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PubMed1995

Towards eradication of measles virus: global progress and strategy evaluation.

Despite an increase in global measles vaccine coverage from under 20% in 1980 to around 80% in 1990, measles remains a major cause of morbidity and mortality world-wide. This paper addresses a number of issues relating to efforts to control measles, namely, (i) at the global level, how might we assess the impact of measles vaccination on the incidence of infection and associated disease, and, (ii), at the strategic level, how can we utilise an understanding of the transmission dynamics of childhood viral infections to aid the design of optimal immunisation programmes? Based on WHO vaccine coverage data, and organising countries according to similarities in demographic and epidemiological parameters, an age-structured model of measles transmission is used to capture the non-linear dynamics of infection and mass vaccination and to generate projections of the impact of measles immunization world-wide. The results provide a crude indication of the percentage reduction in measles cases by year 2000 (compared with no immunization) and suggest an approximately 70% reduction in cases over all ages, and 77% reduction in cases under 5 years (where there is the greatest risk of case fatality); these suggest that WHO targets for 1995 are unlikely to be achieved. In the second part of the paper, examples are given to illustrate the usefulness of a modelling approach in evaluating measles immunization policy. The introduction of MMR vaccine in the UK in 1988 has resulted in measles incidence falling to an all time low and attention has turned to the requirements of elimination. A realistic age structured model, validated using extensive serological data, is used to compare the merits of single or two dose strategies. Based upon recent estimates of vaccine efficacy (90%) and coverage (92% by end of second year of life) it is suggested that a two-dose policy with a pre-school second dose given irrespective of vaccine history is required to prevent the build up of susceptibles to epidemic proportions in the longer term. In a second example, prompted by the success of the campaign approach to polio and measles elimination in Central and South America, simple models are used to explore and quantify the process by which pulse vaccination programmes (i.e. repeated application across a wide age range) act to control transmission.

England↗
PubMed2006

Psychometric evaluation of the smoking cessation Processes of Change scale in an adolescent sample.

The Processes of Change are the cognitions, behaviors, and emotions that people employ to change their behaviors. However, the processes of change remain the least studied dimension of the transtheoretical model. The present study presents a psychometric evaluation of the short form of the processes of change inventory for smoking cessation in an adolescent sample of 798 ninth-grade smokers from 22 Rhode Island high schools. The majority of the sample was white (87.2%), split approximately evenly as regards to gender (48.1% female), with an average age of 14.3 (SD=0.6) years of age. The same hierarchical model established on the adult sample was fit to the 20-item inventory. This model included 10 primary factors representing the processes of change and two second order factors that grouped the processes into five behavioral and five experiential processes of change. Model fit indices (RMSEA=0.08, CFI=0.92) supported the hypothesized structure. External validation was established by testing for stage differences in the use of the ten processes. A significant MANOVA (F(4,793)=18.517, p<0.001) and separate ANOVAs demonstrated that the use of all ten processes increased across the stages, as predicted by the transtheoretical model of behavior change. The processes of change help guide researchers, clinicians, and intervention program developers towards effective strategies to assist individuals at all stages of change progress towards healthier behaviors.

Adolescent↗
PubMed2006

A competency-based virtual reality training curriculum for the acquisition of laparoscopic psychomotor skill.

BACKGROUND: Studies have demonstrated the beneficial effect of training novice laparoscopic surgeons using virtual reality (VR) simulators, although there is still no consensus regarding an optimal VR training curriculum. This study aims to establish and validate a structured VR curriculum to provide an evidence-based approach for laparoscopic training programmes. METHODS: The minimally invasive VR simulator (MIST-VR) has 12 abstract laparoscopic tasks, each at 3 graduated levels of difficulty (easy, medium, and hard). Twenty medical students completed 2 sessions of all tasks at the easy level, 10 sessions at the medium level, and finally 5 sessions of the 2 most complex tasks at the hard level. At the medium level, subjects were randomized into 2 equal groups performing either all 12 tasks (group A) or the 2 most complex tasks (group B). Performance was measured by time taken, path length, and errors for each hand. The results were compared between groups, and to those of 10 experienced laparoscopic surgeons. RESULTS: Baseline performance of both groups was similar at the easy level. At the medium level, learning curves for all 3 parameters reached plateau at the second (group A, P < .05) and sixth (group B, P < .05) repetitions. Performance at the hard level was similar between the 2 groups, and all achieved the pre-set expert criteria. CONCLUSION: A graduated laparoscopic training curriculum enables trainees to familiarise, train and be assessed on laparoscopic VR simulators. This study can aid the incorporation of VR simulation into established surgical training programmes.

