Nonrandomness, nonlinear dependence, and nonstationarity of electroencephalographic recordings from epilepsy patients

To derive tests for randomness, nonlinear-independence, and stationarity, we combine surrogates with a nonlinear prediction error, a nonlinear interdependence measure, and linear variability measures, respectively. We apply these tests to intracranial electroencephalographic recordings (EEG) from patients suffering from pharmacoresistant focal-onset epilepsy. These recordings had been performed prior to and independent from our study as part of the epilepsy diagnostics. The clinical purpose of these recordings was to delineate the brain areas to be surgically removed in each individual patient in order to achieve seizure control. This allowed us to define two distinct sets of signals: One set of signals recorded from brain areas where the first ictal EEG signal changes were detected as judged by expert visual inspection ("focal signals") and one set of signals recorded from brain areas that were not involved at seizure onset ("nonfocal signals"). We find more rejections for both the randomness and the nonlinear-independence test for focal versus nonfocal signals. In contrast more rejections of the stationarity test are found for nonfocal signals. Furthermore, while for nonfocal signals the rejection of the stationarity test increases the rejection probability of the randomness and nonlinear-independence test substantially, we find a much weaker influence for the focal signals. In consequence, the contrast between the focal and nonfocal signals obtained from the randomness and nonlinear-independence test is further enhanced when we exclude signals for which the stationarity test is rejected. To study the dependence between the randomness and nonlinear-independence test we include only focal signals for which the stationarity test is not rejected. We show that the rejection of these two tests correlates across signals. The rejection of either test is, however, neither necessary nor sufficient for the rejection of the other test. Thus, our results suggest that EEG signals from epileptogenic brain areas are less random, more nonlinear-dependent, and more stationary compared to signals recorded from nonepileptogenic brain areas. We provide the data, source code, and detailed results in the public domain.

Comparison of spatial and temporal pattern for fMRI obtained with BOLD and arterial spin labeling

Functional magnetic resonance imaging (fMRI) is presently either performed using blood oxygenation level-dependent (BOLD) contrast or using cerebral blood flow (CBF), measured with arterial spin labeling (ASL) technique. The present fMRI study aimed to provide practical hints to favour one method over the other. It involved three different acquisition methods during visual checkerboard stimulation on nine healthy subjects: 1) CBF contrast obtained from ASL, 2) BOLD contrast extracted from ASL and 3) BOLD contrast from Echo planar imaging. Previous findings were replicated; i) no differences between the three measurements were found in the location of the activated region; ii) differences were found in the temporal characteristics of the signals and iii) BOLD has significantly higher sensitivity than ASL perfusion. ASL fMRI was favoured when the investigation demands for perfusion and task related signal changes. BOLD fMRI is more suitable in conjunction with fast event related design.

Smooth Hazard Function Estimation for Interval Censored Data with Time Varying Covariates

In this paper we propose methods for smooth hazard estimation of a time variable where that variable is interval censored. These methods allow one to model the transformed hazard in terms of either smooth (smoothing splines) or linear functions of time and other relevant time varying predictor variables. We illustrate the use of this method on a dataset of hemophiliacs where the outcome, time to seroconversion for HIV, is interval censored and left-truncated.

Comparison of performance and patient satisfaction of two types of ERG electrodes

BACKGROUND: An age-controlled comparison concerning patient satisfaction and electrical performance of microfibres (DTL) and rigid contact lens (Henkes) corneal ERG electrodes was carried out. METHODS: 36 test persons underwent complete ophthalmological examination and were equally distributed into 3 age groups. Electroretinograms were recorded according to ISCEV standards. Randomly, in one eye a Henkes electrode was used and in the other eye a DTL electrode. Amplitudes of a- and b-waves and implicit times were measured and compared for the two electrode types. RESULTS: 34 of 36 test persons preferred DTL electrodes. Electrical performance concerning b-wave amplitudes was comparable. Statistically significant differences were detected only for scotopic combined cone-rod stimulation in the age groups 20 - 40 and 41 - 60 years between the different electrodes. Other recordings did not show differences. A statistically significant reduction of signal amplitudes with age was detected for scotopic isolated rod signals and combined cone-rod signals. Significance level was p < 0.05. No conjunctival or corneal erosions were found after ERG recordings for either electrode. CONCLUSIONS: Electrical performance is comparable between electrodes. For scotopic stimulations age was a significant influencing factor for signal amplitude and should be respected for normative values. DTL electrodes were preferred by the vast majority of patients. No adverse clinical effects were observed for either electrode. DTL electrodes should be preferred due to hygienic reasons (single use) and patient comfort.

