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Results for “Analytical Approach”

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PubMed2003

Dual excitation multi- fluorescence flow cytometry for detailed analyses of viability and apoptotic cell transition.

The discrimination of live/dead cells as well as the detection of apoptosis is a frequent need in many areas of experimental biology. Cell proliferation is linked to apoptosis and controlled by several genes. During the cell life, specific events can stimulate proliferation while others may trigger the apoptotic pathway. Very few methods (i.e. TUNEL) are now available for studies aimed at correlation between apoptosis and proliferation. Therefore, there is interest in developing new methodological approaches that are able to correlate apoptosis to the cell cycle phases. Recently new approaches have been proposed to detect and enumerate apoptotic cells by flow cytometry. Among these, the most established and applied are those based on the cell membrane modifications induced in the early phases of the apoptotic process. The dye pair Hoechst 33342 (HO) and Propidium Iodide (PI), thanks to their peculiar characteristics to be respectively permeable and impermeable to the intact cell membrane, seems to be very useful. Unfortunately the spectral interaction of these dyes generates a consistent "energy transfer" from HO to PI. The co-presence of the dyes in a nucleus results in a modification in the intensity of both the emitted fluorescences. In order to designate the damaged cells (red fluorescence) to the specific cell cycle phases (blue fluorescence), we have tested different staining protocols aimed to minimize the interference of these dyes as much as possible. In cell culture models, we are able to detect serum-starved apoptotic cells as well as to designate their exact location in the cell cycle phases using a very low PI concentration. Using a Partec PAS flow cytometer equipped with HBO lamp and argon ion laser, a double UV/blue excitation has been performed. This analytical approach is able to discriminate live blue cells from the damaged (blue-red) ones even at 0.05 micro g/mL PI. The same instrumental setting allows performing other multi-colour analyses including AnnexinV-FITC as well as the possibility to make a correlated analysis to phenotype markers.

Apoptosis↗

PubMed1998

Cluster analysis of HIV intervention outcomes among substance-abusing women.

The study described here presents an innovative approach to analyzing intervention outcomes among women substance abusers participating in a national HIV prevention research study funded by the National Institute on Drug Abuse. We used cluster analysis to divide the women in our sample (N=557) into four distinct subgroups predominantly characterized by differences in drug use, injecting risk, sexual behaviors, and drug and sexual risk combined. The four subgroups resulting from this process were primary crack-using women, primary needle-using women, high-frequency needle-using women, and women with multiple drug and sex risk behaviors. Our analysis focuses on changes in self-reported risk behaviors from baseline to 6-month follow-up. In general, the results clearly indicate that the women are heterogeneous; that is, the subgroups exhibit varying patterns of drug use, injecting risk, sexual behavior, and HIV seropositivity. Significant outcomes were found in many areas, indicating positive changes in risk behaviors. The two smaller subgroups of women--high-frequency needle users and those in the multiple-risk behavior subgroup--reported the highest rate of high-risk behaviors and seropositivity but also showed the greatest change at follow-up. A particularly important finding resulting from our analytical approach is that well over half the women in our sample were primary crack users (n=313). This finding is even more significant in light of the fact that the Cooperative Agreement specifically tried to include 70% or more participants who were injectors. Although the rate of HIV seropositivity is not as high for this crack-using subgroup as for the two smaller needle-using subgroups, a greater number of "women who are HIV positive" are in this primary crack-using subgroup than in all the other subgroups. Most of the crack-using women reported that they were not currently injecting drugs and never shared needles, but 10% were seropositive for HIV, suggesting that their risk comes primarily from sexual behaviors. Behaviors in this larger subgroup of women did not change as dramatically as those of women in the smaller subgroups; however, the women did show improvement in areas related to indirect risk (e.g., alcohol and crack use) and in several areas where change is most needed (e.g., trading sex for drugs and using condoms). The results demonstrate a promising alternative approach to analyzing substance abuse and HIV risk behaviors, and they suggest the need for further research on alternative interventions for women with different patterns of risk behaviors.

