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.

Lunar surface radioactivity: preliminary results of the apollo 15 and apollo 16 gamma-ray spectrometer experiments.

Gamma-ray spectrometers on the Apollo 15 and Apollo 16 missions have been used to map the moon's radioactivity over 20 percent of its surface. The highest levels of natural radioactivity are found in Mare Imbrium and Oceanus Procellarum with contrastingly lower enhancements in the eastern maria. The ratio of potassium to uranium is higher on the far side than on the near side, although it is everywhere lower than commonly found on the earth.

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.

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.

Ofloxacin versus trimethoprim-sulphamethoxazole in acute cystitis.

The clinical and bacteriological efficacy and adverse reactions of ofloxacin vs trimethoprim-sulphamethoxazole were investigated in a double-blind, randomised study in 250 female patients (125 in each group) with acute, uncomplicated lower urinary tract infections. The dosages of ofloxacin and trimethoprim-sulphamethoxazole were 100mg and 160mg + 800mg twice daily, respectively. The duration of therapy was 3 days. 81% of the patients had significant bacteriuria. Escherichia coli was isolated in 76% and Staphylococcus saprophyticus in 11% of the infections. The bacteriological elimination, clinical cure and improvement rates of the evaluable patients on ofloxacin treatment were 92 and 95%, respectively. The corresponding figures on trimethoprim-sulphamethoxazole therapy were 88 and 90%. Adverse reactions were clinically unimportant, and none of the patients had to stop treatment. Mild and transient side effects, mainly from the gastrointestinal tract, central nervous system and skin, were reported by 19 and 22% of the patients in the ofloxacin and trimethoprim-sulphamethoxazole groups, respectively. None of the differences in clinical and bacteriological efficacy and side effects of ofloxacin vs trimethoprim-sulphamethoxazole were statistically significant. Ofloxacin appears to be an appropriate antibiotic for short term therapy of acute, uncomplicated, lower urinary tract infections, comparing favourably with trimethoprim-sulphamethoxazole treatment in this study.

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.

Longitudinal study of astronaut health: mortality in the years 1959-1991.

We conducted a historical cohort study of mortality among 195 astronauts who were exposed to space and medical sources of radiation between 1959 and 1991. Cumulative occupational and medical radiation exposures were obtained from the astronaut radiation exposure history data base. Causes of death were obtained from obligatory death certificates and autopsy reports that were on file in the medical records. There was a total of 20 deaths that occurred during the 32-year follow-up period of which 16 were due to accidents. The all-cause standardized mortality ratio (SMR) was 181 (95% confidence interval 110, 279). There was 1 cancer death in the buccal cavity and pharyngeal ICD-9 rubric whose occurrence was significantly beyond expectation. Mortality for coronary disease was 53% lower than expected (2 deaths; SMR = 47; 95% confidence limits 5, 168). The crude death rate for 12 occupationally related accidents was 445 deaths per 100,000 person-years and was an order of magnitude greater than accidental death rates in the mining industries. The SMR of 1346 for fatal accidents was significantly beyond expectation (16 deaths; 95% confidence limits 769, 2168) and was similar to SMRs for accidents among aerial pesticide applicators. The 10-year cumulative risk of occupational fatalities based on the exponential, Weibull, Gompertz, and linear-exponential distributions was 10%. Mortality from motor vehicle accidents was slightly higher than expected, but was not significant (1 death; SMR = 165; 95% confidence limits 2,922). Radiation exposures from medical procedures accounted for a majority of cumulative dose when compared with space radiation exposures. Overall, it was found that astronauts are at a health disadvantage as a result of catastrophic accidents.

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.

Fetomaternal hemorrhage following funipuncture: increase in severity of maternal red-cell alloimmunization.

