE in May 1993. MAIN OUTCOME MEASURES: Opinion whether the QLEx OSCE globally measured the competence of family physicians; opinion whether OSCE cases and stations made it possible to assess the main clinical abilities required of a family physician; opinion on specific statements about each case, such as how frequently the case was seen in the participants' practice, if the participants knew how to deal with the problem, if the simulated patient was believable, if the clinical situation was realistic, and if the duration of the station was adequate; and participants' self-assessment of their performance on the case. RESULTS: Eleven participants (84.6%) agreed that the OSCE globally measured the competence of a family physician. All agreed that the OSCE cases and stations made it possible to assess the main clinical skills required of a family physician. For most of the cases, participants believed that they knew how to deal with the problem, that the clinical situation was realistic, that the simulated patient was believable, and that the case duration was adequate. CONCLUSIONS: The results of this study support the content validity of the QLEx OSCE and confirm that it assesses the main skills needed for practising family medicine and adequately samples possible encounters or cases seen in family practice.

Adult↗

PubMed2004

Does parallel item content on WOMAC's pain and function subscales limit its ability to detect change in functional status?

BACKGROUND: Although the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) is considered the leading outcome measure for patients with osteoarthritis of the lower extremity, recent work has challenged its factorial validity and the physical function subscale's ability to detect valid change when pain and function display different profiles of change. This study examined the etiology of the WOMAC's physical function subscale's limited ability to detect change in the presence of discordant changes for pain and function. We hypothesized that the duplication of some items on the WOMAC's pain and function subscales contributed to this shortcoming. METHODS: Two eight-item physical function scales were abstracted from the WOMAC's 17-item physical function subscale: one contained activities and themes that were duplicated on the pain subscale (SIMILAR-8); the other version avoided overlapping activities (DISSIMILAR-8). Factorial validity of the shortened measures was assessed on 310 patients awaiting hip or knee arthroplasty. The shortened measures' abilities to detect change were examined on a sample of 104 patients following primary hip or knee arthroplasty. The WOMAC and three performance measures that included activity specific pain assessments--40 m walk test, stair test, and timed-up-and-go test--were administered preoperatively, within 16 days of hip or knee arthroplasty, and at an interval of greater than 20 days following the first post-surgical assessment. Standardized response means were used to quantify change. RESULTS: The SIMILAR-8 did not demonstrate factorial validity; however, the factorial structure of the DISSIMILAR-8 was supported. The time to complete the performance measures more than doubled between the preoperative and first postoperative assessments supporting the theory that lower extremity functional status diminished over this interval. The DISSIMILAR-8 detected this deterioration in functional status; however, no significant change was noted for the SIMILAR-8. The WOMAC pain scale demonstrated a slight reduction in pain and the performance specific pain measures did not reflect a change in pain. All measures showed substantial improvement over the second assessment interval. CONCLUSIONS: These findings support the hypothesis that activity overlap on the pain and function subscales plays a causal role in limiting the WOMAC physical function subscale's ability to detect change.

Activities of Daily Living↗

PubMed1997

Computational, pulse-radiolytic, and structural investigations of lysine-136 and its role in the electrostatic triad of human Cu,Zn superoxide dismutase.

Key charged residues in Cu,Zn superoxide dismutase (Cu,Zn SOD) promote electrostatic steering of the superoxide substrate to the active site Cu ion, resulting in dismutation of superoxide to oxygen and hydrogen peroxide, Lys-136, along with the adjacent residues Glu-132 and Glu-133, forms a proposed electrostatic triad contributing to substrate recognition. Human Cu,Zn SODs with single-site replacements of Lys-136 by Arg,Ala, Gln, or Glu or with a triple-site substitution (Glu-132 and Glu-133 to Gln and Lys-136 to Ala) were made to test hypotheses regarding contributions of these residues to Cu,Zn SOD activity. The structural effects of these mutations were modeled computationally and validated by the X-ray crystallographic structure determination of Cu,Zn SOD having the Lys-136-to-Glu replacement. Brownian dynamics simulations and multiple-site titration calculations predicted mutant reaction rates as well as ionic strength and pH effects measured by pulse-radiolytic experiments. Lys-136-to-Glu charge reversal decreased dismutation activity 50% from 2.2 x 10(9) to 1.2 x 10(9) M-1 s-1 due to repulsion of negatively charged superoxide, whereas charge-neutralizing substitutions (Lys-136 to Gln or Ala) had a less dramatic influence. In contrast, the triple-mutant Cu,Zn SOD (all three charges in the electrostatic triad neutralized) surprisingly doubled the reaction rate compared with wild-type enzyme but introduced phosphate inhibition. Computational and experimental reaction rates decreased with increasing ionic strength in all of the Lys-136 mutants, with charge reversal having a more pronounced effect than charge neutralization, implying that local electrostatic effects still govern the dismutation rates. Multiple-site titration analysis showed that deprotonation events throughout the enzyme are likely responsible for the gradual decrease in SOD activity above pH 9.5 and predicted a pKa value of 11.7 for Lys-136. Overall, Lys-136 and Glu-132 make comparable contributions to substrate recognition but are less critical to enzyme function than Arg-143, which is both mechanistically and electrostatically essential. Thus, the sequence-conserved residues of this electrostatic triad are evidently important solely for their electrostatic properties, which maintain the high catalytic rate and turnover of Cu,Zn SOD while simultaneously providing specificity by selecting against binding by other anions.

