Glutathione transferase activities in renal carcinomas and adjacent normal renal tissues : factors influencing renal carcinogenesis induced by xenobiotics

In general, the biological activation of nephrocarcinogenic chlorinated hydrocarbons proceeds via conjugatiton with glutathione. It has mostly been assamed that the main site of initial conjugation is the liver, followed by a mandatory transfer of intermediates to the kidney. It was therefore of interest to study the enzyme activities of subgroups of glutathione transferases (GSTs) in renal cancers and the surrounding normal renal tissues of the same individuals (n = 21). For genotyping the individuals with respect to known polymorphic GST isozymes the following substrates with differential specificity were used: 1-chloro-2,4-dinitrobenzene for overall GST activity (except GST θ); 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole for GST α; 1,2-dichloro-4-nitro-benzene for GST μ; ethacrynic acid and 4-vinylpyridine for GST π; and methyl chloride for GST θ. In general, the normal tissues were able to metabolize the test substrates. A general decrease in individual GST enzyme activities was apparent in the course of cancerization, and in some (exceptional) cases individual activities, expressed in the normal renal tissue, were lost in the tumour tissue. The GST enzyme activities in tumours were independent of tumour stage, or the age and gender of the patients. There was little influence of known polymorphisms of GSTM1, GSTM3 and GSTP1 upon the activities towards the test substrates, whereas the influence of GSTT1 polymorphism on the activity towads methyl chloride was straightforward. In general, the present findings support the concept that the initial GST-dependent bioactivation step of nephrocarcinogenic chlorinated hydrocarbons may take place in the kidney itself. This should be a consideration in toxicokinetic modelling.

Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report [Dapson-induzierte Agranulozytose]

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring. [Article in German]

Primary and substance-induced psychotic disorders in methamphetamine users

This study investigates the rates of primary psychotic disorders (PPD) and substance induced psychotic disorders (SIPDs) in methamphetamine (MA) users accessing needle and syringe programs (NSPs). The aim was to determine if there are systematic differences in the characteristics of MA users with PPDs and SIPDs compared to those with no psychotic disorder. Participants were 198 MA users reporting use in the previous month. Diagnosis was determined using the Psychiatric Research Interview for DSM-IV Substance and Mental Disorders (PRISM-IV). Current psychiatric symptoms and substance use were also measured. Just over half (N=101) of participants met DSM-IV criteria for a lifetime psychotic disorder, including 81 (80%) with a SIPD and 20 (20%) with a PPD. Those with a younger age of onset of weekly MA use were at increased risk of a lifetime SIPD. A current psychotic disorder was found in 62 (39%), comprising 49 SIPDs (79%) and 13 PPDs (21%). MA users with a current PPD were more likely to have received psychiatric treatment in the past month than those with a current SIPD, despite a similar level of psychotic symptom severity. A high proportion of MA users accessing NSPs have psychotic disorders, the majority of which are substance-induced.

Simulated astigmatism impairs academic-related performance in children

Purpose: Astigmatism is an important refractive condition in children. However, the functional impact of uncorrected astigmatism in this population is not well established, particularly with regard to academic performance. This study investigated the impact of simulated bilateral astigmatism on academic-related tasks before and after sustained near work in children. Methods: Twenty visually normal children (mean age: 10.8 ± 0.7 years; 6 males and 14 females) completed a range of standardised academic-related tests with and without 1.50 D of simulated bilateral astigmatism (with both academic-related tests and the visual condition administered in a randomised order). The simulated astigmatism was induced using a positive cylindrical lens while maintaining a plano spherical equivalent. Performance was assessed before and after 20 minutes of sustained near work, during two separate testing sessions. Academic-related measures included a standardised reading test (the Neale Analysis of Reading Ability), visual information processing tests (Coding and Symbol Search subtests from the Wechsler Intelligence Scale for Children) and a reading-related eye movement test (the Developmental Eye Movement test). Each participant was systematically assigned either with-the-rule (WTR, axis 180°) or against-the-rule (ATR, axis 90°) simulated astigmatism to evaluate the influence of axis orientation on any decrements in performance. Results: Reading, visual information processing and reading-related eye movement performance were all significantly impaired by both simulated bilateral astigmatism (p<0.001) and sustained near work (p<0.001), however, there was no significant interaction between these factors (p>0.05). Simulated astigmatism led to a reduction of between 5% and 12% in performance across the academic-related outcome measures, but there was no significant effect of the axis (WTR or ATR) of astigmatism (p>0.05). Conclusion: Simulated bilateral astigmatism impaired children’s performance on a range of academic–related outcome measures irrespective of the orientation of the astigmatism. These findings have implications for the clinical management of non-amblyogenic levels of astigmatism in relation to academic performance in children. Correction of low to moderate levels of astigmatism may improve the functional performance of children in the classroom.