Community-Institutional Relations↗

PubMed1994

The time-dependence of long-term prediction in lupus nephritis.

OBJECTIVE: To assess the clinical, laboratory, and renal biopsy predictors of long-term outcome in lupus nephritis and to investigate the time-dependence of these predictors. METHODS: Eighty-seven lupus nephritis patients were studied retrospectively for the outcomes renal failure and fatality due to renal involvement. In addition to a conventional Cox model analysis, a new generalized time-dependent analytic approach was developed and used to assess the time-dependence of a predictor variable's importance. RESULTS: The mean followup time was 11.9 years. Renal failure (n = 19) was significantly predicted by measures of renal function (abnormal serum creatinine levels, proteinuria, duration of prior renal disease) and immunologic activity (elevated DNA binding, hypocomplementemia, and thrombocytopenia), by overall lupus disease activity measures (le Riche index, Lupus Activity Criteria Count), and by the activity index, the tubulointerstitial index, and the amount of subepithelial deposits on renal biopsy. In general, the laboratory predictors were significantly better prognostic markers in the early years after biopsy, the disease activity measures were best in the later years, and the biopsy variables were significant predictors over the entire observation period. In contrast to the renal failure outcome, the best predictors for death not directly related to lupus nephritis (n = 17) were the extent of comorbid diseases (principally vascular diseases), older age, and the chronicity index. All three predicted well over the extended observation period. CONCLUSION: The major predictor variables for renal outcomes and nonrenal outcomes are distinct. The time-dependence of the predictive ability of some variables may be important in managing individual patients. The new generalized time-dependent analytic technique may have widespread application in studies to identify prognostic factors for established disease or risk factors for the development of disease.

Adolescent↗

PubMed2003

Monitoring and evaluation of human resources for health: an international perspective.

BACKGROUND: Despite the undoubted importance of human resources to the functions of health systems, there is little consistency between countries in how human resource strategies are monitored and evaluated. This paper presents an integrated approach for developing an evidence base on human resources for health (HRH) to support decision-making, drawing on a framework for health systems performance assessment. METHODS: Conceptual and methodological issues for selecting indicators for HRH monitoring and evaluation are discussed, and a range of primary and secondary data sources that might be used to generate indicators are reviewed. Descriptive analyses are conducted drawing primarily on one type of source, namely routinely reported data on the numbers of health personnel and medical schools as covered by national reporting systems and compiled by the World Health Organization. Regression techniques are used to triangulate a given HRH indicator calculated from different data sources across multiple countries. RESULTS: Major variations in the supply of health personnel and training opportunities are found to occur by region. However, certain discrepancies are also observed in measuring the same indicator from different sources, possibly related to the occupational classification or to the sources' representation. CONCLUSION: Evidence-based information is needed to better understand trends in HRH. Although a range of sources exist that can potentially be used for HRH assessment, the information that can be derived from many of these individual sources precludes refined analysis. A variety of data sources and analytical approaches, each with its own strengths and limitations, is required to reflect the complexity of HRH issues. In order to enhance cross-national comparability, data collection efforts should be processed through the use of internationally standardized classifications (in particular, for occupation, industry and education) at the greatest level of detail possible.

Journal Article↗

PubMed1992

Dietary fat and postmenopausal breast cancer.

BACKGROUND: Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal. PURPOSE: The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa. METHODS: Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered. RESULTS: After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association. CONCLUSIONS: These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer. IMPLICATIONS: Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations.

Aged↗

PubMedDate not supplied

Exercise and regional bone mineral density in postmenopausal women: a meta-analytic review of randomized trials.

