B-MYB-p53-related relevant regulator for the progression of clear cell renal cell carcinoma.

PURPOSE: To investigate the mRNA expression of B-MYB and MDM2 together with their p53 relatedness in clear cell renal cell carcinoma (ccRCC). METHODS: Genes were screened for their mRNA expression from 529 patients in a publicly available ccRCC cohort (TCGA). A cohort of 101 patients with ccRCC served as validation by qRT-PCR mRNA tissue expression analysis. RESULTS: Expression: B-MYB expression was significantly higher in high-grade tumours (p < 0.0001 and p = 0.048) and in advanced stages (p = 0.005 and p = 0.037) in both cohorts. Correlation: p53-B-MYB as well as MDM2-B-MYB showed significant correlations in local and low-grade ccRCCs, but not in high grade tumours or advanced stages (r < 0.3 and/or p > 0.05). Survival: Multivariable Cox regression of the TCGA cohort revealed B-MYB upregulation and low MDM2 expression as predictors for an impaired overall survival (OS) (HR 1.97; p = 0.0003; HR 2.94, p < 0.0001) and progression-free survival (PFS) (HR 2.86; p = 0.0005; HR 1.58, p = 0.046). In the validation cohort, the results were confirmed for OS by univariable, but not multivariable regression: high B-MYB expression (HR = 3.05, p = 0.035) and low MDM2 expression (HR 3.81, p value 0.036). CONCLUSION: In ccRCC patients with high-grade tumours and advanced stages, high B-MYB expression is common and is associated with poorer OS and PFS. These patients show a loss of their physiological B-MYB-p53 network correlation, suggesting an additional, alternative regulatory, oncogenic mechanism. Assuming further characterization of its signalling pathways, B-MYB could be a potential therapy target for ccRCC.

Impact of investigator initiated trials and industry sponsored trials on medical practice (IMPACT): rationale and study design.

BACKGROUND: The German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF) initiated large research programs to foster high quality clinical research in the academic area. These investigator initiated trials (IITs) cover important areas of medical research and often go beyond the scope of industry sponsored trials (ISTs). The purpose of this project was to understand to what extent results of randomized controlled IITs and ISTs have an impact on medical practice, measured by their availability for decisions in healthcare and their implementation in clinical practice. We aimed to determine study characteristics influencing a trial's impact such as type of sponsor and place of conduct. In this article, we describe the rationale and design of this project and present the characteristics of the trials included in our study cohort. METHODS: The research impact of the following sub-cohorts was compared: German IITs (funded by DFG and BMBF or by other German non-commercial organizations), international IITs (without German contribution), German ISTs, and international ISTs. Trials included were drawn from the DFG-/BMBF-Websites, the German Clinical Trials Register, and from ClinicalTrials.gov . Research impact was measured as follows: 1) proportion of published trials, 2) time to publication, 3) proportion of publications appropriately indexed in biomedical databases, 4) proportion of openly accessible publications, 5) broadness of publication's target group, 6) citation of publications by systematic reviews or meta-analyses, and 7) appearance of publications or citing systematic reviews or meta-analyses in clinical practice guidelines. We also aimed to identify study characteristics associated with the impact of trials. RESULTS: We included 691 trials: 120 German IITs, 200 International IITs, 171 German ISTs and 200 International ISTs. The median number of participants was 150, 30% were international trials and 70% national trials, 48% drug-trials and 52% non-drug trials. Overall, 72% of the trials had one pre-defined primary endpoint, 28% two or more (max. 36). CONCLUSIONS: The results of this project deepen our understanding of the impact of biomedical research on clinical practice and healthcare policy, add important insights for the efficient allocation of scarce research resources and may facilitate providing accountability to the different stakeholders involved.

Clinical relevance of gene expression in localized and metastatic prostate cancer exemplified by FABP5.