Adolescent↗
PubMed2004

Assessment of primary eye and skin irritants by in vitro cytotoxicity and phototoxicity models: an in vitro approach of new arginine-based surfactant-induced irritation.

Extensive efforts have been made, recently, to find surfactants with lower irritation potential than those presently commercially available, for use in pharmaceutical and cosmetic preparations. Cytotoxic and phototoxic effects of a novel family of dicationic arginine-diglyceride surfactant compounds, 1,2-diacyl,3-O-(l-arginyl)-rac-glycerol with alkyl chain lengths in the range from 8 to 14 carbon atoms, were compared to three commercial surfactants. The end-points used to assess toxicity were the red blood cell lysis assay and uptake of the vital dye neutral red 24h after dosing (NRU), respectively. Two immortalized cell lines, murine fibroblast cell line, 3T3, and one human keratinocyte cell line, HaCaT, were used as in vitro models to predict the potential phototoxicity which could result in irritation, determined by resazurin reduction to resorufin and neutral red uptake (NRU). All tested surfactants had cytotoxicity effects as demonstrated by and decrease of NR uptake, which showed a clear concentration-response relationship. Concentrations resulting in 50% inhibition of NR uptake (IC(50)) range from 1 microM(-1) (hexadecyl trimethyl ammonium bromide) to 565 microM(-1) (12,12-l-arginine). Erythrocyte haemolysis also showed a clear concentration-response relationship, the 50% of haemolysis ranged from 37 microM(-1) (10,10-l-arginine) to 151 microM(-1) (sodium lauryl sulphate). Phototoxicity was performed with 12,12-l-acetyl-arginine, the most stable chemical structure. The validated 3T3 NRU photoxicity assay was used and revealed a phototoxic potential.

Animal Testing Alternatives↗
PubMed1998

Incorporation of [3H]valproic acid into lipids in GT1-7 neurons.

Valproic acid (2-propylpentanoic acid, valproate, VPA), an 8-carbon, branched chain fatty acid, is effectively used in the treatment of mania and epilepsy. The biochemical mechanisms by which this drug has its therapeutic effects are not yet established. The purpose of this study was to partially characterize the incorporation of [3H]VPA into phospholipids of GT1-7 neurons, an immortalized hypothalamic cell line. GT1-7 neurons were grown to confluence in culture dishes, and then were incubated with various concentrations of [3H]VPA between 10 and 400 microg/mL for various times up to 20 hr. Total lipids were extracted and phospholipids were separated from neutral lipids using TLC. Our results indicate that [3H]VPA (10 microg/mL) was incorporated into phospholipids of GT1-7 neurons in a time-dependent and saturable manner over 300 min. Subsequent separation of the lipid fraction by TLC indicated that 44.4% of the radioactivity taken up by the cells was incorporated into phospholipids and neutral lipids. One of the phospholipids migrated with a slightly lower Rf value than authentic phosphatidylcholine. Our results show that the incorporation of VPA into phospholipids and glycerides was linear with VPA concentrations from 10 to 400 microg/mL. Finally, we synthesized 1-acyl-2-valproyl-sn-glycero-3-phosphocholine and validated its structure with nuclear magnetic resonance and electrospray mass spectrometry to verify the structure of this compound, confirming that this compound is structurally possible. We conclude that VPA is incorporated into lipids in GT1-7 neurons and discuss the possible effects of valproyl phospholipids on neuronal functional properties.

Anticonvulsants↗
PubMed2003

Object recognition and attention to object components by preschool children and 4-month-old infants.

The present research investigated attention to and recognition of components in compound stimuli by infants and preschool children. A preliminary experiment was conducted with adults to develop stimulus components and to validate their structure. An experiment using an oddity task with preschoolers (N = 32) and one using the familiarization/novelty-preference task with infants (N = 64) demonstrated successful discrimination among the stimulus components on the basis of edge property information. Separate experiments using a matching task with preschoolers (N = 32) and an habituation task with infants (N = 32) demonstrated that preschoolers and infants are also able to direct attention to and recognize components of compound stimuli. Implications for structural-description theories of object recognition are discussed.

