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PubMedDate not supplied

Neighborhood behavior of in silico structural spaces with respect to in vitro activity spaces-a novel understanding of the molecular similarity principle in the context of multiple receptor binding profiles.

As a consequence of recent advances in the field of High Throughput Screening, the systematic testing ("in vitro profiling") of compounds against a panel of targets covering different therapeutic areas is nowadays used to generate relevant information with respect to the in vivo behavior of drug candidates. However, the development of chemoinformatics tools required for the exploitation of such data is yet in an incipient phase. In this paper, a formalism for the analysis of activity profile vectors (describing the experimental responses of compounds in each of the considered activity tests) is introduced and applied at the study of Neighborhood Behavior (NB; the hypothesis that structurally similar compounds display similar biological properties) of molecular similarity metrics. The experimental activity profiles define an Activity Space in which more than 500 drugs and reference compounds are positioned, their coordinates being inhibitory propensities in the included tests and unambiguously characterizing a molecule in terms of its receptor binding properties. While previous studies of Neighborhood Behavior had to rely on a loose classification of compounds in terms of the therapeutic areas they were designed for, here the NB of a calculated "in silico" similarity metric has been redefined as a relationships between intermolecular dissimilarity scores in the "structural" and "activity" spaces, respectively, and expressed in terms of two quantitative criteria: "consistency" (the propensity of the metric to selectively rank activity-related compound pairs among the structurally most similar pairs) and "completeness" (monitoring the retrieval rate of activity-related compound pairs among the best ranked pairs of structural neighbors). These criteria were used to calibrate and validate a similarity metric based on Fuzzy Bipolar Pharmacophore Fingerprints.

Algorithms↗

PubMed2004

Bayes and health care research.

Bayes' rule shows how one might rationally change one's beliefs in the light of evidence. It is the foundation of a statistical method called Bayesianism. In health care research, Bayesianism has its advocates but the dominant statistical method is frequentism. There are at least two important philosophical differences between these methods. First, Bayesianism takes a subjectivist view of probability (i.e. that probability scores are statements of subjective belief, not objective fact) whilst frequentism takes an objectivist view. Second, Bayesianism is explicitly inductive (i.e. it shows how we may induce views about the world based on partial data from it) whereas frequentism is at least compatible with non-inductive views of scientific method, particularly the critical realism of Popper. Popper and others detail significant problems with induction. Frequentism's apparent ability to avoid these, plus its ability to give a seemingly more scientific and objective take on probability, lies behind its philosophical appeal to health care researchers. However, there are also significant problems with frequentism, particularly its inability to assign probability scores to single events. Popper thus proposed an alternative objectivist view of probability, called propensity theory, which he allies to a theory of corroboration; but this too has significant problems, in particular, it may not successfully avoid induction. If this is so then Bayesianism might be philosophically the strongest of the statistical approaches. The article sets out a number of its philosophical and methodological attractions. Finally, it outlines a way in which critical realism and Bayesianism might work together.

Bayes Theorem↗

PubMedDate not supplied

Obsessive-compulsive disorder in schizophrenia.

OBJECTIVE: To examine the differences in demographic and clinical features of patients with schizophrenia, with or without comorbid obsessive-compulsive disorder (OCD). METHODS: Fifty-two subjects were recruited from clinical services in the city of Edmonton, Alberta and assessed for schizophrenia and OCD with structured clinical interviews and standardized clinical rating scales. RESULTS: The prevalence of OCD in individuals meeting criteria for schizophrenia was 25%. Those subjects having both schizophrenia and OCD scored significantly higher on the Y-BOCS, Hollingshead scale, and GAF; plus significantly lower PANSS negative symptoms and a trend in increased Parkinsonian symptoms compared with individuals with schizophrenia alone. CONCLUSION: Our preliminary findings indicate that patients with schizophrenia and OCD vary in selected demographic and clinical measures when compared to patients with schizophrenia alone. Patients with schizophrenia and OCD appear to have less negative symptoms, which may thus be reflected in the decreased GAF scores. It is speculated that patients with schizophrenia and OCD may have a greater propensity to basal ganglia dysfunction than those with schizophrenia alone resulting in increased Parkinsonian symptoms.

Adult↗

PubMed2006

Molecular architecture of the DNA-binding region and its relationship to classification of basic helix-loop-helix proteins.