Models with Plants, Microorganisms and Viruses for Basic Research in Homeopathy

Most criticism about homeopathy concerns the lack of a scientific basis and theoretical models. In order to be accepted as a valid part of medical practice, a wellstructured research strategy for homeopathy is needed. This is often hampered by methodological problems as well as by gross underinvestment in the required academic resources. Fundamental research could make important contributions to our understanding of the homeopathic and high dilutions mechanisms of action. Since the pioneering works of Kolisko on wheat germination (Kolisko, 1923) and Junker on growth of microorganisms (paramecium, yeast, fungi) (Junker, 1928), a number of experiments have been performed either with healthy organisms (various physiological aspects of growth) or with artificially diseased organisms, which may react more markedly to homeopathic treatments than healthy ones. In the latter case, the preliminary stress may be either abiotic, e.g. heavy metals, or biotic, e.g. fungal and viral pathogens or nematode infection. Research has also been carried out into the applicability of homeopathic principles to crop growth and disease control (agrohomeopathy): because of the extreme dilutions used, the environmental impact is low and such treatments are well suited to the holistic approach of sustainable agriculture (Betti et al., 2006). Unfortunately, as Scofield reported in an extensive critical review (Scofield, 1984), there is little firm evidence to support the reliability of the reported results, due to poor experimental methodology and inadequate statistical analysis. Moreover, since there is no agricultural homeopathic pharmacopoeia, much work is required to find suitable remedies, potencies and dose levels.

Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation

The signals and molecular mechanisms that regulate the replication of terminally differentiated beta cells are unknown. Here, we report the identification and characterization of transmembrane protein 27 (Tmem27, collectrin) in pancreatic beta cells. Expression of Tmem27 is reduced in Tcf1(-/-) mice and is increased in islets of mouse models with hypertrophy of the endocrine pancreas. Tmem27 forms dimers and its extracellular domain is glycosylated, cleaved and shed from the plasma membrane of beta cells. This cleavage process is beta cell specific and does not occur in other cell types. Overexpression of full-length Tmem27, but not the truncated or soluble protein, leads to increased thymidine incorporation, whereas silencing of Tmem27 using RNAi results in a reduction of cell replication. Furthermore, transgenic mice with increased expression of Tmem27 in pancreatic beta cells exhibit increased beta cell mass. Our results identify a pancreatic beta cell transmembrane protein that regulates cell growth of pancreatic islets.

Mechanical signals regulating extracellular matrix gene expression in fibroblasts

Mechanical forces are essential for connective tissue homeostasis. The extracellular matrix (ECM) plays a key role in the transmission of forces generated by the organism (e.g. muscle contraction) and externally applied (e.g. gravity). The expression of specific ECM proteins such as collagens and tenascin-C, as well as of matrix metalloproteinases, involved in their turnover, is influenced by mechanical stimuli. The precise mechanisms by which mechanical strains are translated into chemical signals and lead to differential gene expression are however not fully understood. Cell-matrix adhesion sites are good candidates for hosting a "mechanosensory switch", as they transmit forces from the ECM to the cytoskeleton and vice versa by physically linking the cytoskeleton to the ECM. Integrins, transmembrane proteins located to these adhesion sites, have been shown to trigger a set of internal signaling cascades after mechanical stimulation. We have shown that the expression level of tenascin-C directly correlates with externally applied mechanical stress, as well as with RhoA/RhoA-dependent kinase-mediated cytoskeletal tension. Presumably other genes are regulated in a similar manner. The changes in ECM composition and mechanical properties derived from mechanical stress are relevant in medical intervention after ligament and tendon injury.

Meta-Environment and Executable Meta-Language using Smalltalk: an Experience Report

Object-oriented modelling languages such as EMOF are often used to specify domain specific meta-models. However, these modelling languages lack the ability to describe behavior or operational semantics. Several approaches have used a subset of Java mixed with OCL as executable meta-languages. In this experience report we show how we use Smalltalk as an executable meta-language in the context of the Moose reengineering environment. We present how we implemented EMOF and its behavioral aspects. Over the last decade we validated this approach through incrementally building a meta-described reengineering environment. Such an approach bridges the gap between a code-oriented view and a meta-model driven one. It avoids the creation of yet another language and reuses the infrastructure and run-time of the underlying implementation language. It offers an uniform way of letting developers focus on their tasks while at the same time allowing them to meta-describe their domain model. The advantage of our approach is that developers use the same tools and environment they use for their regular tasks. Still the approach is not Smalltalk specific but can be applied to language offering an introspective API such as Ruby, Python, CLOS, Java and C#.