By using the meta-analytic approach, the purpose of this study was to examine the effects of exercise on regional bone mineral density in postmenopausal women. A total of 11 randomized trials yielding 40 outcome measures and a total of 719 subjects (370 exercise, 349 nonexercise) met the criteria for inclusion: (1) randomized trials; (2) exercise as a primary intervention in postmenopausal women; (3) changes in regional bone mineral density reported; (4) comparative nonexercise group included; (5) studies published in English-language journals between January 1975 and December 1995. Across all designs and categories, treatment effect changes in bone density, weighted by sample size, ranged from -17.10 to 17.30% (mean, 0.27%; 95% confidence interval, 0.16-0.37%). When analyzed separately, sample weighted decreases of approximately -0.51 and -0.86% were found for exercise and nonexercise groups, respectively. Larger effects were observed when groups that did not measure bone density specific to the site loaded and groups that received some type of supplementation (calcium or hormone replacement therapy) were deleted from the model (mean change, 0.76%; 95% confidence interval, 0.6-0.93). Both aerobic and strength training enhanced regional bone mineral density (mean change: aerobic, 1.62% and 95% confidence interval, 1.12-2.12; strength, 0.65% and 95% confidence interval, 0.48-0.83). In conclusion, meta-analytic review of included studies suggests that exercise may slow the rate of bone loss in postmenopausal women. However, it is premature to form strong conclusions regarding the effects of exercise on regional bone mineral density in postmenopausal women. A need exists for additional, well designed studies on this topic before a recommendation can be made regarding the efficacy of exercise as a nonpharmacologic therapy for maintaining and/or increasing regional bone mineral density in postmenopausal women.

Absorptiometry, Photon↗

PubMed2006

Pyrolysis-field ionization mass spectrometry of rhizodeposits - a new approach to identify potential effects of genetically modified plants on soil organisms.

The objectives of the present study were (1) to investigate the qualitative composition of rhizodeposits leached from soils cropped with non-transgenic and genetically modified (GM) potatoes, and disclose if there were GM-specific modifications in potato rhizodeposition, and (2) to compare these results with conventional bulk parameters of microbial activity in soil. We have raised potatoes from a non-transgenic line (Solanum tuberosum L. cv. Désirée) and three GM lines, which expressed a gene for the resistance to kanamycin (DLH 9000) and a gene for T4 lysozyme (DL10 and DL12). A sandy soil placed in 340 cm3-"CombiSart" containers was used, from which the rhizodeposit was leached after a six-week growth period. The freeze-dried leachates were analyzed by pyrolysis-field ionization mass spectrometry (Py-FIMS). The Py-FI mass spectra gave detailed molecular-chemical information about the composition of leachates, indicating that the potato growth generally altered the composition of the soil solution. Moreover, a principal component analysis of the mass spectra showed differences between the leachates from the non-transgenic parent line and the GM potatoes as well as among the latter group. However, these differences in molecular composition could not be assigned to the release of T4-lysozyme into soil. Dehydrogenase activity and substrate-induced soil respiration as more common bulk parameters of soil microbial activity failed to disclose any significant effects of the various potatoes grown. The limitations of the described rhizodeposit leaching and analysis for risk assessment of GM potato cropping under field conditions are discussed critically. However, it could be concluded that the Py-FI mass spectrometric "fingerprint" can be developed as a fast, comprehensive, highly sensitive and reproducible analytical approach to discern any effects GM-crops may exert on soil ecological parameters.

Animals↗

PubMed2006

"You have to cover up the words of the doctor": the mediation of trust in interpreted consultations in primary care.