OBJECTIVE: To determine the prevalence of fetomaternal transplacental hemorrhage after funipuncture and its effect on maternal red-cell alloantibody levels. METHODS: The prevalence and size of transplacental hemorrhages at the Health Sciences Centre were studied in two groups of patients: 174 women who were not alloimmunized or were carrying fetuses whose red cells were negative for the antigen to which they were immunized, and 122 women who were alloimmunized and carrying fetuses whose red cells were positive for the antigen to which they were immunized. In the alloimmunized group with affected fetuses, we surveyed the incidence of maternal antibody increase in titer by two or more doubling dilutions and the Rh(D) antibody increase (in microgram/mL of serum) of more than 50% after funipuncture. RESULTS: One hundred of the 174 women (57.5%) in the nonimmunized group and 69 of the 122 women (56.6%) in the immunized group had evidence of transplacental hemorrhages ranging in volume from 0.03 mL to greater than 5 mL of fetal red blood cells. In the latter group, antibody titer increases of 2 to 9 and doubling dilutions occurred in 37 of 74 women (50%) in whom such measurements were carried out. Increases of anti-D exceeding 50% occurred in 44 of 53 women (83%) in whom quantitative measurements were assayed. CONCLUSION: Funipuncture carries a high risk of fetal transplacental hemorrhage. In the immunized woman carrying an antigen-positive fetus, this will increase the level of her antibody and probably increase the severity of hemolytic disease in her fetus. In alloimmunized women, funipuncture should rarely be carried out to determine the fetal antigen status. Serial amniocenteses combined with careful serial ultrasound observation of the fetus are safer. Funipuncture should not be done in alloimmunized women before the cord vessels are of adequate size to allow immediate intravascular fetal transfusion, if required.

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.

Effectiveness of treatment with a brace in girls who have adolescent idiopathic scoliosis. A prospective, controlled study based on data from the Brace Study of the Scoliosis Research Society.

In a prospective study by the Scoliosis Research Society, 286 girls who had adolescent idiopathic scoliosis, a thoracic or thoracolumbar curve of 25 to 35 degrees, and a mean age of twelve years and seven months (range, ten to fifteen years) were followed to determine the effect of treatment with observation only (129 patients), an underarm plastic brace (111 patients), and nighttime surface electrical stimulation (forty-six patients). Thirty-nine patients were lost to follow-up, leaving 247 (86 per cent) who were followed until maturity or who were dropped from the study because of failure of the assigned treatment. The end point of failure of treatment was defined as an increase in the curve of at least 6 degrees, from the time of the first roentgenogram, on two consecutive roentgenograms. As determined with use of this end point, treatment with a brace failed in seventeen of the 111 patients; observation only, in fifty-eight of the 129 patients; and electrical stimulation, in twenty-two of the forty-six patients. According to survivorship analysis, treatment with a brace was associated with a success rate of 74 per cent (95 per cent confidence interval, 52 to 84) at four years; observation only, with a success rate of 34 per cent (95 per cent confidence interval, 16 to 49); and electrical stimulation, with a success rate of 33 per cent (95 per cent confidence interval, 12 to 60).(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of progression of the curve in girls who have adolescent idiopathic scoliosis of moderate severity. Logistic regression analysis based on data from The Brace Study of the Scoliosis Research Society.

In a study conducted by the Scoliosis Research Society, 159 girls with a mean age of thirteen years (range, ten to fifteen years) who had adolescent idiopathic scoliosis were followed prospectively until skeletal maturity or until the curve had increased 6 degrees or more. All patients had had an initial curve of 25 to 35 degrees and an apical level between the eighth thoracic and first lumbar vertebrae, inclusive. Of the 159 patients, 120 were observed without treatment and thirty-nine were managed with lateral electrical surface stimulation. The curve progressed at least 6 degrees in eighty patients. There was no apparent difference in the outcome between the patients who were managed with observation only and those who were given electrical stimulation. Logistic regression analysis was performed to determine which of eleven factors were predictive of progression of the scoliotic curve. A Risser sign of 0 or 1, an apical level cephalad to the twelfth thoracic vertebra, and an imbalance of ten millimeters or less were found to be independently prognostic of progression of more than 6 degrees. A prognostic model that included these three factors and chronological age allowed correct classification of the curve as either progressive or non-progressive in 81 per cent of these patients who had a thoracic or thoracolumbar adolescent idiopathic scoliosis. The positive predictive value was 82 per cent, the negative predictive value was 80 per cent, and the sensitivity and specificity were each 81 per cent.

Estimation of time as a measure of pain magnitude.

A new method of measuring pain is presented where the patient's estimation of time is used as a pain-related parameter. Pain patients experience a certain time period as increased when compared with pain free control subjects. The increase in time estimation correlates roughly with the clinical estimate of pain severity in different diagnostic groups. Successfully treated patients change their time estimation towards normal. It is considered that this method could be used to evaluate a certain patient's pain and the effectiveness of treatment in relation to the mean time estimate of other patients with the same diagnosis.

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.

Mobility, strength, and fitness after a graded activity program for patients with subacute low back pain. A randomized prospective clinical study with a behavioral therapy approach.