Binding Sites↗

PubMed2003

Crystal structure of the N-terminal dimerisation domain of VicH, the H-NS-like protein of Vibrio cholerae.

The histone-like nucleoid structuring (H-NS) protein is a global modulator of gene expression in Gram-negative bacteria. VicH, the H-NS protein of Vibrio cholerae, regulates the expression of certain major virulence determinants implicated in the pathogenesis of cholera. We present here the 2.5A crystal structure of the N-terminal oligomerisation domain of VicH (VicH_Nt). VicH_Nt adopts the same fold and dimeric assembly as the NMR structure of Escherichia coli H-NS_Nt, thus validating this fold against conflicting data. The structural similarity of V.cholerae VicH_Nt and E.coli H-NS_Nt, despite differences in origin, system of expression, experimental conditions and techniques used, indicates that the fold determined in our studies is robust to experimental conditions. Structural analysis and homology modelling were carried out to further elucidate the molecular basis of the functional polyvalence of the N-terminal domain. Our analysis of members of the H-NS superfamily supports the suggestion that the oligomerisation function of H-NS_Nt is conserved even in more distantly related proteins.

Amino Acid Sequence↗

PubMed1998

Deposition of macromolecular structures.

Macromolecular structures are being determined at an increasing rate, and are of interest to a wide diversity of researchers. Depositing a macromolecular structure with the Protein Data Bank makes it readily available to the community. Accuracy, consistency and machine-readability of the data are essential, as are clear indications of quality, and sufficient information to allow non-experimentalists to interpret the data. Good-quality depositions are necessary to allow this to be achieved. The PDB's AutoDep system allows deposition and some preliminary automatic checking to take place at multiple sites, prior to full processing and release of the structure by the PDB. However, depositing a structure currently requires the manual entry of a large amount of information at the time of deposition. The data-harvesting approach will allow much more information to be deposited, without placing an additional burden on the depositor. Deposition-ready files will be generated automatically during the course of a structure-determination experiment. The additional information will allow improved validation procedures to be applied to the structures, and the data to be made more useful to the wider scientific community.

Database Management Systems↗

PubMed2000

Comparative modeling studies of the calmodulin-like domain of calcium-dependent protein kinase from soybean.

Calmodulin-like domain protein kinases (CDPKs) represent a new class of calcium-dependent protein-phosphorylating enzymes that are not activated by calmodulin or phospholipid compounds. They have been found exclusively in plant and protozoal tissues. CDPKs are typified by four distinct domains: an N-terminal leader sequence, a protein kinase (PK) domain, a calmodulin-like domain (CLD), and a junction domain (JD) between the PK domain and CLD. Structural characterization of the CLD of CDPKalpha from soybean was undertaken based on the amino acid sequence homology of CLD to the structurally well-characterized calmodulin (CaM) family of structures. Tertiary models of apo-CLD, Ca(2+)-CLD complex, and intermolecularly bound Ca(2+)-CLD-JD complexes were obtained via automated and non-automated homology building methods. The resulting structures were compared and validated based on energy differences, phi-psi angle distribution, solvent accessibility, and hydrophobic potential. Circular dichroism, one-dimensional, and two-dimensional nuclear magnetic resonance spectroscopy studies of the CLD and peptides encompassing the JD provide experimental support to the models. The results suggest that there is a possible interaction between the CLD and JD domain similar to that of the CaM/calmodulin-dependent protein kinase II system. At low Ca(2+) levels, the JD may act as an autoinhibitory domain for kinase activity, and during calcium activation an intramolecular CLD-JD complex may form, relieving inhibition of the PK domain. Interactions between the JD and the C terminus of the CLD appear to be particularly important. The outcome of this study supports an intramolecular binding model for calcium activation of CDPK, although not exclusively.

Amino Acid Sequence↗

PubMed2005

Development and evaluation of an instrument to assess social difficulties in routine oncology practice.

