A mesoscale finite element modeling approach for understanding brain morphology and material heterogeneity effects in chronic traumatic encephalopathy.

Chronic Traumatic Encephalopathy (CTE) affects a significant portion of athletes in contact sports but is difficult to quantify using clinical examinations and modeling approaches. We use an in silico approach to quantify CTE biomechanics using mesoscale Finite Element (FE) analysis that bridges with macroscale whole head FE analysis. The sulci geometry produces complex stress waves that interact with one another to create increased shear stresses at the sulci depth that are significantly larger than in analyses without sulci (from 0.5 to 18.0 kPa). Sulci peak stress concentration regions coincide with experimentally observed CTE sites documented in the literature. HighlightsSulci introduce stress localizations at their depth in the gray matterSulci stress fields interact to produce stress concentration sites in white matterDifferentiating brain tissue properties did not significantly affect peak stresses.

Expression profiling using human tissues in combination with RNA amplification and microarray analysis: assessment of Langerhans cell histiocytosis.

Advances in molecular genetics have led to sequencing of the human genome, and expression data is becoming available for many diverse tissues throughout the body, allowing for exciting hypothesis testing of critical concepts such as development, differentiation, homeostasis, and ultimately, disease pathogenesis. At present, an optimal methodology to assess gene expression is to evaluate single cells, either identified physiologically in living preparations, or by immunocytochemical or histochemical procedures in fixed cells in vitro or in vivo. Unfortunately, the quantity of RNA harvested from a single cell is not sufficient for standard RNA extraction methods. Therefore, exponential polymerase-chain reaction (PCR) based analyses, and linear RNA amplification including amplified antisense (aRNA) RNA amplification and a newly developed terminal continuation (TC) RNA amplification methodology have been used in combination with microdissection procedures such as laser capture microdissection (LCM) to enable the use of microarray platforms within individual populations of cells obtained from a variety of human tissue sources such as biopsy-derived samples {including Langerhans cell histiocytosis (LCH)} as well as postmortem brain samples for high throughput expression profiling and related downstream genetic analyses.

Uncertainties in estimates of the risks of late effects from space radiation.

Methods used to project risks in low-Earth orbit are of questionable merit for exploration missions because of the limited radiobiology data and knowledge of galactic cosmic ray (GCR) heavy ions, which causes estimates of the risk of late effects to be highly uncertain. Risk projections involve a product of many biological and physical factors, each of which has a differential range of uncertainty due to lack of data and knowledge. Using the linear-additivity model for radiation risks, we use Monte-Carlo sampling from subjective uncertainty distributions in each factor to obtain an estimate of the overall uncertainty in risk projections. The resulting methodology is applied to several human space exploration mission scenarios including a deep space outpost and Mars missions of duration of 360, 660, and 1000 days. The major results are the quantification of the uncertainties in current risk estimates, the identification of factors that dominate risk projection uncertainties, and the development of a method to quantify candidate approaches to reduce uncertainties or mitigate risks. The large uncertainties in GCR risk projections lead to probability distributions of risk that mask any potential risk reduction using the "optimization" of shielding materials or configurations. In contrast, the design of shielding optimization approaches for solar particle events and trapped protons can be made at this time and promising technologies can be shown to have merit using our approach. The methods used also make it possible to express risk management objectives in terms of quantitative metrics, e.g., the number of days in space without exceeding a given risk level within well-defined confidence limits.

Gene expression changes in mouse brain after exposure to low-dose ionizing radiation.