Child, Preschool↗
PubMed2002

On the role of the crystal environment in determining protein side-chain conformations.

The role of crystal packing in determining the observed conformations of amino acid side-chains in protein crystals is investigated by (1) analysis of a database of proteins that have been crystallized in different unit cells (space group or unit cell dimensions) and (2) theoretical predictions of side-chain conformations with the crystal environment explicitly represented. Both of these approaches indicate that the crystal environment plays an important role in determining the conformations of polar side-chains on the surfaces of proteins. Inclusion of the crystal environment permits a more sensitive measurement of the achievable accuracy of side-chain prediction programs, when validating against structures obtained by X-ray crystallography. Our side-chain prediction program uses an all-atom force field and a Generalized Born model of solvation and is thus capable of modeling simple packing effects (i.e. van der Waals interactions), electrostatic effects, and desolvation, which are all important mechanisms by which the crystal environment impacts observed side-chain conformations. Our results are also relevant to the understanding of changes in side-chain conformation that may result from ligand docking and protein-protein association, insofar as the results reveal how side-chain conformations change in response to their local environment.

Computer Simulation↗
PubMed1999

Chlorothalonil: lack of genotoxic potential.

Based upon analyses using a number of validated structure-activity relationship models, it is concluded that the carcinogenicity in rodents of chlorothalonil is not due to a genotoxic mechanism.

Animals↗
PubMed1983

An assessment of the evidence for the role of ribonucleoprotein particles in the maturation of eukaryote mRNA.

This article has sought to draw together, on the one hand, what is known of mRNA processing and its control and, on the other hand, what is known of the structure and validity of hnRNP and snRNP particles. At the same time, it has attempted to synthesize these two themes into a critical assessment of the evidence which suggests that the particles are intimately involved in processing. It cannot be said that the case is proven. The evidence is compelling but circumstantial. The last few years have seen the development of the first in vitro splicing systems (Weingartner and Keller, 1981; Goldenberg and Raskus, 1981; Kole and Weissman, 1982), the isolation of monoclonal antibodies to defined snRNP (Lerner et al., 1981a; Billings et al., 1982) and hnRNP proteins (Hugle et al., 1982), and the ability to use artificial lipid vesicles to transfer antisera (Lenk et al., 1982) and radioactive snRNA (Gross and Cetron, 1982) into cells. It is to be hoped that further refinements of these and other techniques will allow us to solve this, one of the major outstanding problems of molecular biology.

Animals↗
PubMed2002

MRI volume measurements of hypointense objects. A phantom study using stereological methods.

Volume estimates made from thick slabs overestimate the volume of a positive contrast particle in a translucent matrix and underestimate its volume if the particle has negative contrast and the matrix is opaque. For T2-weighted MRI high signal objects the bias can be corrected according to simple geometric models. For negative contrast or hypointense objects the magnitude of the bias is unknown and no corrections have yet been put forward. We wanted to determine the bias of MRI measurements of hypointense objects of known diameter surrounded by a positive contrast solution. One, 3 and 5 mm slices with three different contrast concentrations were obtained according to a stereological MRI protocol. Results were compared with the true object size to estimate the bias. A simple correction for the bias could not be developed due to interslice cross-talk. Cross-talk makes an object appear in more MRI slices than corresponding to its physical size and larger than the true diameter. For phantom measurements an empirical correction could be developed, but for measurements of non-ideal objects such as brain structures the validity of the correction would be unpredictable. Besides avoiding or reducing cross-talk, the best way to deal with this bias is to measure the object's maximal contrast from edge to edge, a solution which is not perfect.

Magnetic Resonance Imaging↗
PubMed2000

[Informed consent at a primary care area].

OBJECTIVE: Assessment of the understanding and performance of informed consent by primary care doctors and people attending clinics (PAC) in Madrid Area 3. DESIGN: Descriptive cross-sectional study. SETTING: The 20 health centres in Madrid Area 3. PARTICIPANTS: Doctors and PAC in Area 3. MEASUREMENTS AND MAIN RESULTS: It was a structured survey, validated by a pilot study. 98.7% of doctors stated that they informed their patients about illnesses; 91.8% on the risks and benefits. 90.6% and 78.6%, respectively, of the PAC said they were informed. Although 86.8% (CI 83.7-89.9) of the PAC thought they understood the information transmitted well, only 61% (CI 53.4-68.6) of the doctors thought so. 60.4% of the doctors and 54.6% of the PAC thought that the doctors' decisions took into account the patient's view. This was also the preferred option of both groups (46.5% and 59.3%). 29% of the doctors preferred greater power of decision for the patients, and only 16.06% of the PAC. 91.6% (CI 89.1-94.1) of the PAC were satisfied with the information received. CONCLUSIONS: Doctors think they give information better than PAC think. Patients' understanding of the information is given a higher rating by the PAC than by the doctors. Decisions are habitually taken by the doctor, with the patient's views borne in mind. However, doctors would prefer patients to have greater decision-making power.