Multivariate statistical analyses are used to explore the molecular architecture of the DNA-binding and dimerization regions of basic helix-loop-helix (bHLH) proteins. Alphabetic amino acid data are transformed to biologically meaningful quantitative values using a set of 5 multivariate "indices." These multivariate indices summarize variation in a large suite of amino acid physiochemical attributes and reflect variability in polarity-accessibility-hydrophobicity, propensity for secondary structure, molecular size, codon composition, and electrostatic charge. Using these index score data, discriminant analyses describe the multidimensional aspects of physiochemical variation and clarify the structural basis of the prevailing evolutionary classification of bHLH proteins. A small number of amino acids from both the binding dimerization domains, when considered simultaneously, accurately distinguish the 5 known DNA-binding groups. The relevant sites often have well-documented structural and functional characteristics.

Animals↗

PubMed1993

Withdrawal of antiepileptic medication in children--effects on cognitive function: The Multicenter Holmfrid Study.

We present 100 children diagnosed with epilepsy who were seizure-free for more than 1 year and still on monotherapy of antiepileptic drugs (AEDs). We matched each child with a healthy classmate and performed neuropsychological testing and EEG before and after complete withdrawal of the AEDs. The withdrawal phase lasted 3 months, but the dose decrease was individualized for each patient. Three to 4 months after complete withdrawal of the drug all patients were reassessed. Patients with seizure relapse are excluded from the study. Seventeen patients are regarded as dropout, 11 because of seizure relapse and six because of protocol violation. The remaining 83 patients were treated with carbamazepine (n = 56), valproic acid (n = 17), or phenytoin (n = 10). Serum concentrations of the AEDs were measured using peak plasma levels that were taken immediately before or after psychological testing. We used neuropsychological tests to assess psychomotor function and "central" cognitive processing such as information processing or memory function. We found significant improvement attributable to drug withdrawal on only one of the cognitive tests, namely, psychomotor speed, suggesting that the impact of AED treatment on higher-order cognitive function is rather limited. In addition, we found group differences between the epilepsy group and the control group at baseline that persisted after drug withdrawal. Subsequent analysis showed some factors that may have contributed to these group differences. First, patients with a former diagnosis of absence seizures show lower scores both at baseline and after drug withdrawal. We may assume that the seizure propensity has not disappeared completely in these patients. Some evidence is found that phenytoin may have a different cognitive profile than carbamazepine, with more impairment on tests that measure motor and mental speed. Again, this impairment persists after drug withdrawal.

Adolescent↗

PubMed2006

Dissociation, hardiness, and performance in military cadets participating in survival training.

The present study examined the relationship between peritraumatic dissociation, hardiness, and military performance in Norwegian Navy officer cadets (N = 80) after a simulated prisoner of war (POW) exercise. The cadets reported symptoms of peritraumatic amnesia, depersonalization, and derealization in response to a mild stress experience (time point 1) and exhibited a significant increase in such symptoms when subsequently exposed to a highly stressful experience of being placed in a mock POW camp (time point 2). Symptoms of peritraumatic dissociation were significantly and negatively related to performance, and predicted between 16 and 26% of the variance between subjects. A subscale of the personality hardiness measure (i.e., the subdimension of challenge) was negatively associated with peritraumatic dissociation in response to both the mild stress situation and the more stressful POW exercise in study subjects. Hardiness was not significantly associated with military performance scores. The present data indicate that individual differences in attribution style and in a propensity to dissociate significantly affect military performance during exposure to high stress situations.

Adaptation, Psychological↗

PubMed2001

A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder.

The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.

Adult↗

PubMed1998

Reversal of atypical depression, sleepiness, and REM-sleep propensity in narcolepsy with bupropion.

We successfully treated a 46-year-old narcoleptic woman suffering from atypical depression with bupropion hydrochloride. Diagnostic evaluation revealed a Beck Depression Inventory (BDI) score of 24, a short nocturnal REM-sleep latency, subjective and objective sleepiness (mean sleep latency (MSL) = 1.8 minutes), and three sleep onset REM-sleep periods during the five nap multiple sleep latency test. Bupropion (100 mg t.i.d.) normalized her mood (BDI = 6), sleepiness (MSL = 9.1 minutes), and REM-sleep propensity. Upon discontinuation of bupropion, these parameters reverted to pretreatment levels. This "activating" antidepressant's reversal of the sleepiness and REM-sleep propensity in narcolepsy may be due to blockade of dopamine or norepinephrine reuptake. Clinicians need to be alert to the fact that depression can mask the diagnosis of narcolepsy. Bupropion warrants further investigation as a treatment for narcolepsy in an open-label, double-blind, placebo-controlled paradigm.