PURPOSE: Fatty acid-binding protein 5 (FABP5), a transport protein for lipophilic molecules, has been proposed as protein marker in prostate cancer (PCa). The role of FABP5 gene expression is merely unknown. METHODS: In two cohorts of PCa patients who underwent radical prostatectomy (n = 40 and n = 57) and one cohort of patients treated with palliative transurethral resection of the prostate (pTUR-P; n = 50) FABP5 mRNA expression was analyzed with qRT-PCR. Expression was correlated with clinical parameters. BPH tissue samples served as control. To independently validate findings on FABP5 expression, three microarray and sequencing datasets were reanalyzed (MSKCC 2010 n = 216; TCGA 2015 n = 333; mCRPC, Nature Medicine 2016 n = 114). FABP5 expression was correlated with ERG-fusion status, TCGA subtypes, cancer driver mutations and the expression of druggable downstream pathway components. RESULTS: FABP5 was overexpressed in PCa compared to BPH in the cohorts analyzed by qRT-PCR (radical prostatectomy p = 0.003, p = 0.010; pTUR-P p = 0.002). FABP5 expression was independent of T stage, Gleason Score, nodal status and PSA level. FABP5 overexpression was associated with the absence of TMPRSS2:ERG fusion (p < 0.001 in TCGA and MSKCC). Correlation with TCGA subtypes revealed FABP5 overexpression to be associated with SPOP and FOXA1 mutations. FABP5 was positively correlated with potential drug targets located downstream of FABP5 in the PPAR-signaling pathway. CONCLUSION: FABP5 overexpression is frequent in PCa, but seems to be restricted to TMPRESS2:ERG fusion-negative tumors and is associated with SPOP and FOXA1 mutations. FABP5 overexpression appears to be indicative for increased activity in PPAR signaling, which is potentially druggable.

Planning performance in schizophrenia patients: a meta-analysis of the influence of task difficulty and clinical and sociodemographic variables.

BACKGROUND: Despite a large body of research on planning performance in adult schizophrenia patients, results of individual studies are equivocal, suggesting either no, moderate or severe planning deficits. This meta-analysis therefore aimed to quantify planning deficits in schizophrenia and to examine potential sources of the heterogeneity seen in the literature. METHOD: The meta-analysis comprised outcomes of planning accuracy of 1377 schizophrenia patients and 1477 healthy controls from 31 different studies which assessed planning performance using tower tasks such as the Tower of London, the Tower of Hanoi and the Stockings of Cambridge. A meta-regression analysis was applied to assess the influence of potential moderator variables (i.e. sociodemographic and clinical variables as well as task difficulty). RESULTS: The findings indeed demonstrated a planning deficit in schizophrenia patients (mean effect size: ; 95% confidence interval 0.56-0.78) that was moderated by task difficulty in terms of the minimum number of moves required for a solution. The results did not reveal any significant relationship between the extent of planning deficits and sociodemographic or clinical variables. CONCLUSIONS: The current results provide first meta-analytic evidence for the commonly assumed impairments of planning performance in schizophrenia. Deficits are more likely to become manifest in problem items with higher demands on planning ahead, which may at least partly explain the heterogeneity of previous findings. As only a small fraction of studies reported coherent information on sample characteristics, future meta-analyses would benefit from more systematic reports on those variables.

Angular independent silicon detector for dosimetry in external beam radiotherapy.

