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.

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.

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.

Phosphatidylethanol (PEth) in blood samples from "driving under the influence" cases as indicator for prolonged excessive alcohol consumption.

Phosphatidylethanol (PEth) is considered as specific biomarker of alcohol consumption. Due to accumulation after repeated drinking, PEth is suitable to monitor long-term drinking behavior. To examine the applicability of PEth in "driving under the influence of alcohol" cases, 142 blood samples with blood alcohol concentrations (BAC) ranging from 0.0-3.12 ‰ were analyzed for the presence of PEth homologues 16:0/18:1 (889 ± 878 ng/mL; range by LC-MS/MS. With receiver operating characteristic analysis, PEth thresholds were evaluated to differentiate moderate and excessive alcohol consumption with acceptable sensitivity and specificity in accordance with the 1.6 ‰ BAC limit. With a threshold of 700 ng/mL for PEth 16:0/18:1, prolonged excessive alcohol consumption was detected in 65.9 % of drunk drivers with a BAC ≥ 1.6 ‰ and in 31.6 % of the samples with a BAC < 1.6 ‰. Similar results were obtained for PEth 16:0/18:2 with a threshold of 300 ng/mL. Both criteria, PEth 16:0/18:1 and PEth 16:0/18:2, were conform in the evaluation of drinking habits in 88.7 % of blood samples. These results show the possibility to detect prolonged excessive alcohol consumption, even if the BAC is below the legal threshold of 1.6 ‰ for driving aptitude assessment. As a consequence, concentrations of PEth 16:0/18:1 ≥ 700 ng/mL and of PEth 16:0/18:2 ≥ 300 ng/mL may be considered as indicators for the necessity of driving aptitude assessment in addition to BAC.

Cognition and driving in older persons

In Switzerland, approximately 350,000 people aged 70 years or older own a valid driving license. By law, these drivers are medically assessed every other year, most commonly by their general practitioner, to exclude that a medical condition is interfering with their driving skills. A prerequisite for driving is the integration of high-level cognitive functions with perception and motor function. Ageing, per se, does not necessarily impair driving or increase the crash risk. However, medical conditions, such as cognitive impairment and dementia, become more prevalent with advancing age and may contribute to poor driving and an increased crash risk. The extent to which driving skills are impaired depends on the cause of dementia, disease severity, other co-morbidities and individual compensation strategies. Dementia often remains undiagnosed and therefore general practitioners (GPs) can find themselves in the difficult situation to disclose a suspicion about cognitive impairment and queries about medical fitness to drive, at the same time. In addition, the literature suggests that cognitive screening tests, most commonly used by GPs, have a limited role in judging whether an older person remains fit to drive. Further specialist assessment, for example in a memory clinic or on the road testing (ORT), may be helpful when the diagnosis or its implication for driving remain unclear. Here, we review the literature about cognition and driving, for GPs who advise older drivers who wish to continue driving.

A residue close to ?1 loop F disrupts modulation of GABAA receptors by benzodiazepines while their binding is maintained

Benzodiazepines act at the major isoforms of GABA type A receptors where they potentiate the current evoked by the agonist GABA. The underlying mechanism of this potentiation is poorly understood, but hypothesized to be related to the mechanism that links agonist binding to channel opening in these ligand activated ion channels. The loop F of the ?(1) and the ?(2) subunit have been implicated in channel gating, and loop F of the ?(2) subunit in the modulation by benzodiazepines. We have identified the conservative point mutation Y168F located N-terminally of loop F in the ?(1) subunit that fails to affect agonist properties. Interestingly, it disrupts modulation by benzodiazepines, but leaves high affinity binding to the benzodiazepine binding site intact. Modulation by barbiturates and neurosteroids is also unaffected. Residue ?(1) Y168 is not located either near the binding pockets for GABA, or for benzodiazepines, or close to the loop F of the ?(2) subunit. Our results support the fact, that broader regions of ligand gated receptors are conformationally affected by the binding of benzodiazepines. We infer that also broader regions could contribute to signaling from GABA agonist binding to channel opening.

[Driving ability and daytime sleepiness]