PURPOSE: To characterize the cellular functions associated with the altered transcript profiles of mouse brain exposed to low-dose in vivo gamma-irradiation. MATERIALS AND METHODS: Cerebral RNA was isolated at 30 min and 4 h after whole-body irradiation at 0.1 or 2 Gy, hybridized to random oligonucleotide arrays, and evaluated for time and dose-response patterns by multifactorial analyses. RESULTS: Brain irradiation modulated the expression patterns of 1574 genes, of which 855 showed more than 1.5-fold variation. about 30% of genes showed dose-dependent variations, including genes exclusively affected by 0.1 Gy. About 60% of genes showed time-dependent variation with more genes affected at 30 min than at 4 h. Early changes involved signal transduction, ion regulation and synaptic signalling. Later changes involved metabolic functions including myelin and protein synthesis. Low-dose radiation also modulated the expression of genes involved in stress response, cell-cycle control and DNA synthesis/repair. CONCLUSIONS: Doses of 0.1 Gy induced changes in gene expression that were qualitatively different from those at 2 Gy. The findings suggest that low-dose irradiation of the brain induces the expression of genes involved in protective and reparative functions, while down-modulating genes involved in neural signalling activity.

Novel potential ALL low-risk markers revealed by gene expression profiling with new high-throughput SSH-CCS-PCR.

The current systems of risk grouping in pediatric acute lymphoblastic leukemia (ALL) fail to predict therapeutic success in 10-35% of patients. To identify better predictive markers of clinical behavior in ALL, we have developed an integrated approach for gene expression profiling that couples suppression subtractive hybridization, concatenated cDNA sequencing, and reverse transcriptase real-time quantitative PCR. Using this approach, a total of 600 differentially expressed genes were identified between t(4;11) ALL and pre-B ALL with no determinant chromosomal translocation. The expression of 67 genes was analyzed in different cytogenetic ALL subgroups and B lymphocytes isolated from healthy donors. Three genes, BACH1, TP53BPL, and H2B/S, were consistently expressed as a significant cluster associated with the low-risk ALL subgroups. A total of 42 genes were differentially expressed in ALL vs normal B lymphocytes, with no specific association with any particular ALL subgroups. The remaining 22 genes were part of a specific expression profile associated with the hyperdiploid, t(12;21), or t(4;11) subgroups. Using an unsupervised hierarchical cluster analysis, the discriminating power of these specific expression profiles allowed the clustering of patients according to their subgroups. These genes could help to understand the difference in treatment response and become therapeutical targets to improve ALL clinical outcomes.

Rethinking quality in the context of persons with disability.

OBJECTIVE: To review the current health services literature related to quality of care for persons with disabilities and to highlight the need for a unique framework for conceptualizing quality and patient safety issues for this population. DESIGN: Drawing on quality measurement theory, we formulate a multi-dimensional model of quality of care for persons with disability. This model is then used to identify and summarize findings from existing health services research that relate to the quality, of care for persons with disability. STUDY SELECTION: We searched MEDLINE and other databases for primary research and review articles containing the phrases 'quality of care', 'patient safety', 'access', 'patient experience', and 'coordination of care' in conjunction with the words 'disability' or 'impairment'. RESULTS: A review of health services research suggests several potential issues in the areas of clinical quality, access, client experience, and coordination. Physical barriers, transportation, communication difficulties, and client and provider attitudes present barriers to receiving appropriate client-centered care. Communication difficulties between provider and client may increase risk for accidental injury and decrease the quality of the client experience. Frequent contact with the health care system and the complexity of an individual's situation also increase the risk of accidental injury. Coordination, the 'lubricant' that facilitates links for all areas of quality for a person with disability, presents the most significant opportunity for improvement, because multiple medical and social providers are typically involved in the care of individuals with disabling conditions. CONCLUSION: Health care providers need to embrace a multi-disciplinary approach to quality to meet the needs of persons with disabilities. Funders and purchasers need to provide flexibility in funding to enable a comprehensive primary care approach, while health service researchers need to adopt a broad view of quality to capture issues of importance for persons with disabilities.

Screening of gene expression profiles in gastric epithelial cells induced by Helicobacter pylori using microarray analysis.

