The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis

It is unknown whether transforming growth factor beta1 (TGF-beta1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)-13 share in fibrogenesis (e.g., due to regulatory effects on type I pro-collagen expression). TGF-beta1 signaling events were scored in 396 liver tissue samples from patients with diverse chronic liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), Schistosoma japonicum infection, and steatosis/steatohepatitis. Phospho-Smad2 staining correlated significantly with fibrotic stage in patients with HBV infection (n = 112, P < 0.001) and steatosis/steatohepatitis (n = 120, P < 0.01), but not in patients with HCV infection (n = 77, P > 0.05). In tissue with HBx protein expression, phospho-Smad2 was detectable, suggesting a functional link between viral protein expression and TGF-beta1 signaling. For IL-13, immunostaining correlated with fibrotic stage in patients with HCV infection and steatosis/steatohepatitis. IL-13 protein was more abundant in liver tissue lysates from three HCV patients compared with controls, as were IL-13 serum levels in 68 patients with chronic HCV infection compared with 20 healthy volunteers (72.87 +/- 26.38 versus 45.41 +/- 3.73, P < 0.001). Immunohistochemistry results suggest that IL-13-mediated liver fibrogenesis may take place in the absence of phospho-signal transducer and activator of transcription protein 6 signaling. In a subgroup of patients with advanced liver fibrosis (stage > or =3), neither TGF-beta nor IL-13 signaling was detectable. Conclusion: Depending on the cause of liver damage, a predominance of TGF-beta or IL-13 signaling is found. TGF-beta1 predominance is detected in HBV-related liver fibrogenesis and IL-13 predominance in chronic HCV infection. In some instances, the underlying fibrogenic mediator remains enigmatic.

Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators

Patients with an implantable cardioverter defibrillator (ICD) have an ongoing risk of sudden incapacitation that might cause harm to others while driving a car. Driving restrictions vary across different countries in Europe. The most recent recommendations for driving of ICD patients in Europe were published in 1997 and focused mainly on patients implanted for secondary prevention. In recent years there has been a vast increase in the number of patients with an ICD and in the percentage of patients implanted for primary prevention. The EHRA task force on ICD and driving was formed to reassess the risk of driving for ICD patients based on the literature available. The recommendations are summarized in the following table and are further explained in the document. [table: see text] Driving restrictions are perceived as difficult for patients and their families, and have an immediate consequence for their lifestyle. To increase the adherence to the driving restrictions, adequate discharge of education and follow-up of patients and family are pivotal. The task force members hope this document may serve as an instrument for European and national regulatory authorities to formulate uniform driving regulations.

Driving the refactoring of Java Enterprise applications by evaluating the distance between application elements

Java Enterprise Applications (JEAs) are complex systems composed using various technologies that in turn rely on languages other than Java, such as XML or SQL. Given the complexity of these applications, the need to reverse engineer them in order to support further development becomes critical. In this paper we show how it is possible to split a system into layers and how is possible to interpret the distance between application elements in order to support the refactoring of JEAs. The purpose of this paper is to explore ways to provide suggestions about the refactoring operations to perform on the code by evaluating the distance between layers and elements belonging those layers. We split JEAs into layers by considering the kinds and the purposes of the elements composing the application. We measure distance between elements by using the notion of the shortest path in a graph. Also we present how to enrich the interpretation of the distance value with enterprise pattern detection in order to refine the suggestion about modifications to perform on the code.

Shifted Coupling of EEG Driving Frequencies and fMRI Resting State Networks in Schizophrenia Spectrum Disorders