Daytime sleepiness is a complaint of about 5-10% in a normal population. The consequences, such as impaired performance and accidents at the workplace and while driving, have major impact on the affected and on society. According to Swiss federal statistics only 1-3% of all motor vehicle accidents are due to excessive daytime sleepiness, which is in great contrast to a figure of 10 to 20% of all accidents derived from scientific studies. Due to the inadequate statistical representation of the problem, insufficient countermeasures have been realized, and the state of drivers breaching traffic regulations is not adequately investigated in this respect. The most prevalent cause of microsleep induced accidents is certainly lack of sleep due to social or professional reasons. A treating physician must also consider sedating drugs and various diseases. The typical characteristics of accidents due to falling asleep at the wheel and the risk factors involved are well established, so that informing the general public, taking prophylactic countermeasures and a targeted investigation in this respect of drivers who have breached the law are all feasible. Since symptoms of sleepiness can be recognized well before any impairment of performance occurs, the most important countermeasure is information of the drivers on the risk factors and on efficient countermeasures against sleepiness at the wheel. Besides correct diagnosis and treatment, the primary goal of physicians treating patients with pathological daytime sleepiness is to inform them at an early stage about the risks of sleepiness and the large responsibility they bear while driving. This information should be written down in the patients' records. Professional drivers suffering from daytime sleepiness, drivers who have already had an accident due to microsleep and unreasonable drivers should be referred to a centre of sleep disorders for objective measurements of sleepiness.

In vitro induction of lymph node cell proliferation by mouse bone marrow dendritic cells following stimulation with different Echinococcus multilocularis antigens

The immune response of mice experimentally infected with Echinococcus multilocularis metacestodes becomes impaired so as to allow parasite survival and proliferation. Our study tackled the question on how different classes of E. multilocularis antigens (crude vesicular fluid (VF); purified proteinic rec-14-3-3; purified carbohydrate Em2(G11)) are involved in the maturation process of bone-marrow-derived dendritic cells (BMDCs) and subsequent exposure to lymph node (LN) cells. In our experiments, we used BMDCs cultivated from either naïve (control) or alveolar echinococcosis (AE)-infected C57BL/6 mice. We then tested surface markers (CD80, CD86, MHC class II) and cytokine expression levels (interleukin (IL)-10, IL-12p40 and tumour necrosis factor (TNF)-α) of non-stimulated BMDCs versus BMDCs stimulated with different Em-antigens or lipopolysaccharide (LPS). While LPS and rec-14-3-3-antigen were able to induce CD80, CD86 and (to a lower extent) MHC class II surface expression, Em2(G11) and, strikingly, also VF-antigen failed to do so. Similarly, LPS and rec-14-3-3 yielded elevated IL-12, TNF-α and IL-10 expression levels, while Em2(G11) and VF-antigen didn't. When naïve BMDCs were loaded with VF-antigen, they induced a strong non-specific proliferation of uncommitted LN cells. For both, BMDCs or LN cells, isolated from AE-infected mice, proliferation was abrogated. The most striking difference, revealed by comparing naïve with AE-BMDCs, was the complete inability of LPS-stimulated AE-BMDCs to activate lymphocytes from any LN cell group. Overall, the presenting activity of BMDCs from AE-infected mice seemed to trigger unresponsiveness in T cells, especially in the case of VF-antigen stimulation, thus contributing to the suppression of clonal expansion during the chronic phase of AE infection.

Is gamma band EEG synchronization reduced during auditory driving in schizophrenia patients with auditory verbal hallucinations?

Auditory verbal hallucinations (AVH) in schizophrenia patients assumingly result from a state inadequate activation of the primary auditory system. We tested brain responsiveness to auditory stimulation in healthy controls (n=26), and in schizophrenia patients that frequently (n=18) or never (n=11) experienced AVH. Responsiveness was assessed by driving the EEG with click-tones at 20, 30 and 40Hz. We compared stimulus induced EEG changes between groups using spectral amplitude maps and a global measure of phase-locking (GFS). As expected, the 40Hz stimulation elicited the strongest changes. However, while controls and non-hallucinators increased 40Hz EEG activity during stimulation, a left-lateralized decrease was observed in the hallucinators. These differences were significant (p=.02). As expected, GFS increased during stimulation in controls (p=.08) and non-hallucinating patients (p=.06), which was significant when combining the two groups (p=.01). In contrast, GFS decreased with stimulation in hallucinating patients (p=0.13), resulting in a significantly different GFS response when comparing subjects with and without AVH (p<.01). Our data suggests that normally, 40Hz stimulation leads to the activation of a synchronized network representing the sensory input, but in hallucinating patients, the same stimulation partly disrupts ongoing activity in this network.

Brain activation during craving for alcohol measured by positron emission tomography

OBJECTIVE: Craving for alcohol is probably involved in acquisition and maintenance of alcohol dependence to a substantial degree. However, the brain substrates and mechanisms that underlie alcohol craving await more detailed elucidation. METHOD: Positron emission tomography was used to map regional cerebral blood flow (CBF) in 21 detoxified patients with alcohol dependence during exposure to alcoholic and non-alcoholic beverages. RESULTS: During the alcohol condition compared with the control condition, significantly increased CBF was found in the ventral putamen. Additionally, activated areas included insula, dorsolateral prefrontal cortex and cerebellum. Cerebral blood flow increase in these regions was related to self-reports of craving assessed in the alcoholic patients. CONCLUSIONS: In this investigation, cue-induced alcohol craving was associated with activation of brain regions particularly involved in brain reward mechanisms, memory and attentional processes. These results are consistent with studies on craving for other addictive substances and may offer strategies for more elaborate studies on the neurobiology of addiction.