PURPOSE: In this work, the "edgeless" silicon detector technology is investigated, in combination with an innovative packaging solution, to manufacture silicon detectors with negligible angular response. The new diode is also characterized as a dosimeter for radiotherapy with the aim to verify its suitability as a single detector for in vivo dosimetry as well as large area 2D array that does not require angular correction to their response. METHODS: For the characterisation of the "edgeless-drop-in" detector technology, a set of samples have been manufactured with different sensitive areas (1 × 1 and 0.5 × 0.5 mm(2)) and different thicknesses (0.1 and 0.5 mm) in four different combinations of top and peripheral p-n junction fabricated on p-type and n-type silicon substrates. The diode probes were tested in terms of percentage depth dose (PDD), dose rate, and linearity and compared to ion chambers. Measurements of the output factor have been compared to film. The angular response of the diodes probes has been tested in a cylindrical PMMA phantom, rotated with bidirectional accuracy of 0.25° under 10 × 10 cm(2) 6 MV Linac photon beam. The radiation hardness has been investigated as well as the effect of radiation damage on the angular and dose rate response of the diode probes when irradiated with photons from a Co-60 gamma source up to dose of 40 kGy. RESULTS: The PDDs measured by the edgeless detectors show an agreement with the data obtained using ion chambers within ±2%. The output factor measured with the smallest area edgeless diodes (0.5 × 0.5 mm(2)-0.1 and 0.5 mm thick) matches EBT3 film to within 2% for square field size from 10 to 0.5 cm side equivalent distance. The dose rate dependence in a dose per pulse range of 0.9 × 10(-5)-2.7 × 10(-4) Gy/pulse was less than -7% and +300% for diodes fabricated on p-type and n-type substrates, respectively. The edgeless diodes fabricated on the p-type substrate demonstrated degradation of the response as a function of the irradiation dose within 5%-15%, while diodes on the n-type substrate show a variation of approximately 30% after 40 kGy. The angular response of all probes is minimal (within 2%) but the N on N and P on P configurations show the best performances with an angular dependence of ±1.0% between 0° and 180° in the transversal direction. In this configuration, the space charge region of the passive diode extends from the behind and sidewall toward the anode on the top providing beneficial electric field distribution in the peripheral area of the diode. Such performance has also been tested after irradiation by Co-60 up to 40 kGy with no measurable change in angular response. CONCLUSIONS: A new edgeless-drop-in silicon diode fabrication and packaging technology has been used to develop detectors that show no significant angular dependence in their response for dosimetry in radiation therapy. From the characterisation of the diodes, proposed in a wide range of different geometries and configurations, the authors recommend the P-on-P detectors in conjunction with "drop in" packaging technology as the candidate for further development as single diode probe or 2D diode array for dosimetry in radiotherapy.

SU-E-T-171: Missing Dose in Integrated EPID Images.

PURPOSE: A dosimetric artifact has been observed with Varian EPIDs in the presence of beam interrupts. This work determines the root cause and significance of this artifact. METHODS: Integrated mode EPID images were acquired both with and without a manual beam interrupt for rectangular, sliding gap IMRT fields. Simultaneously, the individual frames were captured on a separate computer using a frame-grabber system. Synchronization of the individual frames with the integrated images allowed the determination of precisely how the EPID behaved during regular operation as well as when a beam interrupt was triggered. The ability of the EPID to reliably monitor a treatment in the presence of beam interrupts was tested by comparing the difference between the interrupt and non-interrupt images. RESULTS: The interrupted images acquired in integrated acquisition mode displayed unanticipated behaviour in the region of the image where the leaves were located when the beam interrupt was triggered. Differences greater than 5% were observed as a result of the interrupt in some cases, with the discrepancies occurring in a non-uniform manner across the imager. The differences measured were not repeatable from one measurement to another. Examination of the individual frames showed that the EPID was consistently losing a small amount of dose at the termination of every exposure. Inclusion of one additional frame in every image rectified the unexpected behaviour, reducing the differences to 1% or less. CONCLUSIONS: Although integrated EPID images nominally capture the entire dose delivered during an exposure, a small amount of dose is consistently being lost at the end of every exposure. The amount of missing dose is random, depending on the exact beam termination time within a frame. Inclusion of an extra frame at the end of each exposure effectively rectifies the problem, making the EPID more suitable for clinical dosimetry applications. The authors received support from Varian Medical Systems in the form of software and equipment loans as well as technical support.

Dose reduction from loss of backscatter in superficial x-ray radiation therapy with the Pantak SXT 150 unit.

Loss of backscatter has been measured for a Pantak Therapax SXT 150 superficial x-ray therapy unit. Ionisation chamber measurements at the surface were performed in solid water with and without underlying lead to confirm the applicability of previous published measurements. Measurements of loss of backscatter with and without lead allowed the effect of underlying lead to be separated from the effect of loss of backscatter. It was found that the difference between the effect of lead and that of air on surface dose is minimal for solid water phantom thickness exceeding 3 cm. Differences up to 3% in dose reduction at the surface were found between this work and previous published results with different x-ray units.

Output factor measurements for a kilovoltage X-ray therapy unit.