Adult↗
PubMedDate not supplied

[Variations in the application of medical techniques in primary health care].

OBJECTIVES: To describe the application of medical techniques (ATM) in Spain and to analyze the relationship with diverse characteristics related to general practitioners and the center of primary health. DESIGN: Multicenter cross-sectional study. SETTING: Three hundred nineteen general practitioners working in primary care centers in the restructured public sector of the Autonomous Communities of Andalusia, Basque Country and Catalonia in Spain. MAIN MEASUREMENTS: Structured and validated questionnaire comprising 100 items in four sections: general characteristics of the physician and health center, task profile, and job satisfaction. The questionnaire was sent by mail to the health center (Andalusia and Basque Country) or to the home (Catalonia). For the analysis an index variable was created from the answers to the questions on AMT. RESULTS: The index variable of AMT obtained a mean value of 10.02 (SD = 4.55). Andalusia obtained the highest value (median: 11.11; SD: 4.33) of the three Autonomous Communities in the study (p =.012). AMT acquired significantly higher values when associated with: masculine sex (sample from the three autonomous communities; p =.046), rural environment, teamwork, availability of basic equipment, fewer patients, and reduced work load. CONCLUSIONS: Index of ATM in Spain is significantly different in the three Spanish communities under study. The quality of the sanitary services evaluated from the dimension of the ATM seems to be much related with demographic characteristics, the readiness in the consultations of scientific-technical stuff and the appropriate time for medical consultations.

Cross-Sectional Studies↗
PubMedDate not supplied

[Influence of burnout on pharmaceutical expediture among primary care physicians].

OBJECTIVE: To determine the influence of various factors related to primary care physicians and their level of burnout on pharmaceutical expenditure per policy-holder (PEP-H). METHOD: We performed a cross-sectional study of 220 primary care physicians in the province of Barcelona in 2000. A structured and validated questionnaire was administered through direct interview. The questionnaire was divided into two parts: general sociodemographic and professional data, and the Maslach Burnout Inventory (MBI). At the same time, data on primary care physicians' pharmaceutical expenditure was collected from their corresponding health districts. RESULTS: The mean pharmaceutical expenditure was 264,627.22 euros (95% CI, 252,669.82-276,584.63) and the PEP-H was 152,36 euros (95% CI, 145,73-158,99). The variables associated with greater PEP-H were older age of the primary care physician, greater number of years of service in primary care, permanent work contract, primary care physicians who worked in several centers at the same time, primary care physicians who did not work in accredited teaching centers, urban centers, and high levels of emotional exhaustion in the MBI. CONCLUSIONS: Primary care physicians are subject to various degrees of stress in their daily work. Accumulation of these psychological stressors provokes emotional exhaustion, which complicates decision making when writing prescriptions and tends to lead to a vicious circle. Thus, primary care physicians with a high level of burnout could, on a variety of occasions, compensate for this lack of psychological resources by less efficient management of pharmaceutical expenditure when prescribing.

Burnout, Professional↗
PubMed2000

Automated solid-phase extraction method for the determination of atovaquone in plasma and whole blood by rapid high-performance liquid chromatography.

A bioanalytical method for the determination of atovaquone in plasma and whole blood by solid-phase extraction and high-performance liquid chromatography has been developed and validated. A structurally similar internal standard was added and protein was precipitated from plasma and whole blood with acetonitrile before being loaded on to a C8 solid-phase extraction column. Atovaquone and internal standard were analysed by high-performance liquid chromatography on a C18 J'Sphere ODS-M80 (150x4.0 mm) column with mobile phase acetonitrile-phosphate buffer, 0.01 M, pH 7.0 (65:35, v/v) and UV detection at 277 nm. The intra-assay precisions for plasma and whole blood were 2.2% and 1.9% respectively at 12 microM and 6.0% and 5.6% respectively at 0.75 microM. The inter-assay precisions for plasma and whole blood were 1.4% and 2.1% respectively at 12 microM and 4.9% and 3.4% respectively at 0.75 microM. The lower limit of quantification in plasma and whole blood were 150 nM. The limit of detection in plasma and whole blood were 30 nM.