Differential effects of refractive blur on day and night-time driving performance

Purpose To investigate the effect of different levels of refractive blur on real-world driving performance measured under day and nighttime conditions. Methods Participants included 12 visually normal, young adults (mean age = 25.8 ± 5.2 years) who drove an instrumented research vehicle around a 4 km closed road circuit with three different levels of binocular spherical refractive blur (+0.50 diopter sphere [DS], +1.00 DS, +2.00 DS) compared with a baseline condition. The subjects wore optimal spherocylinder correction and the additional blur lenses were mounted in modified full-field goggles; the order of testing of the blur conditions was randomized. Driving performance was assessed in two different sessions under day and nighttime conditions and included measures of road signs recognized, hazard detection and avoidance, gap detection, lane-keeping, sign recognition distance, speed, and time to complete the course. Results Refractive blur and time of day had significant effects on driving performance (P < 0.05), where increasing blur and nighttime driving reduced performance on all driving tasks except gap judgment and lane keeping. There was also a significant interaction between blur and time of day (P < 0.05), such that the effects of blur were exacerbated under nighttime driving conditions; performance differences were evident even for +0.50 DS blur relative to baseline for some measures. Conclusions The effects of blur were greatest under nighttime conditions, even for levels of binocular refractive blur as low as +0.50 DS. These results emphasize the importance of accurate and up-to-date refractive correction of even low levels of refractive error when driving at night.

BOSTER : an efficient algorithm for mining frequent unordered induced subtrees

Extracting frequent subtrees from the tree structured data has important applications in Web mining. In this paper, we introduce a novel canonical form for rooted labelled unordered trees called the balanced-optimal-search canonical form (BOCF) that can handle the isomorphism problem efficiently. Using BOCF, we define a tree structure guided scheme based enumeration approach that systematically enumerates only the valid subtrees. Finally, we present the balanced optimal search tree miner (BOSTER) algorithm based on BOCF and the proposed enumeration approach, for finding frequent induced subtrees from a database of labelled rooted unordered trees. Experiments on the real datasets compare the efficiency of BOSTER over the two state-of-the-art algorithms for mining induced unordered subtrees, HybridTreeMiner and UNI3. The results are encouraging.

γ-radiation-induced γH2AX formation occurs preferentially in actively transcribing euchromatic loci

The central dogma in radiation biology is that nuclear DNA is the critical target with respect to radiosensitivity. In accordance with the theoretical expectations, and in the absence of a conclusive model, the general consensus in the field has been to view chromatin as a homogeneous template for DNA damage and repair. This paradigm has been called into question by recent findings indicating a disparity in γ-irradiation-induced γH2AX foci formation in euchromatin and heterochromatin. Here, we have extended those studies and provide evidence that γH2AX foci form preferentially in actively transcribing euchromatin following γ-irradiation.

A Gaussian pseudolikelihood approach for quantile regression with repeated measurements

To enhance the efficiency of regression parameter estimation by modeling the correlation structure of correlated binary error terms in quantile regression with repeated measurements, we propose a Gaussian pseudolikelihood approach for estimating correlation parameters and selecting the most appropriate working correlation matrix simultaneously. The induced smoothing method is applied to estimate the covariance of the regression parameter estimates, which can bypass density estimation of the errors. Extensive numerical studies indicate that the proposed method performs well in selecting an accurate correlation structure and improving regression parameter estimation efficiency. The proposed method is further illustrated by analyzing a dental dataset.

Refractive indices with Haag-Streit Lenstar biometer

Purpose: To estimate refractive indices used with the Lenstar biometer. Methods: Axial lengths of model eyes were determined using an IOLMaster biometer and a Lenstar; comparing these lengths gave an overall eye index for the Lenstar. Using the Lenstar Graphical User interface, we determined that boundaries between media could be manipulated so that there were opposite changes in optical pathlength on either side of the boundary and specified changes in distances determined the ratios of media indices. These ratios were combined with the overall eye index to estimate indices. Results: The IOLMaster and Lenstar produced axial length estimates to within ±0.01 mm. Estimations of group refractive indices were 1.340, 1.341, 1.415 and 1.354 for cornea, aqueous, lens and overall eye, respectively. The aqueous and lens indices, but not those for the cornea, are similar to schematic eye indices and reasonable lens indices. Conclusion: The Lenstar appears to use different refractive indices for different ocular media.

Error and variance bounds on sigmoidal neurons with weight and input errors

Bounds on the expectation and variance of errors at the output of a multilayer feedforward neural network with perturbed weights and inputs are derived. It is assumed that errors in weights and inputs to the network are statistically independent and small. The bounds obtained are applicable to both digital and analogue network implementations and are shown to be of practical value.

Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer : an opportunity for intervention

Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

The nature of errors made by drivers [Austroads Publication no: AP-R378-11]

It is important that we understand the factors and conditions that shape driver behaviour – those conditions within the road transport system that contribute to driver error and the situations where driver non-compliance to road regulations is likely. This report presents the findings derived from a program of research investigating the nature of errors made by drivers, involving a literature review and an on-road study. The review indicates that, despite significant investigation, the role of different error types in road traffic crashes remains unclear, as does the role of the wider road transport system failures in driver error causation.