Patients with nonspecific mechanical low back pain (n = 103), examined by an orthopaedic surgeon and a social worker, were randomized to an activity group (n = 51) and a control group (n = 52). Patients with defined orthopaedic, medical, or psychiatric diagnoses were excluded before randomization. No patients were excluded due to place of birth or difficulties in speaking or understanding the Swedish language. The purpose of the study was to compare mobility, strength and fitness after traditional care and after traditional care plus a graded activity program with a behavioral therapy approach. A graded activity program, with a behavioral therapy approach was given under the guidance of a physical therapist. The endpoint of the graded activity program was return to work. This program significantly increased mobility, strength, and fitness more than could be explained by only a time recovery effect, especially in males. The patients in the activity group returned to work earlier than did the patients in the control group. Spinal rotation, abdominal muscle endurance time and lifting capacity were significantly correlated to rate of return to work. Traditional care plus a graded activity program were superior to only traditional care, evaluated in terms of mobility, strength and fitness. The graded activity program proved to be a successful method of restoring occupational function and facilitating return to work in subacute low back pain patients. The patients in the graded activity program learned that it is safe to move, while regaining function.

The effect of graded activity on patients with subacute low back pain: a randomized prospective clinical study with an operant-conditioning behavioral approach.

The aim of this study was to determine whether graded activity restored occupational function in industrial blue-collar workers who were sick-listed for 8 weeks because of subacute, nonspecific, mechanical low back pain (LBP). Patients with LBP, who had been examined by an orthopedic surgeon and a social worker, were randomly assigned to either an activity group (n = 51) or a control group (n = 52). Patients with defined orthopedic, medical, or psychiatric diagnoses were excluded before randomization. The graded activity program consisted of four parts: (1) measurements of functional capacity; (2) a work-place visit; (3) back school education; and (4) an individual, submaximal, gradually increased exercise program, with an operant-conditioning behavioral approach, based on the results of the tests and the demands of the patient's work. Records of the amount of sick leave taken over a 3-year period (ie, the 1-year periods before, during, and after intervention) were obtained from each patient's Social Insurance Office. The patients in the activity group returned to work significantly earlier than did the patients in the control group. The median number of physical therapist appointments before return to work was 5, and the average number of appointments was 10.7 (SD = 12.3). The average duration of sick leave attributable to LBP during the second follow-up year was 12.1 weeks (SD = 18.4) in the activity group and 19.6 weeks (SD = 20.7) in the control group. Four patients in the control group and 1 patient in the activity group received permanent disability pensions. The graded activity program made the patients occupationally functional again, as measured by return to work and significantly reduced long-term sick leave.

Comparison between cefotaxime and a combination of benzylpenicillin and cloxacillin as an antibiotic prophylaxis in cardiac surgery with cardio-pulmonary bypass.

In a prospective randomized trial, 422 patients undergoing elective cardiac surgery with cardiopulmonary bypass were studied for comparing two types of prophylactic antibiotic treatment. One group, 204 patients, received 4 doses of cefotaxime for 2 days. The other group, 198 patients, received 6 doses of benzylpenicillin combined with cloxacillin for 3 days. Sixty percent received the planned cefotaxime prophylaxis (CTX), while 43.4% received the planned combined benzylpenicillin with cloxacillin prophylaxis (BPC). This was because several patients in both groups required additional antibiotics for treatment of high fever (39.7%, CTX-ADD, in the cefotaxime group compared to 56.6%, BPC-ADD in the other group (p less than 0.01). The overall infection rate in the groups receiving the planned prophylaxis was significantly lower (4.1%) in the CTX-group compared to the 14% in the BPC-group (p less than 0.05). Early infections (less than 14 days) were lower in the groups CTX-group (3%) compared to the BPC-group (16%) (p less than 0.046). In the groups receiving additional antibiotics for fever (CTX-ADD and BPC-ADD), the former had a significantly lower number of infections, 16 compared to 23, in the latter group (p less than 0.01). There were significantly fewer early infections in the CTX-ADD compared to the BPC-ADD group (4 vs. 10 respectively, p less than 0.01). No deep infections were seen when CTX or CTX-ADD was used, while 6 deep wound infections occurred when BPC or BPC-ADD was used. The lowest rate of positive cultures of bacteria was seen in the CTX-group (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

A variant of guided exposure to mourning for use with treatment resistant patients.

We report a variant of "guided exposure to mourning," designed for use with patients who have proved resistant to other treatments for unresolved, morbid grief. The work provides some indication as to when such behavioral techniques for resolution of morbid grief are likely to prove successful, and when not.