INTRODUCTION: The cerebral resting state in schizophrenia is altered, as has been demonstrated separately by electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) resting state networks (RSNs). Previous simultaneous EEG/fMRI findings in healthy controls suggest that a consistent spatiotemporal coupling between neural oscillations (EEG frequency correlates) and RSN activity is necessary to organize cognitive processes optimally. We hypothesized that this coupling is disorganized in schizophrenia and related psychotic disorders, in particular regarding higher cognitive RSNs such as the default-mode (DMN) and left-working-memory network (LWMN). METHODS: Resting state was investigated in eleven patients with a schizophrenia spectrum disorder (n = 11) and matched healthy controls (n = 11) using simultaneous EEG/fMRI. The temporal association of each RSN to topographic spectral changes in the EEG was assessed by creating Covariance Maps. Group differences within, and group similarities across frequencies were estimated for the Covariance Maps. RESULTS: The coupling of EEG frequency bands to the DMN and the LWMN respectively, displayed significant similarities that were shifted towards lower EEG frequencies in patients compared to healthy controls. CONCLUSIONS: By combining EEG and fMRI, each measuring different properties of the same pathophysiology, an aberrant relationship between EEG frequencies and altered RSNs was observed in patients. RSNs of patients were related to lower EEG frequencies, indicating functional alterations of the spatiotemporal coupling. SIGNIFICANCE: The finding of a deviant and shifted coupling between RSNs and related EEG frequencies in patients with a schizophrenia spectrum disorder is significant, as it might indicate how failures in the processing of internal and external stimuli, as commonly seen during this symptomatology (i.e. thought disorders, hallucinations), arise.

Vision and night driving abilities of elderly drivers

OBJECTIVE: In this article, we review the impact of vision on older people's night driving abilities. Driving is the preferred and primary mode of transport for older people. It is a complex activity where intact vision is seminal for road safety. Night driving requires mesopic rather than scotopic vision, because there is always some light available when driving at night. Scotopic refers to night vision, photopic refers to vision under well-lit conditions, and mesopic vision is a combination of photopic and scotopic vision in low but not quite dark lighting situations. With increasing age, mesopic vision decreases and glare sensitivity increases, even in the absence of ocular diseases. Because of the increasing number of elderly drivers, more drivers are affected by night vision difficulties. Vision tests, which accurately predict night driving ability, are therefore of great interest. METHODS: We reviewed existing literature on age-related influences on vision and vision tests that correlate or predict night driving ability. RESULTS: We identified several studies that investigated the relationship between vision tests and night driving. These studies found correlations between impaired mesopic vision or increased glare sensitivity and impaired night driving, but no correlation was found among other tests; for example, useful field of view or visual field. The correlation between photopic visual acuity, the most commonly used test when assessing elderly drivers, and night driving ability has not yet been fully clarified. CONCLUSIONS: Photopic visual acuity alone is not a good predictor of night driving ability. Mesopic visual acuity and glare sensitivity seem relevant for night driving. Due to the small number of studies evaluating predictors for night driving ability, further research is needed.

Can a novel web-based computer test predict poor simulated driving performance? A pilot study with healthy and cognitive-impaired participants

BACKGROUND Driving a car is a complex instrumental activity of daily living and driving performance is very sensitive to cognitive impairment. The assessment of driving-relevant cognition in older drivers is challenging and requires reliable and valid tests with good sensitivity and specificity to predict safe driving. Driving simulators can be used to test fitness to drive. Several studies have found strong correlation between driving simulator performance and on-the-road driving. However, access to driving simulators is restricted to specialists and simulators are too expensive, large, and complex to allow easy access to older drivers or physicians advising them. An easily accessible, Web-based, cognitive screening test could offer a solution to this problem. The World Wide Web allows easy dissemination of the test software and implementation of the scoring algorithm on a central server, allowing generation of a dynamically growing database with normative values and ensures that all users have access to the same up-to-date normative values. OBJECTIVE In this pilot study, we present the novel Web-based Bern Cognitive Screening Test (wBCST) and investigate whether it can predict poor simulated driving performance in healthy and cognitive-impaired participants. METHODS The wBCST performance and simulated driving performance have been analyzed in 26 healthy younger and 44 healthy older participants as well as in 10 older participants with cognitive impairment. Correlations between the two tests were calculated. Also, simulated driving performance was used to group the participants into good performers (n=70) and poor performers (n=10). A receiver-operating characteristic analysis was calculated to determine sensitivity and specificity of the wBCST in predicting simulated driving performance. RESULTS The mean wBCST score of the participants with poor simulated driving performance was reduced by 52%, compared to participants with good simulated driving performance (P<.001). The area under the receiver-operating characteristic curve was 0.80 with a 95% confidence interval 0.68-0.92. CONCLUSIONS When selecting a 75% test score as the cutoff, the novel test has 83% sensitivity, 70% specificity, and 81% efficiency, which are good values for a screening test. Overall, in this pilot study, the novel Web-based computer test appears to be a promising tool for supporting clinicians in fitness-to-drive assessments of older drivers. The Web-based distribution and scoring on a central computer will facilitate further evaluation of the novel test setup. We expect that in the near future, Web-based computer tests will become a valid and reliable tool for clinicians, for example, when assessing fitness to drive in older drivers.