PURPOSE: This article explores issues of trust in narratives of interpreted consultations in primary health care. DESIGN/METHODOLOGY/APPROACH: The paper is based on empirical data from a qualitative study of accounts of interpreted consultations in U.K. primary care, undertaken in three north London boroughs. In a total of 69 individual interviews and two focus groups, narratives of interpreted consultations were sought from 18 service users, 17 professional interpreters, nine family member interpreters, 13 general practitioners, 15 nurses, eight receptionists, and three practice managers. The study collected and analysed these using a grounded theory approach and taking the story as the main unit of analysis. It applies a theoretical model that draws on three key concepts: Greener's taxonomy of trust based on the different "faces" of power in medical consultations; Weber's notion of bureaucratic vs traditional social roles; and Habermas' distinction between communicative and strategic action. FINDINGS: Trust was a prominent theme in almost all the narratives. The triadic nature of interpreted consultations creates six linked trust relationships (patient-interpreter, patient-clinician, interpreter-patient, interpreter-clinician, clinician-patient and clinician-interpreter). Three different types of trust are evident in these different relationships--voluntary trust (based on either kinship-like bonds and continuity of the interpersonal relationship over time, or on confidence in the institution and professional role that the individual represents), coercive trust (where one person effectively has no choice but to trust the other, as when a health problem requires expert knowledge that the patient does not have and cannot get) and hegemonic trust (where a person's propensity to trust, and awareness of alternatives, is shaped and constrained by the system so that people trust without knowing there is an alternative). These different types of trust had important implications for the nature of communication in the consultation and on patients' subsequent action. RESEARCH LIMITATIONS/IMPLICATIONS: The methodological and analytic approach, potentially, has wider applications in the study of other trust relationships in health and social care. Practical implications - Quality in the interpreted consultation cannot be judged purely in terms of accuracy of translation. The critical importance of voluntary trust for open and effective communication, and the dependence of the latter on a positive interpersonal relationship and continuity of care, should be acknowledged in the design and funding of interpreting services and in the training of both clinicians, interpreters and administrative staff. ORIGINALITY/VALUE: This is the first study in which interpreted consultations have been analysed from a perspective of critical sociology with a particular focus on trust and power relations.

Communication↗

PubMed2004

Use of multiple nucleic acid amplification tests to define the infected-patient "gold standard" in clinical trials of new diagnostic tests for Chlamydia trachomatis infections.

Nucleic acid amplification tests (NAATs) can be used to define the infected-patient "gold standard" for the purpose of designing studies of the performance of Chlamydia trachomatis diagnostic tests. It is unclear how many test results run by different NAATs and what combinations of specimens comprise the best infected-patient gold standard. We approached this question with data from a large study of the performance of a new NAAT. Data were available from three endocervical swabs and a urine specimen collected from each of 1,412 women and tested by three different NAATs. Results from all three assays were used equally in a rotating fashion to define the infected-patient gold standard. Multiple different infected-patient gold standards for estimating swab and urine specimen sensitivity and specificity for one NAAT method were created by varying the number and combinations of swab and urine comparator results with two different NAATs, The effect of changing the infected-patient gold standard definition was determined by constructing receiver-operator-like curves with calculated sensitivities and specificities for each test. The one-positive-of-two-results or two-positive-of-two-results (same or two different assays) infected-patient gold standard definitions produced low sensitivity and low specificity estimates, respectively. If four comparator NAAT results were used, the any-three-positive-of-four-results definition or the at-least-one-specimen-positive-by-each-of-two-comparator-assays definition appeared to provide better combinations of sensitivity and specificity estimates. The any-two-positive-out-of-three-results definition resulted in estimates that were as good as produced with the former two definitions. This analytic approach provides a means of clearly visualizing the effects of changing NAAT-based infected-patient gold standards and should be helpful in designing future studies of new C. trachomatis diagnostic tests.

Cervix Uteri↗

PubMed2003

Do differences in methods for constructing SF-36 physical and mental health summary measures change their associations with chronic medical conditions and utilization?