Output factors at the surface for treatment cones and lead cut-outs have been measured for a Pantak Therapax SXT 150 superficial therapy unit with x-ray beam qualities from 1 to 13 mm A1 HVL. A variety of phantom materials and two ionisation chambers were tested for their suitability in output factor and percentage depth dose measurement. Solid water proved a useful water-equivalent phantom material with discrepancies between measurements in water and solid water less than 2.3% for percentage depth dose and less than 0.6% for output factors. Larger measurement discrepancies were found for Plastic Water and Perspex. A PTW Markus chamber was found to compare well with a NE 2532/3 low energy chamber in percentage depth dose measurement, but discrepancies arose between the chambers in output factor measurements, up to 5% for small field sizes. Measurements indicated that the Markus chamber had an energy dependent response in the kilovoltage range, which could account for the discrepancy in output factor measurement.

Tin foil as bolus material for therapeutic electron beams from the Varian Clinac 2100C/D.

Tin foils of sub-millimetre thickness have been investigated as bolus material for therapeutic electron beams from the Varian Clinac 2100C/D linear accelerator. Measurements with ionisation chamber and radiographic film in Plastic Water or water were performed under tin foil bolus to determine surface dose, therapeutic ranges, output factor correction, penumbra and dose outside the field edge. Appropriate thicknesses of tin foil for 90% dose at the surface were found to be approximately 0.3 mm for 6 MeV, and 0.4 mm for 9 MeV and 12 MeV. Enhanced therapeutic interval with tin foil bolus over water-equivalent bolus has previously been reported, but was found not to be evident for 12 MeV and for a small (4 x 4 cm2) 9 MeV field. The penumbra width of fields with tin foil and water-equivalent bolus were found to be within 2 mm, while the doses at 1 cm outside the field edge were within 1.5% of peak dose. Output factor corrections for fields with tin foil were measured as within 2% of unity. Air gaps between the tin foil and phantom surface up to 5 mm were observed to have minimal effect on output correction factor, relative surface dose, and therapeutic range.

Radiological properties of normoxic polymer gel dosimeters.

The radiological properties of the normoxic polymer gel dosimeters MAGIC, MAGAS, and MAGAT [methacrylic and ascorbic acid in gelatin initiated by copper; methacrylic acid gelatine gel with ascorbic acid; and methacrylic acid gelatine and tetrakis (hydroxymethyl) phosphonium chloride, respectively] have been investigated. The radiological water equivalence was determined by comparing the polymer gel macroscopic photon and electron interaction cross sections over the energy range from 10 keV to 20 MeV and by Monte Carlo modeling of depth doses. Normoxic polymer gel dosimeters have a high gelatine and monomer concentration and therefore mass density (kg m(-3)) up to 3.8% higher than water. This results in differences between the cross-section ratios of the normoxic polymer gels and water of up to 3% for the attenuation, energy absorption, and collision stopping power coefficient ratios through the Compton dominant energy range. The mass cross-section ratios were within 2% of water except for the mass attenuation and energy absorption coefficients ratios, which showed differences with water of up to 6% for energies less than 100 keV. Monte Carlo modeling was undertaken for the polymer gel dosimeters to model the electron and photon transport resulting from a 6 MV photon beam. The absolute percentage differences between gel and water were within 1% and the relative percentage differences were within 3.5%. The results show that the MAGAT gel formulation is the most radiological water equivalent of the normoxic polymer gel dosimeters investigated due to its lower mass density measurement compared with MAGAS and MAGIC gels.

Effect of saccharide additives on response of ferrous-agarose-xylenol orange radiotherapy gel dosimeters.

Glucose, sucrose, starch, and locust bean gum have been used as additives to the ferrous-agarose-xylenol orange (FAX) gel dosimeter. The saccharide enhanced dosimeters were found to have a higher dose sensitivity over a standard FAX gel as measured by both optical density change and magnetic resonance imaging (MRI). With optical density measurement, OD-dose sensitivity increases were up to 55% for glucose, 122% for sucrose and 43% for starch, while locust bean gum did not give a consistent response. With MRI, R1-dose sensitivity increases were up to 178% with sucrose addition. The FAX gel with sucrose was studied in greatest detail. The OD-dose sensitivity dependence on cooling rate was reduced for the sucrose FAX gel over the standard FAX gel, which has significant implications for uniform dose sensitivity in large gel phantoms. The thermal oxidation rate in the sucrose FAX gel was up to 2.3 times higher than in the standard gel. The OD-dose sensitivity of oxygenated sucrose FAX gels was 4.3 times greater than standard FAX gels, while continued enhancement in OD-dose sensitivity with increased sucrose concentrations beyond 2.0 g/l was found only for the oxygenated sucrose FAX gels. Both the molar absorption coefficient of the ferric ion-xylenol orange complex at 543 nm and gel pH were not affected by the presence of sucrose, with the implication that the higher OD-dose sensitivity of gels with saccharides is due to increased chain reaction production of ferric ions.

