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PubMed1987

Reconstruction of NOESY maps. A requirement for a reliable conformational analysis of biomolecules using 2D NMR.

The modelling of the conformation of a biomolecule in solution is based mainly on the internuclear distances deduced from measurements of nuclear Overhauser effects (nOe) in NOESY correlation maps. The distances are then used as restraints in the energy minimization procedure, which leads to one or several optimized conformations. A general and safe technique for validating these structures with respect to the experimental data is here proposed: from the internuclear distances, the relaxation matrix can be computed under the assumption of a unique rotational correlation time. By stepwise integration of these relaxation equations, the NOESY maps can be accurately reconstructed for any mixing time. Because multi-spin effects are correctly taken into account, any difference between the experimental and theoretical maps can be easily interpreted in terms of conformation, and possible inconsistencies due to conformational averaging can be pointed out. The technique is illustrated for a bacterial lipopeptide, mycosubtilin, the spectrum of which is completely assigned.

Biopolymers↗
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↗
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↗
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↗
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↗
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↗
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↗
PubMed1997

Three-dimensional structure of the cytoplasmic face of the G protein receptor rhodopsin.

Rhodopsin is a G protein receptor from a many-membered family of membrane receptors. No high-resolution structure exists for any member of this family due to the insolubility of membrane proteins and the difficulty in crystallizing membrane proteins. Two new approaches to the structure of rhodopsin are described that circumvent these limitations: (1) individual solution structures of the four cytoplasmic domains of rhodopsin are fitted with the transmembrane domain; (2) the solution structure of a complex of the four cytoplasmic domains is determined from nuclear magnetic resonance data. The two structures are similar. To test the validity of these structures, specific site-to-site distances measured on intact membrane-bound rhodopsin are compared to the same distances on the structures reported here. Excellent agreement is obtained. Furthermore, the agreement is obtained with distances measured on the activated form of teh receptor and not with distances on the dark-adapted form of rhodopsin. This approach may prove to have general applicability for the determination of the structure for membrane proteins.

Circular Dichroism↗
PubMed1997

Do authors of review articles use systematic methods to identify, assess and synthesize information?

PURPOSE: Review articles are an important source of summary information for practising clinicians to assist them in remaining current with the rapidly expanding medical literature. Consequently it is essential that these be of the highest quality. In this study we evaluate, according to published criteria, the methodological quality of review articles (R) including meta-analysis (MA) appearing in a major cancer journal, Journal of Clinical Oncology (JCO), 1983-1995. METHODS: A hand-search of JCO was performed, from the first issue January 1983 through December 1995, to identify R, defined as publications that describe and comment on studies relevant to a specific topic or clinical intervention. Only those dealing with aspects of treatment of human cancer were considered further. Methodological quality was first assessed using 8 criteria proposed by Mulrow, rated independently by two medical oncologists as: specified, unclear or not specified. MA, including studies of dose intensity, were further analyzed according to 23 more detailed criteria proposed by Sacks et al. and rated as adequate, partial or no/unknown compliance. RESULTS: Of 176 review articles, 122 dealt with aspects of treatment of cancer. Compliance with four of Mulrow's eight criteria was generally good, in that 99% clearly stated a purpose, all attempted qualitative synthesis of data. 95% presented a summary and 76% considered future directions. However, in the 106 qualitative reviews (QR), authors rarely gave information on methods of data identification (11.3%), data selection (10.4%) and assessment of validity (8.4%). Structured abstracts seemed to improve the focus and clarity of QR and there was a minor improvement in deficient areas in the later time cohort (1990-1995). Based on 'adequate' compliance with each of the 23 criteria identified by Sacks et al., six dose intensity studies scored 7-12, seven literature data MA scored 10-15 and three individual patient data MA scored 16-18. The highest scores were in the sections relating to prospective design, combinability and statistical analysis. Factors relating to control of bias, sensitivity analysis and application of results were addressed less consistently. CONCLUSIONS: With the exception of MA, the majority of authors contributing reviews to a major cancer journal, JCO, did not use systematic methods to identify, assess and synthesize information. Initiatives such as the Cochrane Collaboration Cancer Network can support and educate clinicians who wish to perform systematic reviews, but quality of reviews would also improve if author, editors and readers systematically applied any of the sets of criteria now available in the literature.

Humans↗
PubMed1999

Linguistic styles: language use as an individual difference.

Can language use reflect personality style? Studies examined the reliability, factor structure, and validity of written language using a word-based, computerized text analysis program. Daily diaries from 15 substance abuse inpatients, daily writing assignments from 35 students, and journal abstracts from 40 social psychologists demonstrated good internal consistency for over 36 language dimensions. Analyses of the best 15 language dimensions from essays by 838 students yielded 4 factors that replicated across written samples from another 381 students. Finally, linguistic profiles from writing samples were compared with Thematic Apperception Test coding, self-reports, and behavioral measures from 79 students and with self-reports of a 5-factor measure and health markers from more than 1,200 students. Despite modest effect sizes, the data suggest that linguistic style is an independent and meaningful way of exploring personality.

Adolescent↗
PubMed2000

Wine drinking and diet in Italy.