Antiprotozoal Agents↗
PubMed1988

Sensitive quantification of pseudoephedrine in human plasma and urine by high-performance liquid chromatography.

An assay for the selective quantification of pseudoephedrine in human plasma and urine was developed using high-performance liquid chromatography with UV detection at 205 nm. Analyte and internal standard were extracted from alkaline plasma or urine into a mixture of n-hexane and diethyl ether, and the organic phase was back-extracted into dilute acid. The chromatographic system comprises microparticulate cyanopropyl-silica as stationary phase and a ternary solvent mixture with ion-pair reagents as mobile phase. Using 0.25 ml plasma, the lower limit of quantification was 25 ng/ml with excellent linearity up to 1000 ng/ml. In urine, the calibration ranged from 2.5 to 100 micrograms/ml. The selectivity of the method was demonstrated for several pharmaceuticals with similar structures. The validated method was applied to a pharmacokinetic study with a single oral dose of 100 mg of pseudoephedrine in two galenic formulations. Precision and accuracy data of the assay and calculated pharmacokinetic parameters are presented.

Adolescent↗
PubMed2001

Atomic motion in enzymatic reaction coordinates.

Atomic excursions of reactants in enzymatic catalytic sites can be estimated from high-resolution crystal structures of enzyme complexes with substrates, transition state analog inhibitors and products. Transition state structures, defined from kinetic isotope effect studies, are compared to crystallographic structures to validate the properties of the transition state analog. Atomic excursions in enzymatic catalytic sites can differ from those in solution and define the role of the enzymatic catalyst in directing atomic motion.

Animals↗
PubMed1994

The development and validation of an age-structured model for the evaluation of disease control strategies for intestinal helminths.

Epidemiological modelling can be a useful tool for the evaluation of parasite control strategies. An age-structured epidemiological model of intestinal helminth dynamics is developed. This model includes the explicit representation of changing worm distributions between hosts as a result of treatment, and estimates the morbidity due to heavy infections. The model is used to evaluate the effectiveness of different programmes of age-targeted community chemotherapy in reducing the amount of morbidity due to helminth infection. The magnitude of age-related heterogeneities is found to be very important in determining the results of age-targeted treatment programmes. The model was verified using field data from control programmes for Ascaris lumbricoides and Trichuris trichiura, and was found to provide accurate predictions of prevalence and mean intensities of infection during and following different control regimes.

Adult↗
PubMed2003

Structural and functional analysis of caspase active sites.

Amino acid sequences of caspases 1, 3, 7, and 8 were aligned with their published three-dimensional (3D) structures. The resultant alignment was used as a template to compare the primary structures of caspases 2, 4-6, and 9-11 to build 3D homology models. The structural models were subsequently refined and validated using structure-activity relationship data obtained from an array of substrate-like inhibitors. All caspases were shown to have identical S1 and catalytic dyad architecture but diverse S2-S4 structures. S2 pockets of these 11 caspases can be briefly categorized into two groups: Csp3, -6, and -7 as one and Csp1, -2, -4, -5, -8, -9, -10, and -11 as the other. S2 pockets of Csp3, -6, and -7 are smaller than those of the other eight caspases, and are limited to binding small P2 residues such as Ala and Val. At the S3 site, the presence of a conserved Arg in all caspases suggests that Glu would be a universally preferred P3 residue. Csp8 and Csp9 have an additional Arg in this pocket that can further enhance the binding of a P3 Glu, whereas Csp2 has a Glu adjacent to the conserved Arg. As such, Csp2 is the only caspase that can accommodate both positively and negatively charged P3. At S4, Csp1, -4, -5, and -11 are closely related with respect to their structures and binder preferences; all have a large hydrophobic pocket and prefer large hydrophobic residues such as Trp. S4 of Csp2, -3, and -7 represents an opposite group with a conformation that is highly specific in binding an Asp. The S4 structures of Csp6, -8, -9, and -10 appear to be hybrids of the two extremes, and have little specificity for any P4. Information revealed from this work provides a guide for designing potent caspase inhibitors with desirable specificity.

Amino Acid Sequence↗