The German business and information technologies project

The Business and Information Technologies (BIT) project strives to reveal new insights into how modern IT impacts organizational structures and business practices using empirical methods. Due to its international scope, it allows for inter-country comparison of empirical results. Germany — represented by the European School of Management and Technologies (ESMT) and the Institute of Information Systems at Humboldt-Universität zu Berlin — joined the BIT project in 2006. This report presents the result of the first survey conducted in Germany during November–December 2006. The key results are as follows: • The most widely adopted technologies and systems in Germany are websites, wireless hardware and software, groupware/productivity tools, and enterprise resource planning (ERP) systems. The biggest potential for growth exists for collaboration and portal tools, content management systems, business process modelling, and business intelligence applications. A number of technological solutions have not yet been adopted by many organizations but also bear some potential, in particular identity management solutions, Radio Frequency Identification (RFID), biometrics, and third-party authentication and verification. • IT security remains on the top of the agenda for most enterprises: budget spending was increasing in the last 3 years. • The workplace and work requirements are changing. IT is used to monitor employees' performance in Germany, but less heavily compared to the United States (Karmarkar and Mangal, 2007).1 The demand for IT skills is increasing at all corporate levels. Executives are asking for more and better structured information and this, in turn, triggers the appearance of new decision-making tools and online technologies on the market. • The internal organization of companies in Germany is underway: organizations are becoming flatter, even though the trend is not as pronounced as in the United States (Karmarkar and Mangal, 2007), and the geographical scope of their operations is increasing. Modern IT plays an important role in enabling this development, e.g. telecommuting, teleconferencing, and other web-based collaboration formats are becoming increasingly popular in the corporate context. • The degree to which outsourcing is being pursued is quite limited with little change expected. IT services, payroll, and market research are the most widely outsourced business functions. This corresponds to the results from other countries. • Up to now, the adoption of e-business technologies has had a rather limited effect on marketing functions. Companies tend to extract synergies from traditional printed media and on-line advertising. • The adoption of e-business has not had a major impact on marketing capabilities and strategy yet. Traditional methods of customer segmentation are still dominating. The corporate identity of most organizations does not change significantly when going online. • Online sales channel are mainly viewed as a complement to the traditional distribution means. • Technology adoption has caused production and organizational costs to decrease. However, the costs of technology acquisition and maintenance as well as consultancy and internal communication costs have increased.

Optimal Workflow and Process-Based Performance Measures for Endovascular Therapy in Acute Ischemic Stroke: Analysis of the Solitaire FR Thrombectomy for Acute Revascularization Study.

BACKGROUND AND PURPOSE We report on workflow and process-based performance measures and their effect on clinical outcome in Solitaire FR Thrombectomy for Acute Revascularization (STAR), a multicenter, prospective, single-arm study of Solitaire FR thrombectomy in large vessel anterior circulation stroke patients. METHODS Two hundred two patients were enrolled across 14 centers in Europe, Canada, and Australia. The following time intervals were measured: stroke onset to hospital arrival, hospital arrival to baseline imaging, baseline imaging to groin puncture, groin puncture to first stent deployment, and first stent deployment to reperfusion. Effects of time of day, general anesthesia use, and multimodal imaging on workflow were evaluated. Patient characteristics and workflow processes associated with prolonged interval times and good clinical outcome (90-day modified Rankin score, 0-2) were analyzed. RESULTS Median times were onset of stroke to hospital arrival, 123 minutes (interquartile range, 163 minutes); hospital arrival to thrombolysis in cerebral infarction (TICI) 2b/3 or final digital subtraction angiography, 133 minutes (interquartile range, 99 minutes); and baseline imaging to groin puncture, 86 minutes (interquartile range, 24 minutes). Time from baseline imaging to puncture was prolonged in patients receiving intravenous tissue-type plasminogen activator (32-minute mean delay) and when magnetic resonance-based imaging at baseline was used (18-minute mean delay). Extracranial carotid disease delayed puncture to first stent deployment time on average by 25 minutes. For each 1-hour increase in stroke onset to final digital subtraction angiography (or TICI 2b/3) time, odds of good clinical outcome decreased by 38%. CONCLUSIONS Interval times in the STAR study reflect current intra-arterial therapy for patients with acute ischemic stroke. Improving workflow metrics can further improve clinical outcome. CLINICAL TRIAL REGISTRATION: URL http://www.clinicaltrials.gov. Unique identifier: NCT01327989.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Characterization and differentiation of body fluids, putrefaction fluid, and blood using Hounsfield unit in postmortem CT

The purpose of the present study was to evaluate the ranges of Hounsfield unit (HU) found in body fluids, putrefaction fluids, and blood on postmortem CT and how these ranges are affected by postmortem interval, temperatures, and CT beam energy. Body fluids, putrefaction fluids, and blood from a total of 53 corpses were analyzed to determine the ranges of HU values from postmortem CT images that were taken prior to autopsy. The fluids measured in CT images were obtained at autopsy and examined in terms of macroscopic and microscopic appearances. Body fluids and blood were also collected in plastic bottles, which were subjected to CT scans at different beam energies (80-130 kV) and at various fluid temperatures (4 to 40 °C). At a postmortem interval of 1 to 4 days, the ranges of HU values of the serous fluids (13-38 HU) and the nonsedimented blood (40-88 HU) did not overlap. In the sedimented blood, the upper serum layer exhibited HU value ranges that overlapped with those of the serous fluids. The putrefaction fluids exhibited a range of HU values between 80 and -130 HU. Elevated HU values were observed in fluids with accretive cell impurities. HU values decreased slightly with increasing temperature and CT beam energy. We concluded that serous fluids and blood in fresh corpses can be characterized and differentiated from each other based on HU value ranges. In contrast, body fluids in decomposed corpses cannot be differentiated by their HU value ranges. Different beam energies and corpse temperatures had only minor influences on HU value ranges and therefore should not be obstacles to the differentiation and characterization of body fluids and blood.