Antidepressive Agents, Second-Generation↗

PubMed2000

BiGGER: a new (soft) docking algorithm for predicting protein interactions.

A new computationally efficient and automated "soft docking" algorithm is described to assist the prediction of the mode of binding between two proteins, using the three-dimensional structures of the unbound molecules. The method is implemented in a software package called BiGGER (Bimolecular Complex Generation with Global Evaluation and Ranking) and works in two sequential steps: first, the complete 6-dimensional binding spaces of both molecules is systematically searched. A population of candidate protein-protein docked geometries is thus generated and selected on the basis of the geometric complementarity and amino acid pairwise affinities between the two molecular surfaces. Most of the conformational changes observed during protein association are treated in an implicit way and test results are equally satisfactory, regardless of starting from the bound or the unbound forms of known structures of the interacting proteins. In contrast to other methods, the entire molecular surfaces are searched during the simulation, using absolutely no additional information regarding the binding sites. In a second step, an interaction scoring function is used to rank the putative docked structures. The function incorporates interaction terms that are thought to be relevant to the stabilization of protein complexes. These include: geometric complementarity of the surfaces, explicit electrostatic interactions, desolvation energy, and pairwise propensities of the amino acid side chains to contact across the molecular interface. The relative functional contribution of each of these interaction terms to the global scoring function has been empirically adjusted through a neural network optimizer using a learning set of 25 protein-protein complexes of known crystallographic structures. In 22 out of 25 protein-protein complexes tested, near-native docked geometries were found with C(alpha) RMS deviations < or =4.0 A from the experimental structures, of which 14 were found within the 20 top ranking solutions. The program works on widely available personal computers and takes 2 to 8 hours of CPU time to run any of the docking tests herein presented. Finally, the value and limitations of the method for the study of macromolecular interactions, not yet revealed by experimental techniques, are discussed.

Algorithms↗

PubMed2001

Factors affecting the likelihood to engage in adequate physical activity to promote health.

The aim of this study was to assess the likelihood of individuals to participate in enough physical activity to promote fitness and, more conservatively, to accrue only health benefits. Sedentary (n = 883; 20.5%) and active (n = 1144; 26.5%) groups were identified from the 1990 Allied Dunbar National Fitness Survey of English adults (n = 4316). The data were analysed using logistic regression. Participants were described using 20 variables identified from previous research, six of which made a significant contribution to the model (P < 0.05). The odds of being sedentary increased with age, self-perception of lifestyle problems, and lower scores on education, self-perception of motivation to exercise, perception of own participation in physical activity and recognition of exercising enough for health benefits. The odds of being active were associated with the opposite characteristics to those observed for sedentary behaviour. The extreme scores varied from individuals who may be 385 times more likely to be sedentary, to those who were 29 times more likely to be active, depending on scores on the selected variables. The results of this study provide a means to determine individual propensity to participate in adequate physical activity, and to identify those who may benefit most from health promotion campaigns.

Adolescent↗

PubMed1992

Emergence and persistence of Pseudomonas aeruginosa in the cystic fibrosis airway.

Colonization in the respiratory tracts of cystic fibrosis (CF) patients by mucoid Pseudomonas aeruginosa correlates with the progression of bronchial airway pathology. There is a direct correlation between the incidence of Pseudomonas colonization and age, clinical score, extent of pulmonary disease, severity of radiographic changes, and level of serum immunoglobulins. The central propensity to Pseudomonas colonization in patients with CF is not freely understood, but we discuss the acquisition and persistence of P aeruginosa in the CF airway. Elucidation of pathogenetic mechanisms of CF inflammatory airways disease is the first essential step to initiating novel therapies. It has been difficult to prove that the ability of P aeruginosa to adhere to the respiratory epithelium and provide selective advantage for this gram-negative bacillus over other potential pathogens for infection in the CF airway. However, flexible filaments (pili) extending from the Pseudomonas cell wall are thought to medicate epithelial cell adherence for nonmucoid P aeruginosa, and similarly, the gelatinous exopolysaccharide alginate produced by mucoid variants of P aeruginosa seems to be the adhesive to tracheal cells. Following the signal event of adherence, this bacterial pathogen competes successfully for iron cofactor and multiplies, releasing proteases with broad substrate specificities that dramatically alter the airway antiprotease screen, and the pathogen creates defects in local antibacterial defenses. Lung inflammation in CF is characterized by massive neutrophil infiltration. Although critical to host defense, neutrophils also cause progressive airway damage by release of bioactive lipids, oxygen metabolites, and granule enzymes such as hydrolases, myeloperoxidase (MPO), lysozyme, and neutral serine proteases. The necessarily circumscribed discussion that follows will focus narrowly on the host cell-derived factors (macrophages and neutrophils) proposed as important components in this pathogenetic scheme.