BACKGROUND: H. pylori infection is a major risk factor in gastric cancer development. The availability of cDNA microarrays creates the unprecedented opportunity to examine simultaneously dynamic changes of multiple pathways affected by H. pylori infection. AIM: In this study we examined broad patterns of gene expression induced by H. pylori in the gastric cancer cell line 1739-CRL AGS cells in culture using the U95A microarray. METHODS: H. pylori were cocultured with AGS cells for 4, 12, 24 and 48 h. Total RNA was extracted and after labelling was used for detection of genes represented in the human U95A microarray set. Data analyses were performed using GeneChip and CLUSFAVOR software. RESULTS: Nearly 6000 genes present in the array were expressed by AGS cells. We report approximately 200 genes that showed the most marked changes. Our studies confirm the up-regulation of c-jun, jun-B, c-fos and cyclin D1 by H. pylori. We report for the first time the induction of the serine threonine kinase pim-1 and ATF3 by H. pylori infection of AGS cells. CONCLUSIONS: In this microarray analysis of gene expression induced by H. pylori in gastric epithelial cells, we identified a large number of unsuspected genes affected by H. pylori. Further, we show that unsupervised hierarchical cluster analysis can provide useful insight into the possible contribution of genes in specific pathways, based on their profile of expression.

Extrapolation of the dna fragment-size distribution after high-dose irradiation to predict effects at low doses.

The patterns of DSBs induced in the genome are different for sparsely and densely ionizing radiations: In the former case, the patterns are well described by a random-breakage model; in the latter, a more sophisticated tool is needed. We used a Monte Carlo algorithm with a random-walk geometry of chromatin, and a track structure defined by the radial distribution of energy deposition from an incident ion, to fit the PFGE data for fragment-size distribution after high-dose irradiation. These fits determined the unknown parameters of the model, enabling the extrapolation of data for high-dose irradiation to the low doses that are relevant for NASA space radiation research. The randomly-located-clusters formalism was used to speed the simulations. It was shown that only one adjustable parameter, Q, the track efficiency parameter, was necessary to predict DNA fragment sizes for wide ranges of doses. This parameter was determined for a variety of radiations and LETs and was used to predict the DSB patterns at the HPRT locus of the human X chromosome after low-dose irradiation. It was found that high-LET radiation would be more likely than low-LET radiation to induce additional DSBs within the HPRT gene if this gene already contained one DSB.

Space radiation cancer risks and uncertainties for Mars missions.

Projecting cancer risks from exposure to space radiation is highly uncertain because of the absence of data for humans and because of the limited radiobiology data available for estimating late effects from the high-energy and charge (HZE) ions present in the galactic cosmic rays (GCR). Cancer risk projections involve many biological and physical factors, each of which has a differential range of uncertainty due to the lack of data and knowledge. We discuss an uncertainty assessment within the linear-additivity model using the approach of Monte Carlo sampling from subjective error distributions that represent the lack of knowledge in each factor to quantify the overall uncertainty in risk projections. Calculations are performed using the space radiation environment and transport codes for several Mars mission scenarios. This approach leads to estimates of the uncertainties in cancer risk projections of 400-600% for a Mars mission. The uncertainties in the quality factors are dominant. Using safety standards developed for low-Earth orbit, long-term space missions (>90 days) outside the Earth's magnetic field are currently unacceptable if the confidence levels in risk projections are considered. Because GCR exposures involve multiple particle or delta-ray tracks per cellular array, our results suggest that the shape of the dose response at low dose rates may be an additional uncertainty for estimating space radiation risks.

Short-term exposure to estrogen and progesterone induces partial protection against N-nitroso-N-methylurea-induced mammary tumorigenesis in Wistar--Furth rats.