Leukocytes infiltrating the pancreatic islets of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy.

Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing beta-cell destruction and autoimmune Type I diabetes. Here, we completely blocked adoptive transfer of diabetes and reduced spontaneous disease incidence from 71% to 17% by simultaneously administering a combination of antibodies directed against alpha4, beta2, and beta7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for 52 and 28 days, respectively. CD4 and CD8 T cells and macrophages were excluded from islets and remained entrapped in a peri-islet location as inactive exiles, no longer expressing normal levels of interferon-gamma, interleukin-4, and iNOS. Only IL-10 expression was retained, which could aid immunosuppression. Infiltrating leukocytes retained a peri-islet location, even 215 days following suspension of antibody treatment, potentially forming a barrier to the entry of active, autoantigen-reactive T cells. Combination treatment was effective against spontaneous disease when administered from 7 days of age but ineffective when initiated late in the prediabetic period (day 40 or 70). Nevertheless, anti-alpha4 subunit mAb monotherapy alone was very effective, reducing insulitis to levels similar to those obtained with combinational antibody treatment, suggesting that alpha4 integrins are major receptors contributing to leukocyte infiltration. Treatment with anti-alpha4 integrin antibody retained some therapeutic benefit when administered from days 7, 40, or 70 of age. The results have implications for the treatment of diabetes and provide a unique insight into the fate of disease-forming leukocytes following anti-CAM therapy.

Effects of glass and backscatter on measurement of absorbed dose in polyacrylamide gel (PAG) dosimeters.

Different methodologies are used for calibrating polyacrylamide gel (PAG) dosimeters. One methodology involves injecting nitrogen-filled glass vials with polymer gel. Due to the vials being pre-filled with nitrogen, a nitrogen-filled space remains in the glass vial above the gel. The glass vial is then irradiated using ionizing radiation to polymerize the PAG. Monte Carlo simulations were performed to examine the effects on the radiation field due to the glass vial and the lack of backscatter material due to the nitrogen-filled space. Results for two different formulations of PAG indicated that the influence of the glass and the nitrogen-filled space are negligible.

Temporal relationship between immune cell influx and the expression of inducible nitric oxide synthase, interleukin-4 and interferon-gamma in pancreatic islets of NOD mice following adoptive transfer of diabetic spleen cells.

Beta cell destruction in NOD mice can be accelerated by adoptive transfer of diabetic spleen cells into irradiated adult NOD mice. Here mice receiving diabetic spleen cells were examined at days 0, 7, 14, 21 and at onset of diabetes for the resulting insulitis and the number of intra-islet CD4 and CD8 cells and macrophages. The progression of insulitis and the number of intra-islet CD4 and CD8 cells and macrophages were correlated with the expression and co-localization of inducible nitric oxide synthase, interferon-gamma and interleukin-4 by dual-label light and confocal immunofluorescence microscopy. Diabetes developed in 7/8 mice by 27 days following cell transfer. The insulitis score increased slightly by day 7 but rose sharply at day 14 (p = 0.001) and was maintained until diabetes. The mean number of intra-islet CD4 and CD8 cells and macrophages showed a similar trend to the insulitis scores and were present in almost equal numbers within the islets. Immunolabelling for inducible nitric oxide synthase was observed at day 7 in only some cells of a few islets but increased sharply from day 14. It was restricted to islets with insulitis and was co-localized in selective macrophages. Weak intra-islet interleukin-4 labelling was observed at days 7 and 14 but became more pronounced at day 21 and at onset of diabetes, being present in selective CD4 cells. Intra-islet labelling for interferon-gamma was first observed at day 21, but became more intense at onset of diabetes and was co-localized in a proportion of macrophages. Both cytokines were expressed in islets with advanced insulitis. Interferon-gamma staining was also observed within endothelial cells located in the exocrine pancreas. We conclude that transfer of diabetic spleen cells results in a rapid influx of CD4 and CD8 cells and macrophages within the pancreas of recipient mice. During the period of heightened insulitis, selective immune cells begin to express inducible nitric oxide synthase and the opposing cytokines, interferon-gamma and interleukin-4. Expression of these molecules becomes more pronounced immediately prior to and during the onset of diabetes.