Selective increases in regional brain glucocorticoid: a novel effect of chronic alcohol

The hypothalamo-pituitary-adrenal axis shows functional changes in alcoholics, with raised glucocorticoid release during alcohol intake and during the initial phase of alcohol withdrawal. Raised glucocorticoid concentrations are known to cause neuronal damage after withdrawal from chronic alcohol consumption and in other conditions. The hypothesis for these studies was that chronic alcohol treatment would have differential effects on corticosterone concentrations in plasma and in brain regions. Effects of chronic alcohol and withdrawal on regional brain corticosterone concentrations were examined using a range of standard chronic alcohol treatments in two strains of mice and in rats. Corticosterone was measured by radioimmunoassay and the identity of the corticosterone extracted from brain was verified by high performance liquid chromatography and mass spectrometry. Withdrawal from long term (3 weeks to 8 months) alcohol consumption induced prolonged increases in glucocorticoid concentrations in specific regions of rodent brain, while plasma concentrations remained unchanged. This effect was seen after alcohol administration via drinking fluid or by liquid diet, in both mice and rats and in both genders. Shorter alcohol treatments did not show the selective effect on brain glucocorticoid levels. During the alcohol consumption the regional brain corticosterone concentrations paralleled the plasma concentrations. Type II glucocorticoid receptor availability in prefrontal cortex was decreased after withdrawal from chronic alcohol consumption and nuclear localization of glucocorticoid receptors was increased, a pattern that would be predicted from enhanced glucocorticoid type II receptor activation. This novel observation of prolonged selective increases in brain glucocorticoid activity could explain important consequences of long term alcohol consumption, including memory loss, dependence and lack of hypothalamo-pituitary responsiveness. Local changes in brain glucocorticoid levels may also need to be considered in the genesis of other mental disorders and could form a potential new therapeutic target.

Effects of minor laboratory procedures, adrenalectomy, social defeat or acute alcohol on regional brain concentrations of corticosterone

Concentrations of corticosterone in brain areas of TO strain mice were measured by radioimmunoassay. The studies examined the effects of routine laboratory maneuvers, variation during the circadian peak, adrenalectomy, social defeat and acute injections of alcohol on these concentrations. Brief handling of mice increased corticosterone levels in plasma but not in striatum and reduced those in the hippocampus. Single injections of isotonic saline raised the plasma concentrations to a similar extent as the handling, but markedly elevated concentrations in the three brain regions. Five minutes exposure to a novel environment increased hippocampal and cerebral cortical corticosterone levels and striatal concentrations showed a larger rise. However, by 30 min in the novel environment, plasma concentrations rose further while those in striatum and cerebral cortex fell to control levels and hippocampal corticosterone remained elevated. Over the period of the circadian peak the hippocampal and striatal concentrations paralleled the plasma concentrations but cerebral cortical concentrations showed only small changes. Adrenalectomy reduced plasma corticosterone concentrations to below detectable levels after 48 h but corticosterone levels were only partially reduced in the hippocampus and striatum and remained unchanged in the cerebral cortex. Single or repeated social defeat increased both brain and plasma concentrations after 1 h. Acute injections of alcohol raised the regional brain levels in parallel with plasma concentrations. The results show that measurements of plasma concentrations do not necessarily reflect the levels in brain. The data also demonstrate that corticosterone levels can change differentially in specific brain regions. These results, and the residual hormone seen in the brain after adrenalectomy, are suggestive evidence for a local origin of central corticosterone.

Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from a hematopoietic stem cell expressing the BCR/ABL fusion protein. Leukemic and dendritic cells (DCs) develop from the same transformed hematopoietic progenitors. How BCR/ABL interferes with the immunoregulatory function of DCs in vivo is unknown. We analyzed the function of BCR/ABL-expressing DCs in a retroviral-induced murine CML model using the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen. BCR/ABL-expressing DCs were found in bone marrow, thymus, spleen, lymph nodes, and blood of CML mice. They were characterized by a low maturation status and induced only limited expansion of naive and memory cytotoxic T lymphocytes (CTLs). In addition, immunization with in vitro-generated BCR/ABL-expressing DCs induced lower frequencies of specific CTLs than immunization with control DCs. BCR/ABL-expressing DCs preferentially homed to the thymus, whereas only few BCR/ABL-expressing DCs reached the spleen. Our results indicate that BCR/ABL-expressing DCs do not efficiently induce CML-specific T-cell responses resulting from low DC maturation and impaired homing to secondary lymphoid organs. In addition, BCR/ABL-expressing DCs in the thymus may contribute to CML-specific tolerance induction of specific CTLs.

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.

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.