OBJECTIVE: To investigate the relation between wine drinking and intake of selected indicator foods, which may vary in various populations. DESIGN: Cross-sectional analysis of the comparison group of a case- control study. SETTING: A network of teaching and general hospitals from six Italian areas. SUBJECTS: 5642 control subjects (3261 females and 2381 males) aged 20-74 y (median age 58 y), admitted for acute, non-neoplastic conditions unrelated to alcohol consumption. Participation rate was over 95%. INTERVENTION: Trained interviewers collected information using a structured and validated questionnaire. The average intakes of selected food items were computed, together with the multivariate odds ratios (OR) of eating above the median of each food. RESULTS: No appreciable difference in either sex for any food indicator considered (fruit, raw vegetables, cooked vegetables, salad and fish) was observed between abstainers, wine, and other alcoholic beverage drinkers. If anything, female wine drinkers reported less frequently high consumption of salad (OR=0.8) and raw vegetables (OR=0.8), both estimates being of borderline significance. CONCLUSIONS: In no instance did wine drinkers or mixed drinkers (who include a large proportion of wine drinkers, too) show an association with indicators of healthy diet. SPONSORSHIP: Italian Association for Cancer Research, Milan, Italy. European Journal of Clinical Nutrition (2000) 54, 177-179

Adult↗
PubMed2000

Refined and whole grain cereals and the risk of oral, oesophageal and laryngeal cancer.

OBJECTIVE: To investigate the possible differential role of refined and whole grain cereals on the risk of upper digestive and respiratory tract neoplasms. DESIGN: Hospital-based case-control study. SETTING: University Hospital of Lausanne, Switzerland. SUBJECTS: A total of 156 incident cases of cancers of the oral cavity and pharynx, 101 of the oesophagus, 40 of the larynx, and 349 control subjects admitted for a wide spectrum of acute non-neoplastic conditions. INTERVENTION: Trained interviewers collected information using a structured and validated questionnaire. Odds ratios (OR) of various cancers for a tertile increment of intake of refined and whole grains were estimated using unconditional multiple logistic regression. RESULTS: Refined grains were directly related to the risk of cancer of the oral cavity and pharynx (OR=1.9 for the highest tertile), oesophagus (OR=3.7) and larynx (OR=4.0). In contrast, whole grain cereals were protective, with OR of 0.6 for oral cavity and pharynx, 0.3 for oesophagus, and 0.7 for larynx. For the three sites combined, the OR for the highest tertile was 5.7 for refined grains and 0.5 for wholegrains. The trends in risk for refined grains were significant for all sites and their combination, and for wholegrain for oesophageal cancer and all sites. CONCLUSIONS: Even if inference on causality and the biological interpretation remain open to discussion, the present data indicate and further quantify that refined cereals are an unfavourable, but whole grain ones a favourable indicator of the risk of upper aerodigestive and respiratory tract neoplasms.

Adult↗
PubMed2000

Assessment of psychiatric patients' competency to give informed consent: legal safeguard of civil right to autonomous decision-making.

Amendment of the Mental Health and Welfare Law in Japan will limit admission for medical care and protection only for those individuals who are incapable of giving consent to admission. This is a first in the history of the Japanese mental health legislation. By reviewing the law and psychiatric literature, it is argued that: (i) informed consent is a legal transaction that embodies the idea of an individual's right to autonomous decision-making in medical settings; (ii) health professionals have a duty to protect those individuals who cannot decide medical matters because of lack of capacity to do so; (iii) some patients are marginally incompetent so assessment of their competency is essential in protecting patients' civil rights; (iv) in order for a competency assessment to be reliable (and hence fair) the method should be psychometrically sound; (v) at the same time, in order for a competency assessment to be valid, the structure of a competency assessment should match the patient's psychological, cultural, and social background; and (vi) because informed consent is a process rather than a cross-sectional event, a competency assessment should be performed in everyday practice. The use of a brief and semistructured interview to assess patients' competency to give informed consent may meet all of the requirements described.

Decision Making↗
PubMed2001

Lymph nodes in the human female breast: a review of their detection and significance.

Our experience led us to test the hypothesis that lymph nodes are not uncommon within the substance of the human female breast mound. The following specimen types and sources were used to survey the presence of intramammary lymph nodes in the human female breast mound: (1) cadaver breasts; (2) community hospital breast specimens; and (3) university and VA hospital specimens. We found true lymph nodes within and associated with breast specific tissue (ie, tissue that includes duct and gland structures), thereby validating the hypothesis posed. We discuss the significance of these findings in terms of our dominant patient care paradigm (the Triple Test-physical examination, imaging, and fine-needle aspiration [FNA]) and the choice of patient care management options. We conclude the following: lymph nodes occur in any quadrant of the breast mound; recognizing the possibility of intramammary lymph nodes is important when choosing between patient management options; intramammary lymph nodes can be sampled by FNA; intramammary lymph nodes can contain various disease processes; and in the Oregon Health Sciences University Multidisciplinary Breast Clinic, these intramammary lymph nodes are commonly identified by imaging methods and are more likely to be sampled by FNA than either by core or excisional biopsy.

Adult↗
PubMed2000

Structure of an 11-mer DNA duplex containing the carbocyclic nucleotide analog: 2'-deoxyaristeromycin.

2'-deoxyaristeromycin (dAr) is a nucleoside analogue that is resistant to the action of DNA glycosylases. High-resolution NMR spectroscopy and molecular dynamics simulations were used to determine the three-dimensional structure of an 11-mer DNA containing a single dAr.T base pair at its center. Analysis of the spectra revealed the existence of a right-handed duplex in solution, stabilized by Watson-Crick hydrogen bonding and base-stacking interactions. The carbocyclic sugar adopted a C1'-exo conformation and sugars of the 3'-flanking base pair had puckers in the O4'-endo range. The dAr.T base pair was mildly propeller twisted, and the dAr analogue showed a positive roll with the 3'-flanking base. Our findings indicate that the observed resistance of dAr-containing oligodeoxynucleotides to the catalytic action of DNA glycosylases relates to its electronic properties rather than structure, and validate the use of dAr and related carbocyclic nucleoside analogues for biological and structure/function relationship studies.

Computer Simulation↗