Learning to drive: learners' self-reported cognitive failure level predicts driving instructor's observation rating of driving performance

OBJECTIVES Evidence increases that cognitive failure may be used to screen for drivers at risk. Until now, most studies have relied on driving learners. This exploratory pilot study examines self-report of cognitive failure in driving beginners and error during real driving as observed by driving instructors. METHODS Forty-two driving learners of 14 driving instructors filled out a work-related cognitive failure questionnaire. Driving instructors observed driving errors during the next driving lesson. In multiple linear regression analysis, driving errors were regressed on cognitive failure with the number of driving lessons as an estimator of driving experience controlled. RESULTS Higher cognitive failure predicted more driving errors (p < .01) when age, gender and driving experience were controlled in analysis. CONCLUSIONS Cognitive failure was significantly associated with observed driving errors. Systematic research on cognitive failure in driving beginners is recommended.

Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages

Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri (Hp). Mice lacking antibodies (JH (-/-)) or activating Fc receptors (FcRγ(-/-)) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae.

Deciphering the driving forces of erosion rates on millennial to million-year timescales in glacially impacted landscapes: An example from the Western Alps

In many regions, tectonic uplift is the main driver of erosion over million-year (Myr) timescales, but climate changes can markedly affect the link between tectonics and erosion, causing transient variations in erosion rates. Here we study the driving forces of millennial to Myr-scale erosion rates in the French Western Alps, as estimated from in situ produced cosmogenic 10Be and a newly developed approach integrating detrital and bedrock apatite fission-track thermochronology. Millennial erosion rates from 10Be analyses vary between ~0.27 and ~1.33 m/kyr, similar to rates measured in adjacent areas of the Alps. Significant positive correlations of millennial erosion rates with geomorphic measures, in particular with the LGM ice thickness, reveal a strong transient morphological and erosional perturbation caused by repeated Quaternary glaciations. The perturbation appears independent of Myr-scale uplift and erosion gradients, with the effect that millennial erosion rates exceed Myr-scale erosion rates only in the internal Alps where the latter are low (<0.4 km/Myr). These areas, moreover, exhibit channels that clearly plot above a general linear positive relation between Myr-scale erosion rates and normalized steepness index. Glacial erosion acts irrespective of rock uplift and thus not only leads to an overall increase in erosion rates but also regulates landscape morphology and erosion rates in regions with considerable spatial gradients in Myr-scale tectonic uplift. Our study demonstrates that climate change, e.g., through occurrence of major glaciations, can markedly perturb landscape morphology and related millennial erosion rate patterns, even in regions where Myr-scale erosion rates are dominantly controlled by tectonics.

A novel computer test to assess driving-relevant cognitive functions - a pilot study

BACKGROUND: The assessment of driving-relevant cognitive functions in older drivers is a difficult challenge as there is no clear-cut dividing line between normal cognition and impaired cognition and not all cognitive functions are equally important for driving. METHODS: To support decision makers, the Bern Cognitive Screening Test (BCST) for older drivers was designed. It is a computer-assisted test battery assessing visuo-spatial attention, executive functions, eye-hand coordination, distance judgment, and speed regulation. Here we compare the performance in BCST with the performance in paper and pencil cognitive screening tests and the performance in the driving simulator testing of 41 safe drivers (without crash history) and 14 unsafe drivers (with crash history). RESULTS: Safe drivers performed better than unsafe drivers in BCST (Mann-Whitney U test: U = 125.5; p = 0.001) and in the driving simulator (Student's t-test: t(44) = -2.64, p = 0.006). No clear group differences were found in paper and pencil screening tests (p > 0.05; ns). BCST was best at identifying older unsafe drivers (sensitivity 86%; specificity 61%) and was also better tolerated than the driving simulator test with fewer dropouts. CONCLUSIONS: BCST is more accurate than paper and pencil screening tests, and better tolerated than driving simulator testing when assessing driving-relevant cognition in older drivers.