BACKGROUND AND OBJECTIVE: Various approaches have been employed to derive physical health and mental health summary scores for the SF-36 and the RAND-36, but head-to-head comparisons of alternative scoring algorithms are rare. We determined whether the associations of the physical and mental health summary scores with chronic medical conditions and utilization would differ depending on the scoring algorithm used. METHODS: We examined 5701 patients receiving medical care from an independent association of 48 physician groups located primarily in the western United States and compared SF-36 and RAND-36 scoring of physical health and mental health summary scores. Associations with the presence of diabetes, heart disease, and kidney disease, as well as with utilization of medical care and mental health care were compared using bivariate and multivariate analysis. To examine the relationship between SF-36 and RAND-36 scores, we regressed the SF-36 physical and mental health composite scores on the RAND-36 physical and mental health summary measures and vice versa. RESULTS: We found that the SF-36 and RAND-36 summary scores generally yielded results similar to one another across measures of heart disease, diabetes, and kidney disease, as well as measures of utilization. However, for each chronic medical condition, the RAND-36 showed a slightly larger decrement in mental health than did the SF-36. CONCLUSIONS: Differences between the two sets of summary scores were consistent with their respective conceptual and analytic approaches. Where comparisons of results between the SF-36 and RAND-36 summary scores are desirable in future studies, they can be estimated using the regression equations derived in this study.

Adult↗

PubMed1996

Elemental carbon-based method for occupational monitoring of particulate diesel exhaust: methodology and exposure issues.

Diesel exhaust has been classified a probable human carcinogen, and the National Institute for Occupational Safety and Health (NIOSH) has recommended that employers reduce workers' exposures. Because diesel exhaust is a chemically complex mixture containing thousands of compounds, some measure of exposure must be selected. Previously used methods involving gravimetry or analysis of the soluble organic fraction of diesel soot lack adequate sensitivity and selectivity for low-level determination of particulate diesel exhaust; a new analytical approach was therefore needed. In this paper, results of investigation of a thermal-optical technique for the analysis of the carbonaceous fraction of particulate diesel exhaust are discussed. With this technique, speciation of organic and elemental carbon is accomplished through temperature and atmosphere control and by an optical feature that corrects for pyrolytically generated carbon, or "char,' which is formed during the analysis of some materials. The thermal-optical method was selected because the instrument has desirable design features not present in other carbon analysers. Although various carbon types are determined by the method, elemental carbon is the superior marker of diesel particulate matter because elemental carbon constitutes a large fraction of the particulate mass, it can be quantified at low levels and its only significant source in most workplaces is the diesel engine. Exposure-related issues and sampling methods for particulate diesel exhaust also are discussed.

Air Pollutants, Occupational↗

PubMed2002

Comparison of two different approaches for the analysis of data from a prospective cohort study: an application to work related risk factors for low back pain.

AIMS: To compare the results of a traditional approach using standard regression for the analysis of data from a prospective cohort study with the results of generalised estimating equations (GEE) analysis. METHODS: The research was part of a three year prospective cohort study on work related risk factors for low back pain. The study population consisted of a cohort of 1192 workers with no low back pain at baseline. Information on work related physical and psychosocial factors and the occurrence of low back pain was obtained by means of questionnaires at baseline and at the three annual follow up measurements. In a traditional standard logistic regression model, physical and psychosocial risk factors at baseline were related to the cumulative incidence of low back pain during the three year follow up period. In a GEE logistic model, repeated measurements of the physical and psychosocial risk factors were related to low back pain reported at one measurement point later. RESULTS: The traditional standard regression model showed a significant effect of flexion and/or rotation of the upper part of the body (OR = 1.8; 95% CI: 1.2 to 3.0), but not of moving heavy loads (OR = 1.4; 95% CI: 0.7 to 3.1). The GEE model showed a significant effect of both flexion and/or rotation of the upper part of the body (OR = 2.2; 95% CI: 1.5 to 3.3) and moving heavy loads (OR = 1.5; 95% CI: 1.0 to 2.4). No significant associations with low back pain were found for the psychosocial work characteristics with either method, but the GEE model showed weaker odds ratios for these variables than the traditional standard regression model. CONCLUSIONS: Results show that there are differences between the two analytical approaches in both the magnitude and the precision of the observed odds ratios.

Follow-Up Studies↗

PubMed2006

Systematic approach to obtain analytic solutions of quasi steady state species in reduced mechanisms.