Development of a CCD array imaging system for measurement of dose distributions in doped agarose gels.

An imaging system for agarose gel sections has been investigated for applications in rapid two-dimensional radiation dosimetry. The imaging system, with white light illumination and CCD camera detection, was designed for measurement of the radiation-induced optical density changes in iron- and xylenol orange dye-doped agarose gels. The performance of the imaging system was compared with that of a laser scanning system for the gels and with the accepted dosimetry standard, the ionization chamber. In measurement of beam profiles of two therapeutic radiation fields, relative dose values from the CCD camera imaging system were on average within 3% ranging from 0.005% to 7.5%) of values recorded with a parallel plate ionization chamber. In comparison with the laser scanner, the CCD camera imaging system provided comparable spatial resolution and an increased rate of data acquisition, although a consistently reduced signal to noise ratio was observed. Suggestions for improving the camera imaging technique include noise reduction through camera cooling and further frame averaging.

Dichloroacetylene: effects on the rat trigeminal nerve somatosensory evoked potential.

Humans overexposed to trichloroethylene (TCE), under specific conditions, were reported to develop trigeminal nerve dysfunction. A degradation byproduct dichloroacetylene (DCA), however, has been suggested as the probable neurotoxicant rather than TCE. Studies in mice, rats, and rabbits support the hypothesis of DCA-induced trigeminal neurotoxicity. This study, therefore, was conducted to characterize DCA-induced trigeminal nerve dysfunction in rats using the electrodiagnostic procedure trigeminal nerve-stimulated somatosensory evoked potential (TSEP). A group of six rats was exposed once to DCA (approximately 300 ppm) or room air for 2.25 h and a separate group of six rats was not exposed and served as controls. Trigeminal nerve somatosensory evoked potentials (TSEPs) were collected before exposure and 2, 4, and 7 days postexposure. Because DCA was manufactured from TCE with acetylene added as a stabilizer, another group of rats was exposed to TCE and acetylene without generation of DCA. TSEPs from DCA-exposed rats were smaller and slower compared to their baseline recordings and to the concurrent negative controls. TSEPs from the controls and the TCE/acetylene-exposed rats were unchanged. Neuropathology did not reveal treatment-related lesions. It was concluded that the rat is mildly to markedly susceptible to DCA-induced trigeminal nerve dysfunction as assessed by TSEP, but that the kidney was the likely target organ based on gross observations and the DCA literature.

[Incidence of alcohol abuse among patients with emergency admissions to a psychiatric department. Evaluation based on clinical and biochemical markers]. / Forekomst af alkoholmisbrug hos patienter modtaget akut på psykiatrisk afdeling. Vurdering ud fra kliniske og biokemiske markører.

Alcoholism and drug abuse were investigated in psychiatric patients, who were acutely admitted to a general psychiatric ward at Silkeborg Hospital in Denmark during a six month period. Several standardized diagnostic systems and assessment instruments were applied: ICD-8 and DSM-III diagnoses and the WHO Alcohol Use Disorder Identification Test (AUDIT) and Short Michigan Alcoholism Screening Test (SMAST). Furthermore, several biochemical markers were studied, including carbohydrate-deficient-transferrin (CDT), gamma-glutamyltransferase (GGT), and S-ethanol. Finally, thin layer chromatography of the urine was used to detect drugs abuse. A diagnosis of Alcoholism (code 303) was obtained in 39% of the included patients, while 13% were considered drug abusers (main and subsidiary diagnosis). These findings are in accordance with several previously published Danish studies and illustrate that alcohol abuse is a common diagnosis among acutely admitted patients to a psychiatric department situated outside the metropolitan areas in Denmark. When comparing alcohol abuse as assessed by clinical information and by biochemical markers, only CDT and GGT gave estimates similar to clinical evaluations. CDT was positive in 41% of the patients. Taking ICD-8 diagnoses of alcoholism as "golden standards" the sensitivity and specificity of the marker was 0.67 and 0.74, respectively. Although this is not as high as previously found values, these figures suggest CDT to be a useful biological marker in the delineation of alcohol related problems in psychiatric patients.