Adult↗

PubMed1997

Automated design of the surface positions of protein helices.

Using a protein design algorithm that quantitatively considers side-chain interactions, the design of surface residues of alpha helices was examined. Three scoring functions were tested: a hydrogen-bond potential, a hydrogen-bond potential in conjunction with a penalty for uncompensated burial of polar hydrogens, and a hydrogen-bond potential in combination with helix propensity. The solvent exposed residues of a homodimeric coiled coil based on GCN4-p1 were designed by using the Dead-End Elimination Theorem to find the optimal amino acid sequence for each scoring function. The corresponding peptides were synthesized and characterized by circular dichroism spectroscopy and size exclusion chromatography. The designed peptides were dimeric and nearly 100% helical at 1 degree C, with melting temperatures from 69-72 degrees C, over 12 degrees C higher than GCN4-p1, whereas a random hydrophilic sequence at the surface positions produced a peptide that melted at 15 degrees C. Analysis of the designed sequences suggests that helix propensity is the key factor in sequence design for surface helical positions.

Algorithms↗

PubMed2006

Fine-grained statistical torsion angle potentials are effective in discriminating native protein structures.

Modelling of drug targets requires the reliable selection of an accurate and representative structure from large ensembles of alternate models. Statistical potentials developed to discriminate native protein structures generally represent pairwise interactions between atoms, which are less sensitive to local conformational details. The discrimination of local distortions is therefore particularly difficult. Local interaction preferences, expressed through torsion angles, are rarely used, as some controversy exists in the literature regarding their discrimination power. The present study aims to benchmark the efficiency of different implementations of torsion angle propensities for selecting the native structure from ensembles of well-constructed decoys. Several statistical potentials derived from fine-grained discretisations of torsion angle space are constructed and evaluated. Results from a comparison with nine widely used statistical scoring functions show the torsion angle potentials to be more effective in recognising native structures and to improve with the number of torsion angles considered. These data suggest local structural propensities to be important for estimating the overall quality of native-like models.

Models, Chemical↗

PubMed1997

Prediction of protein-protein interaction sites using patch analysis.

A method for defining and analysing a series of residue patches on the surface of protein structures is used to predict the location of protein-protein interaction sites. Each residue patch is analysed for six parameters; solvation potential, residue interface propensity, hydrophobicity, planarity, protrusion and accessible surface area. The method involves the calculation of a relative combined score that gives the probability of a surface patch forming protein-protein interactions. Predictions are made for the known structures of protomers from 28 homo-dimers, large protomers from 11 hetero-complexes, small protomers from 14 hetero-complexes, and antigens from six antibody-antigen complexes. The predictions are successful for 66% (39/59) of the structures and the remainder can usually be rationalized in terms of additional interaction sites.

Antigens↗

PubMed2003

The strength-dexterity test as a measure of dynamic pinch performance.

We have developed a method to quantify the dynamic interaction between fingertip force magnitude (strength) and directional control (dexterity) during pinch with a novel strength-dexterity (S-D) test based on the principle of buckling of compression springs. The test consists of asking participants to use key and opposition pinch to attempt to fully compress springs, in random order, with a wide range of combinations of strength and dexterity requirements. The minimum force required to fully compress the spring and the propensity of the spring to buckle define the strength and dexterity requirements, respectively. The S-D score for each pinch style was the sum of the strength values of all springs successfully compressed fully. We tested 3 participant groups: 18 unimpaired young adults ( 40yr), and 14 adults diagnosed with carpo-metacarpal osteoarthritis (CMC OA) (>or = 36yr). We investigated the repeatability of the S-D test with 74 springs by testing 14 young adults twice on different days. The per-spring repeatability across subjects was >or = 94%. A minimum performance score for young adults was found as they all could compress a subset of 39 springs. Using this subset of springs, we compared the ability of the S-D score vs. maximal pinch force values to distinguish unimpaired hands from those with CMC OA of the thumb. The score for this 39-spring S-D test distinguished between CMC OA and asymptomatic older adults, whereas pinch meter readings did not (p<0.05). We conclude that the S-D test is repeatable and applicable to clinical research. We propose including the S-D test in studies aiming to quantify impairment and compare treatment outcomes in orthopaedic and neurological afflictions that degrade dynamic manipulation.