A systematic approach was developed to obtain analytic solutions for the concentrations of the quasi steady state (QSS) species in reduced mechanisms. The nonlinear algebraic equations for the QSS species concentrations were first approximated by a set of linear equations, and the linearized quasi steady state approximations (LQSSA) were then analytically solved with a directed graph, namely a QSSG, which was abstracted from the inter-dependence of QSS species. To obtain analytic solutions of high computational efficiency, the groups of strongly connected QSS species were first identified in the QSSG. The inter group couplings were then resolved by a topological sort, and the inner group couplings were solved with variable elimination by substitution. An efficient algorithm was developed to identify a near-optimal sequence for the variable elimination process. The proposed LQSSA-QSSG method was applied to generate a 16-step reduced mechanism for ethylene/air, and good accuracy and high efficiency were observed in simulations of auto-ignition and perfectly stirred reactors with the reduced mechanism.

Journal Article↗

PubMed2002

Complete androgen insensitivity syndrome: effect on human meibomian gland secretions.

OBJECTIVE: To determine whether androgen receptors affect the fatty acid profiles of neutral and polar lipids in human meibomian gland secretions. METHODS: Meibomian gland secretion samples were obtained from both eyes of (1) women with complete androgen insensitivity syndrome, a condition characterized by dysfunctional androgen receptors, and (2) age-matched female and male controls. Samples were processed for high-performance liquid chromatography, mass spectrometry, or both and for analysis of the mass spectra of neutral and polar lipid fatty acid fragment ions by 3 different methods. RESULTS: Androgen receptor dysfunction is associated with significant alterations in the appearance of numerous molecular species in the neutral and polar lipid fractions of meibomian gland secretions. The ability to detect these differences, and to assess their nature and extent, was facilitated by the use of several analytic approaches. Sex-related differences exist in the expression of a variety of neutral and, especially, polar fatty acid products in meibomian gland secretions. CONCLUSIONS: Androgens exert a significant effect on neutral and polar lipids in human meibomian gland secretions, and these hormonal effects may be mediated through androgen receptors.

Adult↗

PubMed2002

Identification of population subgroups of children and adolescents with high asthma prevalence: findings from the Third National Health and Nutrition Examination Survey.

OBJECTIVES: To provide national estimates of asthma prevalence in African-American, Mexican American and white (non-Latino) children and adolescents using several common definitions; to evaluate familial, sociodemographic, and environmental risk factors that are independently associated with current asthma in children; and to identify subgroups at particular risk for current asthma using 2 complementary data analytic approaches. DESIGN: Cross-sectional study, using the Third National Health and Nutrition Examination Survey, 1988-1994. SETTING: Eighty-nine mobile examination centers in the United States. PARTICIPANTS: Twelve thousand three hundred eighty-eight African American, Mexican American, and white (non-Latino) children and adolescents, aged 2 months through 16 years, selected from a systematic random, population-based, nationally representative sample. MAIN OUTCOME MEASURE: Current asthma, defined by caregivers who reported that their child currently had doctor-diagnosed asthma. RESULTS: The overall prevalence of current asthma was 6.7% (95% confidence interval [CI], 5.6-7.8). Odds ratios for current asthma from the multiple regression analysis were 4.00 (95% CI, 2.90-5.52) for children with a parental history of asthma or hay fever, 1.94 (95% CI, 1.09-3.46) for children with body mass index (calculated as weight in kilograms divided by the square of height in meters) greater than or equal to the 85th percentile, and 1.64 (95% CI, 1.20-2.26) for children of African American ethnicity. African American and Mexican American children showed a consistent prevalence of current asthma across age while white children showed an increase in prevalence with age. The 2 highest-risk subgroups identified by the signal detection analysis were composed of children with a parental history of asthma or hay fever who were 10 years or older with a body mass index greater than or equal to the 85th percentile (31.0% current asthma), and children with a parental history who were 10 years or younger and of African American ethnicity (15.6% current asthma). CONCLUSIONS: The findings from this analysis show a strong independent association between obesity and current asthma in children and adolescents, and confirm previous reports of a parental history of asthma or hay fever and African American ethnicity as additional important risk factors.