Testing random number generators for Monte Carlo applications.

Central to any system for modelling radiation transport phenomena using Monte Carlo techniques is the method by which pseudo random numbers are generated. This method is commonly referred to as the Random Number Generator (RNG). It is usually a computer implemented mathematical algorithm which produces a series of numbers uniformly distributed on the interval [0,1). If this series satisfies certain statistical tests for randomness, then for practical purposes the pseudo random numbers in the series can be considered to be random. Tests of this nature are important not only for new RNGs but also to test the implementation of known RNG algorithms in different computer environments. Six RNGs have been tested using six statistical tests and one visual test. The statistical tests are the moments, frequency (digit and number), serial, gap, and poker tests. The visual test is a simple two dimensional ordered pair display. In addition the RNGs have been tested in a specific Monte Carlo application. This type of test is often overlooked, however it is important that in addition to satisfactory performance in statistical tests, the RNG be able to perform effectively in the applications of interest. The RNGs tested here are based on a variety of algorithms, including multiplicative and linear congruential, lagged Fibonacci, and combination arithmetic and lagged Fibonacci. The effect of the Bays-Durham shuffling algorithm on the output of a known "bad" RNG has also been investigated.

In vitro kinetics of styrene and styrene oxide metabolism in rat, mouse, and human.

Styrene oxide (SO), a labile metabolite of styrene, is generally accepted as being responsible for any genotoxicity associated with styrene. To better define the hazard associated with styrene, the activity of the enzymes involved in the formation (monooxygenase) and destruction of SO (epoxide hydrolase and glutathione-S-transferase) were measured in the liver and lungs from naive and styrene-exposed male Sprague-Dawley rats and B6C3F1 mice (three daily 6-h inhalation exposures at up to 600 ppm styrene) and Fischer 344 rats (four daily 6-h inhalation exposures at up to 1000 ppm styrene), and in samples of human liver tissue. Additionally, the time course of styrene and SO in the blood was measured following oral administration of 500 mg styrene/kg body weight to naive Fischer rats and rats previously exposed to 1000 ppm styrene. The affinity of hepatic monooxygenase for styrene, as measured by the Michaelis constant (Km), was similar in the rat, mouse, and human. Based on the Vmax for monooxygenase activity and the relative liver and body size, the mouse had the greatest capacity and humans the lowest capacity to form SO from styrene. In contrast, human epoxide hydrolase and a greater affinity (i.e., lower Km) for SO than epoxide hydrolase from rats or mice while the apparent Vmax for epoxide hydrolase was similar in the rat, mouse, and human liver. However, the activity of epoxide hydrolase relative to monooxygenase activity was much greater in the human than in the rodent liver. Hepatic glutathione-S-transferase activity, as indicated by the Vmax, was 6- to 33-fold higher than epoxide hydrolase activity. However, the significance of the high glutathione-S-transferase activity is unknown because hydrolysis, rather than conjugation, is the primary pathway for SO detoxification in vivo. Human hepatic glutathione-S-transferase activity was extremely variable between individual human livers and much lower than in rat or mouse liver. Prior exposure to styrene had no effect on monooxygenase activity or on blood styrene levels in rats given a large oral dose of styrene. In contrast, prior exposure to styrene increased hepatic epoxide hydrolase activity 1.6-fold and resulted in lower (0.1 > P > 0.05) blood SO levels in rats given a large oral dose of styrene. Qualitatively, these data indicate that the mouse has the greatest capacity and the human the lowest capacity to form SO. In addition, human liver should be more effective than rodent liver in hydrolyzing low levels of SO.(ABSTRACT TRUNCATED AT 400 WORDS)