PURPOSE: To develop and preliminarily evaluate a Social Difficulties Inventory (SDI) for use in oncology practice. METHODS: Item generation from patients (n = 96), staff (n = 49) and the literature. Questions constructed and pre-tested (n = 42) resulting in a 22-item questionnaire. Psychometric evaluation (n = 271) assessed frequency of endorsement, factor structure, summated scales and construct validity followed by randomisation to criterion validity or test-retest arms. RESULTS: Items met preset frequency of endorsement criteria. Factor analysis revealed a four-factor structure, three clearly definable, (1) Physical ability, (2) Providing for the family and (3) Contact with others, explaining 45.8% variance. Summated scales developed from these demonstrated good reliability (Cronbach's alpha > 0.7) and were used to test and confirmed construct validity. Several comparators from the Life Events and Difficulties Schedule (LEDS) and Cancer Rehabilitation Evaluation System Short Form (CARES-SF) tested criterion validity and majority agreements were moderate to good. Test-retest reliability was good with most kappa values > 0.6. One item was eliminated resulting in a 21-item questionnaire. CONCLUSION: The SDI is relevant and easy to understand. Initial psychometric evaluation was encouraging. Ongoing work to evaluate the clinical meaning and utility of the instrument and to examine the relationships between SDI scores and clinical outcomes will provide guidance about its usefulness as an assessment tool in routine oncology practice.

Factor Analysis, Statistical↗

PubMed2003

Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC).

Resilience may be viewed as a measure of stress coping ability and, as such, could be an important target of treatment in anxiety, depression, and stress reactions. We describe a new rating scale to assess resilience. The Connor-Davidson Resilience scale (CD-RISC) comprises of 25 items, each rated on a 5-point scale (0-4), with higher scores reflecting greater resilience. The scale was administered to subjects in the following groups: community sample, primary care outpatients, general psychiatric outpatients, clinical trial of generalized anxiety disorder, and two clinical trials of PTSD. The reliability, validity, and factor analytic structure of the scale were evaluated, and reference scores for study samples were calculated. Sensitivity to treatment effects was examined in subjects from the PTSD clinical trials. The scale demonstrated good psychometric properties and factor analysis yielded five factors. A repeated measures ANOVA showed that an increase in CD-RISC score was associated with greater improvement during treatment. Improvement in CD-RISC score was noted in proportion to overall clinical global improvement, with greatest increase noted in subjects with the highest global improvement and deterioration in CD-RISC score in those with minimal or no global improvement. The CD-RISC has sound psychometric properties and distinguishes between those with greater and lesser resilience. The scale demonstrates that resilience is modifiable and can improve with treatment, with greater improvement corresponding to higher levels of global improvement.

Adaptation, Psychological↗

PubMed2006

Engineering aromatic L-amino acid transaminase for the asymmetric synthesis of constrained analogs of L-phenylalanine.

An enzymatic asymmetric synthesis was carried out for the preparation of enantiomerically pure L-diphenylalanine using the rationally engineered aromatic L-amino acid transaminase (eAroATEs) obtained from Enterobacter sp. BK2K-1. To rationally redesign the enzyme, structural model was constructed by the homology modeling. The structural model was experimentally validated by the site-directed mutagenesis of the predicted pyridoxal-5'-phosphate (PLP) binding site and the substrate-recognition region, and the cell-free protein synthesis of mutated enzymes. It was suggested that Arg281 and Arg375 were the key residues to recognize the distal carboxylate and alpha-carboxylate group of the substrates, respectively. The model also predicted that Tyr66 forms hydrogen bond with the phosphate moiety of PLP and interacts with the side chain attached to beta-carbon of the amino acid substrate. Among the various site-directed mutants, Y66L variant was able to synthesize L-diphenylalanine with 23% conversion yield for 10 h, whereas the wild-type AroATEs was inactive for the transamination between diphenylpyruvate and L-phenylalanine as amino acceptor and amino donor, respectively.

Amino Acids, Aromatic↗

PubMed1995

Brief diagnostic interviews (SDDS-PC) for multiple mental disorders in primary care. A pilot study.