The lifetime protective effect of a full term pregnancy for breast cancer is a reproducible and consistent finding in human beings and in rodent models. The duration of pregnancy necessary to confer protection has yielded contradictory results. As the administration of estrogen and progesterone mimics the full-term pregnancy effect on conferring protection, we examined whether short-term exposure to estrogen and progesterone confers protection against N-nitroso-N-methylurea-induced mammary carcinogenesis in Wistar--Furth rats. The results reported herein show that treatment of rats with estrogen or progesterone alone for 21 days does not confer protection, but a 10-day exposure to the same concentrations of estrogen and progesterone induced a partial protective effect. The significance of these results are discussed in terms of the contradictory results in the literature and the role of morphological differentiation in conferring the protective effect.

The silent consumer: women's reports and ratings of abortion services.

BACKGROUND: Abortion is one of the most common surgical procedures performed on women in the United States, and its safety has been demonstrated. Little research has focused, however, on women's reports and ratings of the service. OBJECTIVES: This study explored the association of demographic factors, medical outcomes, and client ratings of service dimensions with global satisfaction. RESEARCH DESIGN: For this cross-sectional study, permission to access clinic medical records was obtained. Surveys were distributed after the procedure, with instructions to return by mail. SUBJECTS: Study subjects were 797 women who underwent an outpatient surgical abortion at 1 of 2 New England health centers in 1996 and 1997. MEASURES: Demographic data, pregnancy history, and information on the procedure were collected from medical records. Survey items measured reports of access, medical outcomes, and satisfaction ratings with service domains. RESULTS: Women with positive ratings of staff sensitivity and of the counseling process and information received and those who had the procedure at a younger gestational age were less likely to report that care could be better. Although very few women reported a medical complication, this was associated with agreement that care could have been better, as was reporting agreement that the wait between the preexamination visit and the procedure was too long. CONCLUSIONS: Satisfaction with abortion services is high. Education and counseling play very important roles. Survey items could routinely be used to monitor services.

Eradication of non-typhoid salmonellae in acute enteritis after therapy with ofloxacin for 5 or 10 days.

Eradication of non-typhoid salmonellae was evaluated in a randomized, double-blinded study of 49 patients with acute enteritis after therapy with ofloxacin 400 mg once daily for 5 or 10 days. Early eradication of salmonellae was found in 57% of patients in the 5 day therapy group and in 74% of patients in the 10 day therapy group. This difference was larger among severely ill patients. Together with our previous study of ofloxacin therapy for 3 days or placebo, this shows that early eradication of non-typhoid salmonellae increases with duration of ofloxacin therapy without an increase in persistence of salmonellae in stools or development of resistant strains.

Identification of in-hospital complications from claims data. Is it valid?

OBJECTIVES: This study examined the validity of the Complications Screening Program (CSP) by testing whether (1) ICD-9-CM codes used to identify a complication are coded completely and accurately and (2) the CSP algorithm successfully separates conditions present on admission from those occurring in the hospital. METHODS: We compared diagnosis and procedure codes contained in the Medicare claim with codes abstracted from an independent re-review of more than 1,200 medical records from Connecticut and California. RESULTS: Eighty-nine percent of the surgical cases and 84% of the medical cases had their CSP trigger codes corroborated by re-review of the medical record. For 13% of the surgical cases and 58% of the medical cases, the condition represented by the code was judged to be present on admission rather than occurring in-hospital. The positive predictive value of the claim was greater than 80% for the surgical risk pool, suggesting the value of the CSP as a screening tool. CONCLUSIONS: The CSP has validity as a screen for most surgical complications but only for 1 medical complication. The CSP does not have validity as a "stand-alone" tool to identify more than a few in-hospital surgery-related events. The addition of an indicator to the Medicare claim to capture the timing of secondary diagnoses would improve the validity of the CSP for identifying both surgical and medical in-hospital events.

Mammography behavior after receiving a negative BRCA1 mutation test result in the Ashkenazim: a community-based study.