Adolescent↗

PubMed1997

Penile erection: a reflection of sexual arousal and arousability in male chimpanzees.

A study was conducted to determine if sexual motivation in male chimpanzees, defined by the two components, sexual arousal and arousability, could be quantified by measuring penile erection during laboratory pair-tests of sexual behavior. Sexual arousal, the momentary level of sexual excitation, was quantified by single measurements on a scale of penile erection. Sexual arousability, the propensity for arousal, was quantified by the rate of approach to full erection and by mean erection scores. Sexual arousability, as defined, was related to the frequency of male courtship displays, copulations, and ejaculations, which were highest at midcycle and positively correlated with a quantitative measure of female anogenital swelling. Sexual arousal was negatively correlated with continued exposure to the female and least variable during midcycle. These operational definitions of sexual motivation in the male chimpanzee facilitate comparative research in which analogous indexes of sexual motivation are required such as when extrapolating from animal to human.

Animals↗

PubMed1999

Individual traits and family contexts predict sons' externalizing behavior and preliminary relative risk ratios for conduct disorder and substance use disorder outcomes.

An ontogenetic framework for elucidating the etiology of substance use disorders (SUD) requires identifying how individual traits and family contexts combine to increase risk for SUD outcomes. In this study, we examine individual traits in family context to identify processes that account for the relationship between fathers' SUD + status and sons' externalizing behaviors. Results obtained from SUD + (n = 89) and SUD - (n = 139) families show that fathers' abusive propensities toward their sons mediated the relationship between fathers' SUD + status and sons' externalizing behavior scale (EBS) scores 2 years later. Moreover, individual traits, family contextual variables and deviant peer affiliations accounted for 58% of the variance on sons' EBS scores. Also, high risk cluster (HRC) and low risk cluster (LRC) memberships were derived from cluster analyses of the continuous risk factor scores that predicted sons' EBS scores. Preliminary relative risk ratios show that sons classified into the HRC at age 10-12 were at greater risk for DSM-III-R conduct disorder and SUD outcomes at age 16 than sons assigned to the LRC, SUD + or SUD - groups. Implications for selected family-based prevention initiatives are presented.

Adolescent↗

PubMed2006

Development of chronic hydrocephalus and early cranial CT findings in spontaneous intracerebral/intraventricular hemorrhage.

INTRODUCTION: Since intracerebral hemorrhage (ICH) is frequently associated with intraventricular bleeding (IVH), we sought to detect cranial computed tomography features that would indicate early on in the patient's history the development of chronic hydrocephalus with a permanent need for cerebrospinal fluid (CSF) diversion. METHODS AND MATERIALS: A total of 25 consecutive cases presenting with ICH/IVH was studied retrospectively. Outcome was assessed using the Glasgow Outcome Scale at an average of 8 months subsequently. Diagnosis of ICH/IVH and (acute) hydrocephalus was made by early cranial CT scanning employing a selection of radiological criteria according to the literature including the Evans ratio. All patients then received external ventricular drainage. Chronic hydrocephalus was diagnosed by intraventricular pressure monitoring or by cranial CT follow-up after removal of the external drainage. RESULTS: None of the radiological criteria nor the scores obtained differed between the two groups. However, the ratio of scores for IVH/ICH was higher among the patients who developed a chronic hydrocephalus. All other parameters including volume of ICH and IVH were equally distributed. Overall outcome was poor with a median GOS score of 3. CONCLUSIONS: The ICH/IVH ratio presented here can be interpreted as an individual measure of propensity to impairment of CSF circulation. Further studies on larger populations will be needed to show whether this can be employed as an early diagnostic criterion with respect to chronic hydrocephalus.

Aged↗