OBJECTIVE: To pilot test the feasibility and validity of new, brief, structured, physician-administered diagnostic interviews for six mental disorders in primary care patients identified from a patient-completed screen. DESIGN: Comparison of the new diagnostic interviews with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, version P (SCID-P), administered independently by a mental health professional. SETTING: Three Rhode Island family practices and a South Carolina family medicine residency. SUBJECTS: Consecutive patients of either sex, aged 18 to 70 years, who were able to read and write English were eligible for screening; 775 patients completed the screen. Of these, 246 screened positive for at least one disorder and received at least one module. Of these, 158 received a SCID-P interview. RESULTS: The diagnostic interviews were found useful by all 16 participating physicians. Eighty-seven percent reported that they diagnosed a new mental problem, and 93% said that the modules clarified suspected symptoms. However, 26% thought the procedure was too time consuming, and 80% believed that reimbursement would be necessary for routine use. Detection of cases using the diagnostic modules was associated with physician intervention and with independent assessment of patient impairment. Over three quarters of the patients (76.4%) who were classified as positive by the physician interview for any of the diagnoses also tested positive on the SCID-P. Two thirds of the patients (62.7%) with at least one of the disorders (according to SCID-P) were classified by the physician interview as having a mental disorder. However, the operating characteristics varied across specific disorders and indicated a need for revisions and testing in larger samples. CONCLUSIONS: These brief physician-administered diagnostic interview modules are part of a screening and diagnostic system (Symptom-Driven Diagnostic System for Primary Care [SDDS-PC], The UpJohn Co, Kalamazoo, Mich) to detect mental disorders in primary care patients. The pilot results help establish their feasibility and validity.

Adult↗

PubMed1989

Validity and reliability of the DSM-III criteria for posttraumatic stress disorder. Experience with a structured interview.

The DSM-III criteria for posttraumatic stress disorder (PTSD) were operationally defined for use in a structured interview. Acceptable interrater and test-retest reliabilities were shown; diagnostic validity was demonstrated relative to a standard diagnostic interview procedure; construct validity was shown in relation to a PTSD self-rating scale and to degree of combat exposure; the structured interview score correlated significantly with observer symptom scales for depression and anxiety.

Humans↗

PubMed2004

Diagnosing comorbid psychiatric disorders in substance abusers: validity of the Spanish versions of the Psychiatric Research Interview for Substance and Mental Disorders and the Structured Clinical Interview for DSM-IV.

OBJECTIVE: The authors' goal was to assess the validity of DSM-IV diagnoses obtained with the Spanish versions of the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) and the Structured Clinical Interview for DSM-IV (SCID) compared with the longitudinal, expert, all data (LEAD) procedure in a group of substance abusers. METHOD: A total of 105 substance abusers recruited at a drug abuse treatment center in Barcelona, Spain, were assessed. The PRISM and SCID were administered blindly by independent research interviewers. LEAD diagnoses were made by two senior psychiatrists who were blind to PRISM and SCID diagnoses. The kappa statistic was used to measure concordance between the LEAD procedure and the PRISM and SCID. RESULTS: Affective and anxiety disorders were diagnosed more frequently by the PRISM and SCID than by the LEAD procedure. Use of the PRISM resulted in more diagnoses of substance-induced depression, and use of the SCID resulted in more diagnoses of primary major depression than the LEAD procedure. Kappas between the LEAD procedure and the PRISM in current major depression, past substance-induced depression, and borderline personality disorder were better than those obtained between the LEAD procedure and the SCID. The concordance among the three methods for diagnoses of current dependence disorders was good or excellent for alcohol, anxiolytic, cocaine, and heroin dependence and fair for cannabis dependence. Abuse diagnoses showed poor concordance. CONCLUSIONS: Using the LEAD procedure as a "gold standard," the authors conclude that the Spanish version of the PRISM seems to be a better instrument than the Spanish version of the SCID for diagnosing major depression and borderline personality disorders in substance abusers.

Comorbidity↗

PubMed1999

Methodological issues in volumetric magnetic resonance imaging of the brain in the Edinburgh High Risk Project.

The Edinburgh High Risk Project is a longitudinal study of brain structure (and function) in subjects at high risk of developing schizophrenia in the next 5-10 years for genetic reasons. In this article we describe the methods of volumetric analysis of structural magnetic resonance images used in the study. We also consider potential sources of error in these methods: the validity of our image analysis techniques; inter- and intra-rater reliability; possible positional variation; and thresholding criteria used in separating brain from cerebro-spinal fluid (CSF). Investigation with a phantom test object (of similar imaging characteristics to the brain) provided evidence for the validity of our image acquisition and analysis techniques. Both inter- and intra-rater reliability were found to be good in whole brain measures but less so for smaller regions. There were no statistically significant differences in positioning across the three study groups (patients with schizophrenia, high risk subjects and normal volunteers). A new technique for thresholding MRI scans longitudinally is described (the 'rescale' method) and compared with our established method (thresholding by eye). Few differences between the two techniques were seen at 3- and 6-month follow-up. These findings demonstrate the validity and reliability of the structural MRI analysis techniques used in the Edinburgh High Risk Project, and highlight methodological issues of general concern in cross-sectional and longitudinal studies of brain structure in healthy control subjects and neuropsychiatric populations.

Adolescent↗