Adolescent↗

PubMed1999

Structure-based analysis of protein dynamics: comparison of theoretical results for hen lysozyme with X-ray diffraction and NMR relaxation data.

An analytical approach based on Gaussian network model (GNM) is proposed for predicting the rotational dynamics of proteins. The method, previously shown to successfully reproduce X-ray crystallographic temperature factors for a series of proteins is extended here to predict bond torsional mobilities and reorientation of main chain amide groups probed by 15N-H nuclear magnetic resonance (NMR) relaxation. The dynamics of hen egg-white lysozyme (HEWL) in the folded state is investigated using the proposed approach. Excellent agreement is observed between theoretical results and experimental (X-ray diffraction and NMR relaxation) data. The analysis reveals the important role of coupled rotations, or cross-correlations between dihedral angle librations, in defining the relaxation mechanism on a local scale. The crystal and solution structures exhibit some differences in their local motions, but their global motions are identical. Hinge residues mediating the cooperative movements of the alpha- and beta-domains are identified, which comprise residues in helix C, Glu35 and Ser36 on the loop succeeding helix B, Ile55 and Leu56 at the turn between strands II and III. The central part of the beta-domain long loop and the turn between strands I and II display an enhanced mobility. Finally, kinetically hot residues and key interactions are identified, which point at helix B and beta-strand III as the structural elements underlying the stability of the tertiary structure.

Animals↗

PubMed1999

Inherited genetic predisposition in breast cancer. A population-based perspective.

Two classes of inherited susceptibility genes may be considered in the etiology of breast and other common cancers. First, genes have been identified that confer a high degree of breast cancer (BC) risk, usually associated with hereditary syndromes, but disease-associated germline variants in these genes are relatively rare in the general population. These include BRCA1, BRCA2, and TP53. The proportion of BC in the general population that can be explained by these genes is relatively small. Second, variant genotypes at other loci may confer a relatively smaller degree of cancer risk, but they are carried by a larger proportion of the general population. As a result, the proportion of BC that could be explained by these genes may be relatively large. To understand the genetic basis for BCs in the general population, both of these classes of genes may need to be considered. This paper presents an overview of genes thought to be involved in BC susceptibility. Genes that confer a high degree of risk are more likely to result in hereditary patterns of cancer that are amenable to identification by genetic epidemiologic methods using pedigree data. More common (e.g., nonhereditary) forms of BC may be optimally analyzed by molecular epidemiologic studies using case-case, case-control, or cohort designs. The use of an appropriate study design is crucial to the identification of genes with relatively small effects on BC risk. To understand the inherited factors that explain BC in the general population, consideration should be given to genes with different allele frequencies and magnitudes of effect, using appropriate analytical approaches. By understanding the complex interactions of these genes with one another and with exposures, improved risk assessment and potential for targeted cancer prevention strategies may be possible.

Breast Neoplasms↗

PubMed1998

Structural analysis and quantitative evaluation of the modifications produced in human hemoglobin by methyl bromide using mass spectrometry and Edman degradation.

The present study reports a procedure developed for the identification and quantitative analysis of the adducts formed by interaction of methyl bromide with human hemoglobin, based on combined analysis by electrospray mass spectrometry and automated Edman degradation of either intact globin chains or tryptic peptides of globin chains. The procedure has allowed identification of the reactive sites in human hemoglobin, and has been applied to the analysis of samples modified in vitro by methyl bromide. The results obtained represent the basis for the complete structural characterization of the modified hemoglobin and demonstrate the usefulness of the proposed analytical approach for the evaluation of the degree of alkylation and the identification of modified amino acids in proteins.

Amino Acid Sequence↗