PURPOSE: To define the impact of a negative BRCA1 test result on subsequent breast cancer screening behavior in women. METHODS: Longitudinal study of a community-based sample of Ashkenazi Jews offered testing for the 185delAG BRCA1 mutation in 1996. Of 309 participants, 118 women were mutation negative, of average risk (based on family history of cancer), unaffected with breast cancer, and provided complete data at baseline, and Year 1 and Year 2 follow-up questionnaires. RESULTS: Women age 50 and older had 91.7% compliance with mammography for the year prior to entry (baseline), 88.3% during Year 1, 91.7% during Year 2 (no significant change; P = 0.775). Women under age 50 demonstrated an increase in mammography (49.2% at baseline, 62.7% Year 1, and 67.1% Year 2; P = 0.035). Both groups demonstrated significant decreases in breast cancer worry and perceived risk. Logistic regression analysis on having a mammogram at Year 2 showed that age, physician recommendation, worry, and perceived risk were all significant. CONCLUSION: Receipt of negative BRCA1 test results in a cohort of Ashkenazi Jewish women did not have a negative impact on mammography behavior 2 years after genetic testing.

Assessing linkage of monoamine oxidase B in a genome-wide scan using a univariate variance components approach.

We report results when one alcoholism related quantitative trait, monoamine oxidase B (MAOB), is analyzed by the variance components approach for linkage [Amos, 1994; Amos et al., 1996] using the Collaborative Study on the Genetics of Alcoholism data set provided for the Genetic Analysis Workshop 11. We used two different covariate models, one with age at interview, sex, ethnicity, and smoking status and the other with age at interview, sex, and ethnicity. The univariate analysis showed 24 markers on four different chromosomes (1, 4, 9, and 12) to have evidence for linkage with the quantitative trait (single-point and multipoint linkage). However, when outliers for MAOB were removed, the significant evidence for linkage disappeared.

Genome scans for genetic predisposition to alcoholism by use of transmission disequilibrium test analyses.

We report the results of the analysis of three measures of alcoholism and six associated symptoms using transmission disequilibrium (TDT) analysis on data from the Collaborative Study on the Genetics of Alcoholism data set. Implementation of identity-by-state (IBS) routines for error checking revealed 10 reported full siblings that were rejected as a full sibling to all of their purported full siblings with p < 0.05. TDT analysis revealed two loci with significant transmission disequilibrium (p < 0.001) on chromosomes 1 and 7. Analysis by parental origin found alleles at three loci displaying significant disequilibrium in the transmission of the paternal alleles for at least three of the nine tested traits. These loci are on chromosomes 6, 9, and 13. Analyses of Caucasian families alone and the use of a single affected individual from each family also yielded significant results for the loci on chromosomes 6, 9, and 13.

A genome-wide search for susceptibility genes linked to alcohol dependence.

We performed two-point linkage analysis during a genome-wide search for susceptibility genes that predispose to alcohol dependence with the Collaborative Study on the Genetics on Alcoholism (COGA) data made available for the Genetic Analysis Workshop 11 (GAW11). For chromosomes 1 and 4 our findings supported results reported by Reich et al. [1998] based on the same data. We found similarity between our findings in regions on chromosomes 8 and 10 and reported results for schizophrenia linkage studies. Differences between our results with COGA data and those obtained by Reich et al. [1998] are due to our use of a lod score method versus their use of the affected relative pair (sib pair) method.

Comparison of various D-dimer tests for the diagnosis of deep venous thrombosis.

Analyses of D-dimers in plasma are frequently used as diagnostic tools for deep venous thrombosis (DVT). Enzyme-linked immunosorbent assays (ELISAs) are considered to be the method of choice for quantitative assays, but are time consuming. Therefore, we have assessed plasma levels of D-dimers in patients with clinically suspected DVT using quantitative (Asserachrom D-Di ELISA and TintElize), semiquantitative (Minutex latex, D-Di latex, NycoCard D-Dimer) and qualitative (INSTANT.I.A) assays. Phlebography was used as the gold standard to verify or exclude the suspected diagnosis. We conclude that the fast assays, INSTANT.I.A and Minutex, have essentially the same negative predictive value [91% and 89%, respectively, using a cut-off value < 0.5 mg/l fibrinogen equivalent units (FEU)] for excluding DVT as the Asserachrom D-Di ELISA and TintElize tests (92%). The D-Di Latex assay had a negative predictive value of 82% (cut-off < 0.5 mg/l FEU) and turned out to be less useful in our material. The NycoCard D-dimer assay had a negative predictive value of 100% when using the cut-off value < 0.5 mg/l FEU, but this was substantially lower when the cut-off was changed to < or = 0.5 mg/l. Thus, we conclude that several fast tests offer a simpler and more rapid way of determining plasma levels of D-dimer than conventional ELISA methods without loss of clinical usefulness in excluding DVT.

Monte Carlo mixture model of lifetime cancer incidence risk from radiation exposure on shuttle and international space station.

Estimating uncertainty in lifetime cancer risk for human exposure to space radiation is a unique challenge. Conventional risk assessment with low-linear-energy-transfer (LET)-based risk from Japanese atomic bomb survivor studies may be inappropriate for relativistic protons and nuclei in space due to track structure effects. This paper develops a Monte Carlo mixture model (MCMM) for transferring additive, National Institutes of Health multiplicative, and multiplicative excess cancer incidence risks based on Japanese atomic bomb survivor data to determine excess incidence risk for various US astronaut exposure profiles. The MCMM serves as an anchor point for future risk projection methods involving biophysical models of DNA damage from space radiation. Lifetime incidence risks of radiation-induced cancer for the MCMM based on low-LET Japanese data for nonleukemia (all cancers except leukemia) were 2.77 (90% confidence limit, 0.75-11.34) for males exposed to 1 Sv at age 45 and 2.20 (90% confidence limit, 0.59-10.12) for males exposed at age 55. For females, mixture model risks for nonleukemia exposed separately to 1 Sv at ages of 45 and 55 were 2.98 (90% confidence limit, 0.90-11.70) and 2.44 (90% confidence limit, 0.70-10.30), respectively. Risks for high-LET 200 MeV protons (LET=0.45 keV/micrometer), 1 MeV alpha-particles (LET=100 keV/micrometer), and 600 MeV iron particles (LET=180 keV/micrometer) were scored on a per particle basis by determining the particle fluence required for an average of one particle per cell nucleus of area 100 micrometer(2). Lifetime risk per proton was 2.68x10(-2)% (90% confidence limit, 0.79x10(-3)%-0. 514x10(-2)%). For alpha-particles, lifetime risk was 14.2% (90% confidence limit, 2.5%-31.2%). Conversely, lifetime risk per iron particle was 23.7% (90% confidence limit, 4.5%-53.0%). Uncertainty in the DDREF for high-LET particles may be less than that for low-LET radiation because typically there is very little dose-rate dependence. Probability density functions for high-LET radiation quality and dose-rate may be preferable to conventional risk assessment approaches. Nuclear reactions and track structure effects in tissue may not be properly estimated by existing data using in vitro models for estimating RBEs. The method used here is being extended to estimate uncertainty in spacecraft shielding effectiveness in various space radiation environments.

Eliciting expert opinion using the Delphi technique: identifying performance indicators for cardiovascular disease.

Combining opinion from expert panels is becoming a more common method of selecting criteria to define quality of health care. The Rand Corporation pioneered this method is the 1950s and 1960s in the context of forecasting technological events. Since then, numerous organizations have adopted the methodology to develop local and national policy. In the context of quality of care, opinion is typically elicited from a sample of experts regarding the appropriateness or importance of a medical treatment for several well-defined clinical cohorts. The information from the experts is then combined in order to create a standard or performance measure of care. This article describes how to use the panel process to elicit information from diverse panels of experts. Methods are demonstrated using the data from five distinct panels convened as part of the Harvard Q-SPAN-CD study, a nationally-funded project whose goal is to identify a set of cardiovascular-related performance measures.